DIABETES.Pdf

The Diabetic Patient and Chronic Kidney Disease A Guide to Clinical Practice All rights are reserved by the author and publisher, including the rights of reprinting, reproduction in any form and translation. No part of this book may be reproduced, stored in a retrieval system or transmitted, in any form or by means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher.

First edition: September 2011

European Dialysis and Transplant Nurses Association/ European Renal Care Association (EDTNA/ERCA) Pilatusstrase 35, Postfach 3052, 6002 Luzern, Switzerland www.edtnaerca.org

ISBN: 978-84-615-0906-5

D.L.: M-20964-2011

Layout, Binding and Printing: Imprenta Tomás Hermanos Río Manzanares, 42-44 · E28970 Humanes de Madrid Madrid - Spain www.tomashermanos.com 5

Acknowledgements The Diabetic Patient and Chronic Kidney Disease

6 Acknowledgements

This book was an initiative of EDTNA/ERCA with the intention to follow the series of books: “Guide to Clinical Practice”. The idea is to cover all areas of renal care to offer guides for integrated care for all patients with renal disease. This book has been divided into two different parts. The ﬁ rst one focused on scientiﬁ c content with the collaboration of experts in Diabetes and Diabetic Nephropathy. The second section concentrates on clinical practice. It has not been easy to compile all the information/input received regarding the important and major disease of Diabetes and its interaction with Chronic Kidney Disease. For that reason, the EDTNA/ERCA would like to recognize all those who contributed to the consolidation of this publication. Thank you to the authors of the chapters of this book. Without your knowledge and effort it would not have been possible.

Editors María Cruz Casal, RN, Nephrology Department, University Hospital 12 de Octubre, Madrid, Spain

Jitka Pancirova, RN, EDTNA/ERCA Executive Director and Immediate Past President, Prague, Czech Republic Acknowledgements

7 Reviewers The EDTNA/ERCA would like to thank the following health care professionals for dedicating their time in reviewing the chapters of this book. They were a key element in ﬁ nalizing chapter content, layout and accuracy for this book.

María Cruz Casal, RN, University Hospital 12 de Octubre, Madrid, Spain

Enrique Morales, Nephrologist, University Hospital 12 de Octubre, Madrid, Spain

Eduardo Gutiérrez, Nephrologist, University Hospital 12 de Octubre, Madrid, Spain

Dirk Struijk, MD, PhD, Dianet, Academic Medical Centre, University of Amsterdam, the Netherlands

Aase Riemann, RN, Bc, Consultant Nephrology and Geriatrics, Amsterdam, the Netherlands

Angela Henson, RN, MN, Grad Dip Nephrology, Princess Alexandra Hospital, Brisbane, Australia

The EDTNA/ERCA and especially the editors of this book would like to thank Nichole LaPeer for her contribution in proof- reading and translations of these texts. Nichole is a native English speaker with a degree in Spanish and Linguistics from UCLA and a certiﬁ cate in General Translation from International House, Barcelona.

Table of Contents The Diabetic Patient and Chronic Kidney Disease

Preface ...... 15

Jitka Pancírová, RN, EDTNA/ERCA Immediate Past President and Executive Director

SECTION I - DIABETES AND THE KIDNEY

1. Epidemiology Of Diabetes ...... 19

Enrique Morales, Nephrologist, University Hospital 12 de Octubre, Madrid, Spain

2. Obesity, Diabetes and the Kidney ...... 33

Manuel Praga, Nephrologist, University Hospital 12 de Octubre, Madrid, Spain

3. Pathogenesis and Risk Factors of Diabetic Nephropathy ...... 49

Ioanna Makriniotou, Nephrologist, General Hospital of Nikea, Nikea, Greece

4. Treatment of Diabetic Nephropathy ...... 63

Enrique Morales, Nephrologist, University Hospital 12 de Octubre, Madrid, Spain Table of Contents

5. Oral Anti-Diabetics and Insulin in Patients with Diabetic Nephropathy ...... 79

María Ángeles Valero, MD, Endocronology and Nutrition, University Hospital 12 de Octubre, Madrid, Spain

6. Diabetes Mellitus and Renal Transplantation .... 107

Eduardo Gutiérrez, Nephrologist, University Hospital 12 de Octubre, Madrid, Spain

7. Diabetes Mellitus and Pancreas-Renal Transplantation ...... 123

Eduardo Gutiérrez, Nephrologist, University Hospital 12 de Octubre, Madrid, Spain

SECTION II - CARING FOR DIABETICS WITH CHRONIC KIDNEY DISEASE

1. Assessment of Glycaemic Control in the Dialysis Population ...... 139

Lina Schwarz, RN, BN, MHA, Nephrology Department, Soroka University Medical Center, Beer-Sheva, Israel

Nurit Cohen, RN, BN, Master of Public Health (MPH), Nephrology Department, Soroka University Medical Center, Beer-Sheva, Israel The Diabetic Patient and Chronic Kidney Disease

2. Chronic Complications in Diabetic Patients ...... 151

José Luis Cobo Sánchez, RN, University Hospital Marqués de Valdecilla, Santander, Spain

Raquel Menezo Viadero, RN, University Hospital Marqués de Valdecilla, Santander, Spain

3. Acute Complications in Diabetics Patients ...... 167

José Luis Cobo Sánchez, RN, University Hospital Marqués de Valdecilla, Santander, Spain

Raquel Menezo Viadero, RN, University Hospital Marqués de Valdecilla, Santander, Spain

4. Haemodialysis and the Diabetic Patient ...... 181

Lyn Allen, RN, Derby Hospitals NHS Foundations Trust, Derby, United Kingdom

Catherine Fielding,RN, Derby Hospitals NHS Foundations Trust, Derby, United Kingdom

5. Peritoneal Dialysis in Patients with Diabetic Nephropathy ...... 195

Lyn Allen, RN, Derby Hospitals NHS Foundations Trust, Derby, United Kingdom

Nicola Beech, RN, Derby Hospitals NHS Foundations Trust, Derby, United Kingdom Table of Contents

6. Diabetes Treatment and CKD ...... 209

José Luis Cobo Sánchez, RN, University Hospital Marqués de Valdecilla, Santander, Spain

Raquel Menezo Viadero, RN, University Hospital Marqués de Valdecilla, Santander, Spain

7. Diet for Patients with Diabetes and CKD ...... 233

Raquel Menezo Viadero, RN, University Hospital Marqués de Valdecilla, Santander, Spain

José Luis Cobo Sánchez, RN, University Hospital Marqués de Valdecilla, Santander, Spain

8. Health Education in Diabetic and CKD Patients ...... 245

Raquel Menezo Viadero, RN, University Hospital Marqués de Valdecilla, Santander, Spain

José Luis Cobo Sánchez, RN, University Hospital Marqués de Valdecilla, Santander, Spain

9. De Novo Diabetes Mellitus in Post-transplant ...... 257

Isabel Delgado, RN, University Hospital 12 de Octubre, Madrid, Spain

Eduardo Gutiérrez, Nephrologist, University Hospital 12 de Octubre, Madrid, Spain

Preface The Diabetic Patient and Chronic Kidney Disease

16 The EDTNA/ERCA promotes quality in renal care through professional education, implementation of clinical standards and research in renal care throughout Europe. The Association has published various renal speciﬁ c handbooks (Peritoneal Dialysis, Kidney Transplantation), however there is a need to implement a broader focus, because Chronic Kidney Disease (CKD) can have a number of causes and appears as a wide range of symptoms requiring medical interventions. Diabetes is an increasingly important cause of renal failure and has now become the most common cause of end stage renal disease which requires renal replacement therapy. The number of people with diabetes is increasing due to population growth, aging, urbanization, and increasing prevalence of obesity and physical inactivity.1 Diabetes is challenging to manage in patients who have end-stage renal disease, as both uraemia and dialysis can complicate glycaemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin.2 All the facts mentioned above demonstrate that multidisci- plinary management is the cornerstone in the successful treatment of CKD patients with diabetes. We do hope this handbook will guide you in your daily clinical practice as the EDTNA/ERCA has the responsibility to continually strive to improve the quality of nephrology practice and to ensure the highest level of professional competence among its international members.

References

1. Wild S, Roglic G,Green A, Global Prevalence of Diabetes –Estimates for the year 2000 and projections for 2030. Diabetes Care, volume 27, number 5, May 2004. 2. Shrishrimal K,Hart P,Michota F, Cleveland Clinic Journal of Medi- cine, volume 76 number11, November 2009. SECTION I - DIABETES AND THE KIDNEY

Epidemiology of Diabetes The Diabetic Patient and Chronic Kidney Disease 20

Learning outcomes • Knowledge of the current world situation of diabetic nephropathy • Knowledge of the predictors and progression of diabetic nephropathy

INTRODUCTION Today, DM is one of the greatest social and health problems in the world. It is prevalent in 2-6% of the general population and increases with age, reaching double in those over 65. Recently, there has been a signiﬁ cant increase in the number of patients with DM, especially type 2 DM. The global projections

Figure 1. Prevalence (%) estimates of diabetes (20-79 years), 2030 Epidemiology of Diabetes 21 indicate that the number of diabetics worldwide will double in just 30 years (2000-2030) (Fig 1). These estimates place the prevalence of DM at 170 to 300 million in 2030, with a large proportion of this increase in developing countries (Fig 2). However, it is possible that these projections have been underestimated.

AT A GLANCE 2010 2030

Total world population (billions) 7.0 8.4

Adult population (20-79 years billions) 4.3 5.6

DIABETES AND IGT (20-79 years) Diabetes Global prevalence (%) 6.6 7.8 Comparative prevalence (%) 6.4 7.7 Number of people with diabetes (millions) 285 438

IGT Global prevalence (%) 7.9 8.4 Comparative prevalence (%) 7.8 8.4 Number of people with IGT (millions) 344 472

Figure 2. Current understanding of diabetes in the world

When the oral glucose tolerance test was used as a diagnostic test, in half of the patients DM did not appear. Moreover, the observed increase in obesity will lead to a higher number of diabetic patients.1 DM is included among the major cardiovascular risk factors (along with hypertension, dyslipidaemia, and tobacco use) it is associated with an increased cardiovascular risk.2 Chronic complications of diabetes mellitus, among which vascular complications are frequent and severe, and have important consequences, including functional limitations, increased The Diabetic Patient and Chronic Kidney Disease 22 morbidity and mortality, personal and social suffering, and very high economic costs.3 Diabetic nephropathy (DN) is deﬁ ned as the presence of persistent proteinuria (urinary protein >500mg/24h or albumin >300mg/24 hours or albumin/creatinine ratio >300) in the urine of diabetics.4 DN is one of the most serious microangiopathic complications of the disease. In the course of evolution it is usually accompanied by high blood pressure (hypertension) and a decline in renal function. Cardiovascular disease is the leading cause of death in diabetic patients due to the increased prevalence of the disease in patients with renal impairment related to diabetes.5

DIABETIC NEPHROPATHY Today, DN is the leading cause of end stage renal disease (ESRD) requiring renal replacement therapy. One third of patients with DM have DN, this data combined with micro and macrovascular complications result in very high annual health expenditures.6

TYPE I OR JUVENILE DIABETES Studies from the 80s and 90s revealed that only a small proportion of patients (<5%) developed renal disease in the ﬁ rst 10 years of evolution.7 The epidemiology of DN is better studied in type 1 diabetes because the onset of renal impairment is detected early. Studies show that 25-45% of patients with type 1 diabetes mellitus developed DN at some point in their lives. However, the percentage of patients who developed DN after 40 years of the development of diabetes was very low, which means that there is individual susceptibility to develop this condition regardless of time of evolution.8 Epidemiology of Diabetes 23 Regarding sex, there is a male predominance in the development of proteinuria, which has also been found in the development of proliferative retinopathy. This ﬁ nding may be related to sex hormones which was found in experimental animals (castrated rats had fewer complications than non- diabetic castrated). Over the decades there has been a decline in the proportion of patients with DN; this reduction may be explained by the changes in management and care of diabetes, better and earlier treatment of hypertension and, mainly, dietary changes.9

TYPE II OR ADULT DIABETES Currently considered the great epidemic of 21st century. In these patients the duration of DM is essential for the development of DN. In the United States and Europe the number of patients requiring renal replacement as a result of the development of DN has grown. The incidence of type 2 diabetes mellitus in the general population is increasing, partly because society is aging.10 The prevalence of type 2 diabetes mellitus increases with age, partly due to a change in lifestyle parallel to economic development, reduced physical activity and more fat in the diet; all factors that favor insulin resistance. Binomial insulin resistance and insufﬁ cient insulin secretion are key to their appearance.11, 12

NEPHROPATHY AND PREDICTIVE FACTORS OF THE PROGRESSION OF DIABETIC NEPHROPATHY An interesting aspect is the fact that the DN was observed in one third of patients with DM, contrary to what happens experimentally. This is due to the numerous factors affecting the injury-repair mechanisms of the kidney and eventually causing the development of DN (see Table 1): The Diabetic Patient and Chronic Kidney Disease 24 Table 1: Factors and predictors of progression of diabetic nephropathy

Genetic predisposition

Racial and socioeconomic aspects

Factors of progression of diabetic nephropathy - Hyperglycaemia - Plasma renin activity - Hypertension - Proteinuria - Glomerular hyperﬁ ltration - Obesity - Dyslipidaemia - Smoking

1. Genetic susceptibility This appears to be important in determining the incidence and severity of diabetic nephropathy. The risk of DN has been linked to speciﬁ c chromosomal locations. They have recently been identiﬁ ed through techniques called “genome-wide linkage scan” in regions of the chromosomes which contain susceptibility genes for DN. In this respect, we can comment that it is more likely the twin brother of a patient with diabetic nephropathy will develop nephropathy than a diabetic without nephropathy. The DD polymorphism (insertion/deletion) of the gene converting enzyme angiotensin, which produces a higher concentration of the enzyme in blood and tissues, and consequently increases angiotensin II synthesis, has been associated with an increased risk and severity of nephropathy.13

R ace2. Race2. This factor is more severe in certain populations (Blacks, Pima Indians, Mexican-Americans, and Canary Islanders). In addition to the genetic factors of these Epidemiology of Diabetes 25 populations, there is talk of socioeconomic factors, poor metabolic control or obesity. Very interesting pathogenic factors were found in these populations that inﬂ uence the development of nephropathy. However, the genetic aspect explains the high incidence found which was not justiﬁ ed by environmental factors, compared with white diabetics.14

3. Glomerular hyperfi ltration Another risk factor that is associated with the presence of poorly controlled diabetes mellitus, from the metabolic viewpoint. Up to 50% of patients with type 1 have a GFR between 25-50% above normal. This hyperfi ltration is a risk factor for development of DN. Although less apparent in type 2 DM, there are studies in which a diabetic population was followed from the onset of the illness and hyperfi ltration was observed in a similar proportion. In the pathogenesis, in addition to hyperglycaemia by itself, or by hormones, peptides and cytokines, there are numerous factors that may be involved. But whatever the pathogenic mechanism, the conclusion is the close relationship between hyperglycaemia and hyperfi ltration and therefore continuous strict metabolic control is essential. Therapeutic measures aimed at reducing hyperfi ltration also decrease proteinuria and therefore improve renal outcome.15

4. Plasma prorenin activity It is relatively common the alteration in the conversion of prorrenin to active renin in diabetic patients. This defect can lead to hypoaldosteronism and hyperkalaemia, and an increased possibility of the development of nephropathy or retinopathy. On the other hand, there is hyperactivation of the renin-angiotensin system. This local hyperactivation increases the concentration of angiotensin II, which increases cytokines, growth factors and oxidative stress. The Diabetic Patient and Chronic Kidney Disease 26 The hyperactivity of angiotensin II ampliﬁ es the effects of hyperglycaemia and hypertension.16

5. Duration of diabetes. Glycemic control Patients with poor metabolic control of diabetes have a much higher prevalence of DN, up to 50% have this condition after 20 years of the onset of diabetes. Hyperglycaemia is responsible for the nonenzymatic glycosylation of circulating and structural proteins. This process may play a role in glomerular hemodynamic changes (glomerular hyperﬁ ltration) and the production of cytokines and growth factors that cause tissue damage. Several clinical studies, including the Diabetes Control and Complications Trial (DCCT) in type 1 diabetics and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetes have shown that levels of HbA1c<7% are associated with a lower risk of appearance of clinical and structural diabetic nephropathy.17,18

6. Hypertension Elevated blood pressure causes vascular damage and increased intraglomerular pressure. Hypertension results in mesangial proliferation and glomerular damage. In various prospective studies patients with poorer control of blood pressure more frequently developed nephropathy. For years major studies have shown that drugs that block the renin-angiotensin-aldosterone system (RAAS) have additional renoprotective effects in patients with DN.19

7. Proteinuria Numerous clinical studies have shown that the amount of proteinuria is a very important prognostic marker for nephropathy. However, recent studies point to the role of proteinuria as an actively contributing factor in the progression of renal damage, showing that the Epidemiology of Diabetes 27 abnormal passage of these proteins by the tubules and glomerular structures induce speciﬁ c lesions. It is possible that DN leads to microalbuminuria from its beginnings to the renal injury through cellular activation tubular interstitial injury. This causes the evolution of nephropathy to renal failure. Diabetic patients with proteinuria have a much higher mortality than diabetic patients without proteinuria. From the onset of persistent proteinuria, 25% of patients develop ESRD within 10 years. It is important to remember that drugs that block the RAAS and reduce proteinuria independent of blood pressure reduction are key in the management of these patients.20

8. Smoking This is an important cardiovascular risk factor and recent studies show that it causes major kidney impairment. It has been associated with an increased risk of albuminuria in both types of diabetes with a higher rate of progression of DN. Snuff or chewing tobacco can play a role in the pathogenesis of renal injury through the activation of the sympathetic system, increased endothelin production and impaired vasodilatation mechanisms related to endothelial cells.21

9. Lipid abnormalities Hyperlipidaemia is a common fi nding in diabetic patients, increasing their likelihood of developing renal failure and the appearance of the proteinuria. Lipid alterations may play a role in the mechanism of renal disease progression. Hyperlipidaemia is clearly related to the development of atherosclerosis, a factor complicating diabetic nephropathy in the atherosclerotic lesions of the aorta and main renal arteries and secondary problems. However, there are no studies examining whether the treatment of dyslipidaemia can prevent the development of DN or delay the onset of renal injury.22 The Diabetic Patient and Chronic Kidney Disease 28 10. Obesity The presence of obesity is a factor in the incidence of type 2 diabetes; obesity also causes kidney damage itself, particularly glomerulosclerosis and promotes the progression of renal failure and glomerular hyperfi ltration. Weight reduction improves the control of the DM, BP, the glomerular hyperfi ltration, proteinuria and metabolic syndrome. Some adipocytokines such as leptin can lead to the development of nephropathy.23

Conclusion The natural history of DN is deﬁ ned as a progression from the renal functional impairment to ESRD through intermediate stages marked by the appearance of albuminuria and proteinuria.

In recent years there have been important advances in the pathogenesis of this disease, describing new mechanisms determining the onset and progression of DN. Also, there is more advanced knowledge of new therapeutic aspects that can change the course of DM. Epidemiology of Diabetes 29

Key Points • Diabetes Mellitus (DM) is one of the greatest social and health problems in the world. The global projections indicate that the number of diabetics worldwide will double in 30 years.

• There is an increased prevalence of type 2 DM with age, partly due to a change in lifestyle parallel to economic development, reduced physical activity and increased fat in the diet, factors that favor the appearance of insulin resistance.

• Currently, DN is the ﬁ rst global cause of chronic renal failure requiring replacement therapy.

• Heredity and race, duration of diabetes, hypertension, proteinuria, smoking, dyslipidaemia and obesity are considered key factors in the development of diabetic nephropathy.

• Hyperglycaemia is a key factor in the development of complications associated with diabetes and its control is essential.

• The natural history of DN is deﬁ ned as a progressive way from the renal functional impairment to ESRD through intermediate stages marked by the appearance of albuminuria and proteinuria. The Diabetic Patient and Chronic Kidney Disease 30 References

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047-1053. 2. Asociación Española de Nefrología Pediatrica, Sociedades Españolas de Diabetes, Endocrinología y Nutrición, Medicina Familiar y Comunitaria, Medicina Rural y Generalista y Nefrología. Documento Consenso sobre la detección y tratamiento de la nefropatía diabética en España. Nefrología 2002; 22:521-530. 3. Martinez-Castelao A, Gorriz JL, De ALvaro F, Navarro JF. Epidemiologia de la diabetes mellitus y la nefropatía diabética. Repercusiones sociales de la pandemia. Nefro Plus 2008; 1:8-15. 4. Gross JL, De Azevedo MJ, Silverio SP, Canana LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention and treatment. Diabetes Care 2005; 28:176-188. 5. American Diabetes Association. Nephropaty in diabetes (position Statement). Diabetes Care 2004; 27:S79-83. 6. Mata M, Antoñanzas F, Tafalla M, Sanz P. The cost of type 2 diabetes in Spain: the CODE-2 study. Gac Sanit 2002; 16:511-520. 7. Andersen AR, Christiansen JS, Andersen JT, Kreiner S, Deckert Y. Diabetic nephropathy in type I (insulin dependent) diabetes: and epidemiological study. Diabetologia 1983; 25:496-501. 8. Hovind P, Tarnow L, Rossing P, Jensen BR, Graae M, Torp I, Binder C, Parving HH. Predictors of the development of microalbuminuria and microalbuminuria in patients with type 1 diabetes: inception cohort study. BMJ 2004; 328:1105-1108. 9. Wong TY, Shankar A, Klein R, Klein BE. Retinal vessel diameters and the incidence of gross proteinuria and renal insufﬁ ciency in people with type I diabetes. Diabetes 2004; 53:179-184. 10. Ortuño J. Diabetes mellitus y nefropatía diabética. ¿Cuál es la magnitud del problema?. Nefrologia 2001; 21:S4-11. 11. Lipscombe L, Hux JE. Trends in diabetes, prevalence, incidente and mortality in Notario, Canada 1995-2005: a population-based study. Lancet 2007; 369:750-756. 12. Friedman EA, Friedman AL, Eggers P. End-stage renal disease in diabetic persons: is the pandemic subsiding?. Kidney Int 2006; 70:S51-54. 13. The Family Investigation of Nephropathy and Diabetes Research Group. Genetic determinants of diabetic nephropathy: the family Epidemiology of Diabetes 31 investigation of nephropathy and diabetes (FIND). J Am Soc Nephrol 2003; 14:S202-204. 14. Brancati FL, Whitttle JC, Whelton PK et al. The excess incidence of diabetic end-stage renal disease among blacks. A population-based study of potential explanatory factors. JAMA 1993; 268:3079-3084. 15. Rudberg S, Persson B, Dahlquist G. Increased glomerular ﬁ ltration rate as predictor of diabetic nephropathy: an 8-year prospective study. Kidney Int 1992; 41:822-828. 16. Troya M, Cañas L, Salinas I, Romero R. Una aproximación terapéutica al enfermo con nefropatía diabética. Nefro Plus 2008; 1:7-15. 17. The Diabetes Control and Complications Trial Research Group: the effect of intensive treatment of diabetes on the development and progresión of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-986. 18. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood- glucose control with sulphonilureas of insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-852. 19. Bakris GL. A practical approach to achieving recommended blood pressure goals in diabetic patients. Arch Intern Med 2001; 161:2661-2667. 20. González E, Ortiz M, Praga M. Diabetes y riñón: predictores de nefropatía y factores de progresión. Nefrologia 2001; 23 (S3):S46-51. 21. Ritz E, Ogata H, Orth SR. Smoking: a factor promoting onset and progression of diabetic nephroapthy. Diabetes Metab 2000; 26 (S4):S54-63. 22. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001; 59:260-269. 23. Praga M, Morales E. Obesity-related renal damage: changing diet to avoid progression. Kidney Int. 2010 Oct;78(7):633-5.

Obesity, Diabetes and the Kidney The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To review the epidemiology of obesity-related renal disease and diabetic nephropathy • To understand the pathophysiology of renal involvement in obesity and diabetes • To know the main clinical manifestations, prognosis and cardiovascular complications of renal disease induced by obesity and diabetes • To review therapeutic measures that should be implemented in these patients

OBESITY AND THE KIDNEY Recent epidemiological studies have demonstrated that obesity is an independent risk factor for the appearance of end-stage renal disease (ESRD).1 The majority of these studies have been performed on subjects without any known renal disease in whom several demographic, clinical and laboratory parameters were registered in a fi rst evaluation. A second evaluation (performed more than a decade after the fi rst one) allowed the identifi cation of those factors associated with the occurrence of renal failure. In addition to several well known risk factors such as hypertension, smoking and hyperlipidaemia, obesity and overweight consistently emerged as new factors associated with ESRD. As shown in Figure 1, the greater the baseline Body Mass Index (BMI) the greater the risk for developing ESRD. BMI (weight in kilograms divided by the square of the height in meters) is the commonest used parameter to defi ne overweight (BMI 25-29.9 Kg/m2) and obesity (BMI higher than 30 Kg/ m2). Obesity, Diabetes and the Kidney

Figure 1. Relative risk of End-stage renal disease, according to baseline Body Mass Index (Adapted from reference 1 with permission)

Obesity, Proteinuria and Glomerulosclerosis The aforementioned epidemiological studies do not allow the identiﬁ cation of those mechanisms through which obesity induces renal damage. Hypertension and hyperlipidaemia, common complications of obesity, very likely play a role in the development of obesity-associated renal disease. In addition, several studies have shown that albuminuria and proteinuria are found more frequently in obese people than in lean subjects.2 Obesity-related proteinuria can reach nephrotic-range levels (higher than 3.5 grams/day) and, as in any renal disease, the greater the proteinuria the faster the renal function loss. The most frequently found lesion in obese patients with severe proteinuria who undergo a renal biopsy is focal glomerulosclerosis.3,4 The reported worldwide increase in the incidence of focal glomerulosclerosis in the last years is likely related, among other factors, to the current global epidemy of obesity. The Diabetic Patient and Chronic Kidney Disease

The prognosis of focal glomerulosclerosis induced by obesity 36 is serious. When proteinuria higher than 0.5-1 g/d persists for a long time, the risk of progressive renal function loss and ESRD is high.

Pathophysiology of obesity-related renal disease In addition to hypertension and hyperlipidaemia, a great majority of obese subjects (even those without albuminuria or proteinuria) typically show renal haemodynamic changes consisting of: • Renal vasodilatation, mainly affecting preglomerular vessels • Increased glomerular ﬁ ltration rate • Hypertension within glomerular capillaries

This characteristic “hyperfi ltration” haemodynamic profi le is thought to be the main initial pathogenic mechanism causing glomerular damage.2 Hyperfi ltration shows a clear correlation with BMI and weight loss is rapidly accompanied by a reversal to normal renal haemodynamic. Another pathogenic way of great interest is the activation of the renin-angiotensin-aldosterone system (RAAS) that is consistently found in the obese. Adipose tissue produces all the components of RAAS in addition to many cytokines and growth factors that induce oxidative damage and infl ammation affecting renal parenchyma and other organs.

Obesity as a detrimental factor in the outcome of renal diseases In spite of the almost constant association between obesity and glomerular hyperfi ltration, only a minority of the obese develops renal abnormalities. On the other hand, a number of studies strongly suggest that the presence of obesity or being Obesity, Diabetes and the Kidney overweight accelerates the progression of renal damage in many renal diseases of different causes. This statement 37 is more evident in those clinical conditions characterized by a reduced number of nephrons, such as unilateral renal agenesis, unilateral nephrectomy, extensive surgical removal of renal parenchyma or any renal disease that severely diminishes functioning renal mass. When the number of functioning nephrons decreases below a critical level, surviving nephrons adopt haemodynamic compensations that reproduce the haemodynamic profi le of hyperfi ltration, typical of obesity. Therefore, obesity-induced hyperfi ltration aggravates the hyperfi ltration caused by the specifi c renal disease, thus worsening the prognosis of renal diseases in obese subjects.5 This detrimental infl uence of obesity is limited not only to acquired renal mass reduction. Renal transplant patients (in whom only one kidney is transplanted) or people with a reduced nephron endowment at birth (like children with very low weight at birth) are prone to the occurrence of hypertension, proteinuria and renal failure when they develop obesity, whereas people with a higher nephron number are more resistant to these complications.6

Treatment Obviously, the best therapeutic option in patients with obesity- related renal disease is weight loss.7 Some preliminary studies have demonstrated that weight loss induced by low calorie diets decreases proteinuria, and that the degree of proteinuria reduction parallels the degree of weight loss (Figure 2). This benefi cial effect is observed not only in renal diseases directly caused by obesity; indeed, weight loss is followed by signifi cant reductions in proteinuria in most chronic renal diseases. Some recent reports analyzing the effects of bariatric surgery on patients with morbid obesity illustrate how dramatic the infl uence of weight loss on proteinuria can be.8 The Diabetic Patient and Chronic Kidney Disease

Figure 2. Correlation between weight loss induced by low calorie diet and proteinuria decrease (adapted from reference 7 with permission)

However, sustained weight loss is difﬁ cult to obtain in many obese patients. RAAS blockade, either by ACE inhibitors (ACEI) or angiotensin receptor antagonists (ARB), represents an important therapeutic option, through their antiproteinuric and antihypertensive properties. In addition, RAAS blockade counteracts haemodynamic changes of hyperﬁ ltration, decreasing intraglomerular hypertension.9 Preliminary studies suggest that aldosterone antagonists (ARA) might be particularly effective agents in obese patients with obesity-related renal abnormalities. It is important to emphasize that obesity and proteinuria/ albuminuria are independent risk factors for cardiovascular complications, and that all the above referred therapeutic options (weight loss, RAAS blockers) are renoprotective and also cardioprotective therapies that should be implemented in conjunction with the measures summarized in Table 1. Obesity, Diabetes and the Kidney

Table 1.

Therapeutic measures in patients with obesity-associated renal disease 39

Prevention and treatment of obesity (Low calorie diet)

Low salt diet

Strict control of Blood Pressure

ACE inhibitors (ACEI), Angiotensin Receptor Blockers (ARB), or Antialdosteronic agents (ARA), adjusting doses to obtain targets of blood pressure (<125-130/75-80 mmHg) and proteinuria (<0.5-1 g/day)

Combination of ACEI, ARB and ARA if proteinuria targets are not obtained

No smoking

Regular physical exercise

Treatment of Hyperlipidaemia

Low Protein diet (if chronic renal insufﬁ ciency)

DIABETIC NEPHROPATHY Epidemiology Diabetic nephropathy is the leading cause of end-stage renal disease in Western societies and its incidence among developing countries is increasing alarmingly.10 There are two main types of diabetes mellitus, type 1, caused by autoimmune mechanisms that destroy pancreatic cells, and type 2, that is mediated by insulin resistance and has a close relationship with metabolic syndrome and obesity. Whereas type 1 diabetes is common in childhood, manifesting prior to the age of 30 years, type 2 is typically a disease of older adults. Importantly, not all diabetic patients will develop renal involvement. Diabetic nephropathy appears in 30-40% of both type 1 and type 2 diabetics. The reasons why a majority of diabetics does not develop renal disease in spite of long lasting diabetes are not well understood, although most studies point to a genetically determined predisposition. The Diabetic Patient and Chronic Kidney Disease

Although the prevalence of renal involvement is roughly the 40 same in type 1 and 2 diabetes, the current worldwide epidemic of diabetic nephropathy is caused by type 2 diabetes, since it is 10 to 15 times more common than type 1. Some susceptibility factors that determine the development of diabetic nephropathy have been identifi ed. • Ethnicity. Ethnic origin plays a very important role, as demonstrated by the higher rates of ESRD among diabetic patients of Native American populations, African Americans, Mexican Americans and South Asians in comparison with Caucasians. The causes for these ethnic differences are multifactorial. In addition to a genetically determined predisposition, there are different rates of hypertension and obesity, and socioeconomic problems hampering an adequate metabolic control and early diagnosis of renal involvement. • Gender. Diabetic males have a higher risk of developing diabetic nephropathy than diabetic females, with a male:female ratio of 1.7:1. • Obesity. A large proportion of type 2 diabetic patients are obese, and obesity plays a determinant role in the pathogenesis of diabetes by inducing insulin resistance. In addition, obesity has a synergic effect with diabetes to induce albuminuria/proteinuria. In the typical type 2 diabetic patient with obesity and proteinuria it is diffi cult to separate the pathogenic role of obesity from true diabetic nephropathy. The infl uence of congenital (reduced nephron and pancreatic endowment) and socioeconomic factors in the appearance of type 2 diabetic nephropathy are summarized in Figure 3. • Smoking. Retrospective studies clearly demonstrate that, in addition to a higher risk of cardiovascular events, smoking is associated with a very high rate of diabetic nephropathy and ESRD. Obesity, Diabetes and the Kidney

Figure 3. Factors implicated in the current worldwide epidemic of type 2 diabetic, hypertension and renal failure.

How diabetes mellitus affects the kidney? The following factors play an important role in the appearance and progression of diabetic nephropathy: • Hyperfi ltration. Diabetic patients show the same haemodynamic changes than obese subjects and patients with a reduced number of functioning nephrons, as commented above. Causes of this hyperfi ltration are not entirely clear, but it induces glomerular hypertension and is an almost universal fi nding in earlier stages of diabetic nephropathy. • Hypertension. • Hyperlipidaemia. • Hyperglycaemia and poor metabolic control. Persistent hyperglycaemia causes abnormal glycosylation of proteins (such as glycated haemoglobin) and induces the appearance of so-called advanced glycation The Diabetic Patient and Chronic Kidney Disease

end-products (AGE), whose involvement in the 42 pathogenesis of structural abnormalities in the diabetic kidney has been demonstrated. • Inﬂ ammation and Oxidative damage.

Clinical and Histological manifestations of diabetic nephropathy In the majority of patients, diabetic nephropathy is a slowly progressive disease that can be divided in several stages: • Stage1. It is characterized by hyperfi ltration (increased glomerular fi ltration rate and renal plasma fl ow) usually accompanied by renal hypertrophy. • Stage 2. In addition to persistent hyperfi ltration, structural changes (thickness of glomerular basal membrane, mesangial expansion) in the kidney start to develop, usually accompanied by low levels of albuminuria (less than 30mg/day). • Stage 3. It is defi ned by the presence of persistent microalbuminuria (30-300mg/day or 20-200μg/min), together with incipient increase of blood pressure and return of renal function to normal values. • Stage 4. Overt nephropathy, defi ned by the presence of albuminuria > 300mg/day, proteinuria, hypertension and progressive renal function decline. Diffuse or nodular glomerulosclerosis is found in renal biopsies (renal biopsy is usually not performed in diabetic patients unless the clinical course suggests the presence of a different type of renal disease). Proteinuria can reach nephrotic range. • Stage 5. Renal function continues to decline towards ESRD.

Important key points to be considered is that these 5 Stages are usually separated by 5-10 years (although the variability Obesity, Diabetes and the Kidney can be striking in type 2 diabetes) and that the advance of diabetic nephropathy is paralleled by the progression of 43 extra-renal complications (retinopathy, peripheral vascular disease, polyneuropathy, atherosclerosis).10 Cardiovascular mortality and morbidity are dramatically increased in diabetic patients with renal involvement, and they further increase as renal function declines and albuminuria raises.11 On the other hand, lesions of diabetic nephropathy can regress when appropriate treatment is prescribed in non-advanced stages of the disease.

Treatment Treatment of diabetic nephropathy should be based on the following points, most of them summarized in Table 1. • Strict metabolic control, including diet, oral antidiabetic agents and insulin, when required. The type of antidiabetic agents should be carefully chosen according to the level of renal function. • RAAS blockade. As commented above, ACEI, ARB and ARA are powerful antiproteinuric agents, in addition to their antihypertensive effect. Their doses and combination should be adjusted to avoid an increase in albuminuria or to reduce proteinuria in those patients presenting with overt nephropathy. • Strict Blood Pressure Control. As in any other proteinuric diseases, blood pressure should be targeted to <125-130/75-80mmHg. RAAS blockade is the basis of antihypertensive treatment, but the addition of other agents may be necessary to obtain BP targets. • Other antiproteinuric measures. In patients with increasing or excessive albuminuria in spite of optimized RAAS blockade, other antiproteinuric measures (weight loss, low salt diets) should be emphasized. New agents with antiproteinuric effect, The Diabetic Patient and Chronic Kidney Disease

such as vitamin D receptor agonists, are being actively 44 investigated. • Prevention and treatment of obesity. • Health life style, treatment of hyperlipidaemia and cardiovascular watchfulness. Due to the huge cardiovascular morbidity and mortality of patients with diabetic nephropathy, continuous monitoring, advising and treatment of risk factors (smoking, sedentarism, diet) for cardiovascular complications are mandatory.

Fortunately, the aforementioned therapeutic points have demonstrated their effi cacy in order to decrease the epidemic of ESRD due to diabetic nephropathy. As shown in Figure 4, in spite of the continuous increase in the number of diabetic patients, the incidence of diabetic ESRD is fl attening in the last years.12 This encouraging data represents a major advance in the fi ght against renal complications of diabetes.

Figure 4. Adjusted rates of incident ESRD in United States (Adapted with permission from reference 12). Obesity, Diabetes and the Kidney

Key Points 45 • The current worldwide epidemic of obesity and type 2 diabetes has a large impact on renal diseases. Type 2 diabetic nephropathy is currently the leading cause of ESRD.

• Both diabetes and obesity share pathophysiologic mechanisms (glomerular hyperﬁ ltration) that explain their harmful synergic effects on kidneys.

• Albuminuria and proteinuria are the main clinical expression of obesity-related nephropathy and diabetic nephropathy. Their level is the best method to evaluate the progression of the disease and the efﬁ cacy of therapeutic measures.

• Hypertension commonly accompanies proteinuria and contributes to the decline in renal function.

• Cardiovascular morbidity and mortality are dramatically increased in obese and diabetic patients with renal involvement. All cardiovascular risk factors should be monitored and treated.

• Metabolic control, weight loss, antihypertensive treatment, RAAS blockade and a healthy life style are the basis of the treatment. The Diabetic Patient and Chronic Kidney Disease

References

46 1. Hsu CY, McCulloch CE, Iribarren C, Darbinian J, Go AS. Body-mass index and risk for end-stage renal disease. Ann Intern Med 144: 21-28, 2006. 2. Praga M, Morales E. Obesity, proteinuria and progression of renal failure. Curr Op Nephrol Hypertens. 15: 481-486, 2006. 3. Praga M, Hernández E, Morales E, et al: Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis. Nephrol Dial Transplant 16: 1790-1798, 2001. 4. Kambham N, Markowitz G, Valeri AM, et al: Obesity-related glomerulopathy: An emerging epidemic: Kidney Int 59: 1498-1509, 2001. 5. Praga M: Synergy of low nephron number and obesity: a new focus on hyperfi ltration nephropathy. Nephrol Dial Transplant 20: 2594-2597, 2005. 6. Barker DJP, Bagby SP, Hanson MA. Mechanisms of Disease: in utero programming in the pathogenesis of hypertension. Nat Rev Nephrol 2006; 2: 700-707. 7. Morales E, Valero MA, León M et al. Benefi cial effects of weight loss in overweight patients with chronic proteinuric nephropathies. Am J Kidney Dis 2003; 41: 319-327. 8. Praga M, Morales E. : Weight loss and proteinuria. In “Obesity and the kidney”. Contributions to Nephrology, Ed: Gunter Wolf. Karger Publishers. Vol 151, pgs 221-229, 2006. 9. Taal MW, Brenner BM. Renoprotective benefi ts of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int 57: 1803-1817, 2000. 10. Ritz E, Orth SR: Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 341: 1127-1133, 1999. 11. Hostetter TH: Prevention of end-stage renal disease due to type 2 diabetes. N Engl J Med 345:910-912, 2001. 12. Hsu CY. Where Is the Epidemic in Kidney Disease?. J Am Soc Nephrol 21: 1607-1611, 2010. Obesity, Diabetes and the Kidney

Pathogenesis and Risk Factors of Diabetic Nephropathy The Diabetic Patient and Chronic Kidney Disease

50 Learning outcomes • To known the natural history of diabetic nephropathy • To understand the pathogenesis of diabetic nephropathy • To review the renal pathology • To known the main cardiovascular risk factors in patients with diabetic nephropathy

THE PROGRESSION OF DIABETIC NEPHROPATHY Diabetic Nephropathy (DN) is a microvascular complication of Diabetes Mellitus (DM) characterized by progressive decrease of Glomerular Filtration Rate (GFR) and gradual increase of Urine Albumin Excretion (UAE) rate in the absence of any other renal disease. A major clinical problem is the association of DN with other microvascular (e.g., retinopathy, neuropathy) and macrovascular complications (mainly coronary heart disease and peripheral artery disease). The natural history of DN is an insidious process that progresses over years. 5 stages have been deﬁ ned for clinical evolution of DN, each characterized by functional and structural manifestations1:

• Stage 1 (years 1-3): Hyperﬁ ltration (increase GFR 25-50%) and renal hypertrophy. Onset of hypertension only in DM type 2. • Stage 2 (years 1-5): Usually normal GFR, onset of hypertension only in DM type 2. • Stage 3 (years 6-15) – Incipient Nephropathy: Microalbuminuria (30-300 mg/24h) and hypertension. Pathogenesis and Risk Factors of Diabetic Nephropathy

Mesangial expansion, glomerular basement membrane (GBM) thickening and arteriolar hyalinosis. • Stage 4 (years 15-25) – Overt Nephropathy: Diffuse or nodular glomerulosclerosis (Kimmelstiel-Wilson 51 lesions), tubulointerstitial ﬁ brosis. Proteinuria, nephrotic syndrome, decreased GFR and hypertension. • Stage 5 (years 20-30) – End-stage renal disease (ESRD): Histologic pattern worsening and renal replacement therapy is necessary.

This scheme is valid for type 1 diabetes, but less reliable in type 2 diabetes. DN develops in only 30-40% of patients with type 1 diabetes and 10-20% of those with type 2 diabetes.2

PATHOGENESIS OF DIABETIC NEPHROPATHY Direct effects of glucose: role of Protein Kinase C Glucose infl ux in renal cells stimulates them by producing humoral factors, cytokines and growth factors that are responsible for the structural alterations seen in DN. Glucose induces cell hypertrophy, extracellular matrix synthesis and transforming growth factor β (TGF-β) production. Many of the adverse effects of hyperglycaemia are due to activation of protein kinase C (PKC). PKC activation leads to blood fl ow abnormalities, vascular and capillary occlusion, angiogenesis and oxidative stress via upregulation of factors such as, endothelin-1 (ET-1), TGF-β1, angiotensin II (AII), plasminogen activator inhibitor (PAI-1)… Hyperglycaemia is the primary mediator of diabetic microvascular and macrovascular complications. Independently and in combination with haemodynamic, genetic and other risk factors (hypertension, hyperlipidaemia), it leads to tissue damage and fi nally to DN. Tissue damage is prominent in those organs whose cells are not capable of reducing glucose infl ux when blood glucose levels are high (retinal, mesangial, neu- The Diabetic Patient and Chronic Kidney Disease

ronal cells). Hyperglycaemia produces tissue damage through different intracellular metabolic processes: • Increased advanced glycation end products (AGEs). 52 • Increased the polyol pathway ﬂ ux; effect of sorbitol • Activation of PKC.

Effects of AGEs Chronic hyperglycaemia can lead to the nonenzymatic glycation of amino acids and proteins. Glucose binds non- enzymatically to amino residues forming glycated Schiff bases and then reversible Amadori products.3 AGEs leave the cell, accumulate in plasma and tissues and can form complex cross-links over years of hyperglycaemia. AGEs bind to a variety of cell types, including the endothelial and mesangial cells and macrophages. AGEs induce the production of reactive oxidative species (ROS), and can contribute to renal damage stimulating the production of cytokines, growth and ﬁ brotic factors. In fact, some growth factors like TGF-β, platelet derived growth factors (PDGF) and vascular endothelial growth factors (VEFG), which are upregulated in DN, contribute to further renal damage through angiogenesis and mesangial matrix expansion.

Effect of sorbitol: The polyol pathway Hyperglycaemia induces the generation of polyols. Excess glucose is reduced to sorbitol by aldose reductase. An accumulation of sorbitol can cause the cell to become vulnerable to oxidative stress.

Haemodynamic changes Hyperfi ltration is common in early diabetes and this can be corrected with good glycaemic control. The effects on afferent arteriolar dilation with concomitant efferent vasoconstriction, mediated by a range of vasoactive factors are responsible for the mechanism of hyperfi ltration. Hyperfi ltration may predict the Pathogenesis and Risk Factors of Diabetic Nephropathy development of DN especially in type 1 diabetes.4 Therapeutic measures should be aimed at reducing glomerular pressure: reduction of systemic blood pressure, low protein diet, blockade of renin-angiotensin system (RAS) and vascular endothelial growth factors. These measures can reduce de glomerular 53 damage and proteinuria.5

Genetic factors A genetic background is justifi ed by the fact that only 30%-40% of type 1 diabetes and 10%-20% of type 2 diabetes develop nephropathy. Nephropathy may appear in some patients despite good glycaemic control, these fi ndings suggest that hereditary factors also contribute to the development of DN. The prevalence of nephropathy varies according to racial and ethnic factors (higher in African Americans, Mexican Americans, Australian Aborigines and Pima Indians). Gene polymorphisms may also contribute to familiar clustering and progression of the disease.6 Genetic investigation confi rmed that a diabetic susceptibility locus is present on chromosome 10.

Histological changes Glucose infl ux in renal cells stimulates them by producing humoral factors, cytokines and growth factors that are responsible for the structural alterations seen in DN. Increased deposits of extracellular matrix in the mesangium, expansion of the mesangium and glomerular basement membrane thickening are almost universal features (Fig 1). However, the fi rst morphology change is associated with early hyperfi ltration induced glomerulomegaly and renal organomegaly. The hallmark of DN is mesangial expansion, sometimes ending with the development of nodular diabetic glomerulosclerosis (the Kimmelstiel-Wilson nodule) (Fig 2). The mesangial expansion is mediated by the direct effects of both glucose and glucose-induced AGEs, and some growth factors (TGF-β, VEGF, PDGF…) may contribute to the production and deposit The Diabetic Patient and Chronic Kidney Disease

Figure 1: Electron microscope of structural changes in diabetic nephropathy. Glomerular basement membranes are diffusely thickened (270 to 359 nm).

more mesangial matrix (Fig 3). Widening GBM and alterations of podocyte function are principally responsible for genesis of proteinuria.7 Increased glomerular permeability will allow plasma proteins to escape into the urine. Some of these proteins will be reabsorbed by the proximal tubular cells to start an inﬂ ammatory process leading to interstitial ﬁ brosis. This latter process is usually seen in the later stages of DN and is a strong predictor of renal failure.

Figure 2: Light microscopy of structural changes in diabetic nephropathy. Nodular glomerular lesions: as well as mesangial expansion, there is a typical Kimmelstiel-Wilson nodule. Pathogenesis and Risk Factors of Diabetic Nephropathy

Figure 3: Pathogenesis of diabetic nephropathy: Growth factors and mesangial expansion and nodule formation.

CONTROL RISK FACTORS Hyperglycaemia Poor glycaemic control and duration of disease are the principal risk factors for the development of DN. Different studies have shown that good glycaemic control is directly correlated with the decrease of microvascular and macrovascular complications. Glycosylated haemoglobin (HbA1c) is used worldwide to evaluate glycaemic control. The target value of HbA1c is ≤ 6,5%. The American Diabetes Association (ADA, 2006) and European Association for the study of diabetes (EASD, 2006) recommended to add insulin if HbA1c values still exceeded 7% (The dose of insulin must be reduced in ESRD). Results from the Diabetes Control and Complications Trial (DCCT) showed that adequate glycaemic control was associated with a signiﬁ cant decrease in the development of microalbuminuria and other microvascular complications.8 Studies have surprisingly shown that normalization of blood glucose after pancreas transplantation was associated with a decrease of the diabetic glomerulosclerosis after 10 years.9 The United Kingdom Diabetes Prospective Study (UKPS), conducted in type 2 diabetics, reﬂ ects that intensive glycaemic control (HbA1c 7% vs 7,9%) resulted in a decrease in the The Diabetic Patient and Chronic Kidney Disease

development of microalbuminuria and proteinuria (lowered by 25-30%) and doubling of serum creatinine (lowered by 50%) between the intensiﬁ ed and conventionally treated groups.10 Some studies suggest that with a good glycaemic 56 control (deﬁ ned as HbA1c < 7%), only 9% of type 1 diabetics will develop ESRD compared with a historical prevalence of around 40%.11 Hypertension A good control of blood pressure reduces the rate of progression.12 RAS blockade has proven to be one of the most important therapeutic approaches in the DN. The pathogenesis of hypertension in DN is essential for treatment selection: • Sodium retention and hypervolaemia: Dietary sodium restriction and diuretics. • Activation of RAS: RAS-blocking agents.13,14 • Activation of the sympathetic nervous system: β-blockers.

The Modifi cation of Diet in Renal Disease (MDRD) study showed that lowering blood pressure slows the progression of renal disease.15 The Seventh Joint National Committee and other societies recommend low targets for instituting antihypertensive therapy in diabetic patients: 130/85 for diabetic patients and 125/75 for those with proteinuria >1g/24h.16 The prevalence of hypertension in type 1 diabetics is 20% in the absence of microalbuminuria, and in the presence of it this increases to 40% and 80% when there is proteinuria. Hyperlipidaemia In the general population, there is a strong relationship between reduced LDL levels and decreased cardiovascular events. Hyperlipidaemia is manifested in the early stages of diabetes and may accelerate renal injury. Some studies suggested that statins slow the progression of incipient and overt DN, and there is no doubt that statins are indicated for cardiovascular Pathogenesis and Risk Factors of Diabetic Nephropathy protection of renal dysfunction, although some controlled studies in diabetics on haemodyalisis or kidney transplants were negative.17-19 Statins are recommended for suitable lipid control and especially for lowering LDL. In addition, statins offer an important benefi t on endothelial function, infl ammation 57 and fi brotic processes, via TGF-β1 downregulation. It is important to adjust the dose of statins when GFR is less than 30mL/min, except with atorvastatin and fl uvastatin which are metabolised in the liver. When further LDL lowering is needed, ezetimibe can be added with no dose adjustament. The hypertriglyceridaemia is a common problem despite adequate glycaemic control and a low fat and alcohol free diet. This condition can be treated with fi brates when blood levels exceed 500 mg/dl. The dose of fi brates should be reduced in the presence of renal failure and its combination with statins in ESRD cases should be avoided due to the high risk of rhabdomyolysis.20

ANTIPLATELET THERAPY The use of aspirin (75-162 mg/day) is recommended as a secondary prevention strategy in diabetics with a history of cardiovascular disease and as primary prevention strategy in type 1 and type 2 diabetic patients with cardiovascular risk factors (age > 40 years, family history, hypertension, dyslipidaemia, renal disease, albuminuria, smoker…).21 The Diabetic Patient and Chronic Kidney Disease

Key Points • The natural history of DN is an insidious process that 58 progresses over years. • A major clinical problem is the association of DN with other microvascular (e.g., retinopathy, neuropathy) and macrovascular complications (mainly coronary heart disease and peripheral artery disease).

• DN develops only between 30-40% of patients with type 1 diabetes and 10- 20% of patients with type 2 diabetes.

• Hyperglycaemia is the primary mediator of diabetic microvascular and macrovascular complications. Adequate glycaemic control is associated with a signiﬁ cant decrease in the development of microalbuminuria and other microvascular complications.

• A good control of blood pressure reduces the rate of progression; the different guidelines recommended: 130/85 and 125/75 for patients with proteinuria > 1g/24h.

• Antiplatelet therapy should be assessed for all diabetic patients. Pathogenesis and Risk Factors of Diabetic Nephropathy

References

1. Mogensen CE. How to protect the kidney in diabetic patients with special reference to NIDDM. Diabetes 1997; 56 (Suppl 2): 104-111. 2. Hasslacher C, Ritz E, Wahl P, et al. Similar risks of nephropathy 59 in patients with type I or type II diabetes mellitus. Nephrol Dial Transplant 1989; 4: 795-808. 3. Vlassara H, Striker LJ, Teichberg S, et al. Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci USA 1994; 91: 11704-11708. 4. Amin R, Turner C, van Aken S, et al. The relationship between microalbuminuria and glomerular ﬁ ltration rate in young type 1 diabetic subjects: The Oxford Regional Prospective Study. Kidney Int 2005; 68: 1740-1749. 5. Zatz R, Dunn BR, Meyer TW, et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 1986; 77: 1925-1930. 6. Schmidt S, Ritz E. Angiotensin I converting enzyme gene polymorphism and diabetic nephropathy in type II diabetes. Nephrol Dial Transplant 1997; 12 (Suppl 2): 37-41. 7. Wolf G, Chen S, Ziyadeh FN. From the periphery of the glomerular capillary wall toward the center of disease: Podocyte injury comes of age in diabetic nephropathy. Diabetes 2005; 54: 1626-1634. 8. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993; 329: 977-986. 9. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339; 69-75. 10. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Uk Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837-853. 11. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643-2653. 12. Parving HH, Andersen AR, Smidt UM, et al. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1983; 1: 1175-1179. The Diabetic Patient and Chronic Kidney Disease

13. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851-860. 14. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on 60 renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-869. 15. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modifi cation of Diet in Renal Disease Study Group. N Engl J Med 1994; 330: 877-884. 16. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206-1252. 17. Tonolo G, Ciccarese M, Brizzi P, et al. Reduction of albumin excretion rate in normotensive microalbuminuria type 2 diabetic patients during long-term simvastatin treatment. Diabetes Care 1997; 20: 1891-1895. 18. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238-248. 19. HoldaasH, Fellstrom B, Cole E, et al. On behalf of the Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators: Long- term cardiac outcomes in the renal transplant recipients receiving fl uvastatin: The ALERT Extension Study. Am J Transplant 2005; 5: 2929-2936. 20. Polanco N, Hernández E, González E, et al. Deterioro de función renal inducido por fi bratos. Nefrología 2009; 29: 208-213. 21. Smith SC, Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: Endorsed by the National Lung, heart and Blood Institute. Circulation 2006; 113: 2363-2372. Pathogenesis and Risk Factors of Diabetic Nephropathy

Treatment 63 of Diabetic Nephropathy The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • Knowledge of different therapeutic alternatives in the 64 treatment of proteinuria in diabetic nephropathy • Knowledge of potential side effects of drugs that block the renin-angiotensin-aldosterone • Knowledge of the causes of anaemia in patients with diabetes and its treatment

INTRODUCTION Early detection of diabetes mellitus (DM), its prevention and control are the basis for successful prevention and treatment of micro and macrovascular complications of this disease. Patients with type 2 diabetes are often accompanied by obesity, dyslipidaemia, hypertension, nephropathy, impaired ﬁ brinolysis and the presence of an inﬂ ammatory state. The presence of these alterations is associated with a further increase in premature morbidity and mortality in diabetic patients.1 The key to the treatment of diabetic nephropathy (DN) is the prevention of progression from micro to macroalbuminuria, avoiding the progressive reduction of renal function in patients with proteinuria and cardiovascular complications.2

Albuminuria, Proteinuria The amount of proteinuria is a major risk factor for the progression of most renal diseases. This value forecast, known for many years, has been reinforced by data that shows how the decline in proteinuria with various therapeutic measures (low- protein diet, drugs blocking the renin-angiotensin-aldosterone Treatment of Diabetic Nephropathy system (RAAS)) predicted in the early weeks of treatment, has a favourable effect on renal function.3 The serial determination of microalbuminuria (MAU) should be performed routinely after the diagnosis of diabetes, since the level of MAU is correlated with the development of nephropathy and cardiovascular involvement. The screening should be done both in DM type 1 and type 2, as recommended by consensus 65 documents and current guidelines for clinical practice.4 Inhibition of the Renin-Angiotensin-Aldosterone (RAAS) Although adequate control of blood pressure (BP) is considered a key point in strategies for renoprotection of diabetic nephropathy, specifi c inhibition of the RAAS may confer an additional benefi t, given the key role played by this system in the pathophysiology of DN.5 RAAS blockage has proven to be one of the most important therapeutic approaches in the DN, which was acknowledged by the clinical practice guidelines as a fi rst line strategy for reducing urinary protein excretion and slowing the progression of renal damage, see Table 1.6 Level of Nephropathy Treatment Reference evidence Diabetic nephropathy ACEI vs Placebo A ACEI Type 1 ACEI vs other 9 B Type 2 drugs ARB vs Placebo A 10 ARBs Diabetic nephropathy ARB vs CCB A 14 Diabetic nephropathy ACEI ACEI+ARBs B 19 + Type 1 ACEI+ARBs B ARBs Type 2

Table 1. Evidence for the renoprotective effect of ACE inhibitors and ARBs ARBs: receptor antagonists of angiotensin II ACEI: angiotensin converting enzyme inhibitors CCB: calcium chanel blockers Level of evidence: A: Clear and unquestionable recommendation for clinical practice usual. It relies on data from multiple clinical trials randomized, double-blind, prospective, with large number of patients and longer follow-up time. Meta-analysis including trials of this nature. B: Recommendation moderate evidence for practice usual care. Based on a single randomized clinical trial. Or prospective controlled trials without evident randomization. Cohort studies. Prevalence studies. The Diabetic Patient and Chronic Kidney Disease

Inhibitors of angiotensin converting enzyme (ACEI) inhibitors were added to the antihypertensive treatment in the 80’s, and were the fi rst antihypertensive drug group based on RAS blockage. About 10 years later, angiotensin II receptor antagonists (ARBs) were added to antihypertensive therapy. The mechanism of action based on AT1 receptor blockage of the A-II, 66 rather than inhibition of the enzyme conversion, determines a more complete inhibition of the system, accompanied by a lower prevalence of side effects, namely the absence of cough (5-20% with ACEI) and angioedema (0.1-0.2% with ACEI). In the following years, numerous studies have shown that ARBs have a similar antihypertensive effect to ACEI and cardio and renoprotective effects comparable to that of such drugs.7, 8 In the specifi c context of DN, ACE inhibitors and ARBs have demonstrated their effectiveness in different developmental stages of the disease. A meta-analysis of 12 trials involving 698 patients microalbuminuric normotensive with type 1 diabetes showed that treatment with ACE inhibitors reduced risk of progression to macroalbuminuria by 60% and increased the proportion of patients whose urinary albumin excretion levels return to normoalbuminuria.9 ARBs are also effective in reducing the development of macroalbuminuria in type 2 diabetics with microalbuminuria10, see Table 2. One aspect of interest related to the blockage of RAS in DN is the use of this strategy in normotensive patients. In the case of type 1 diabetes, studies with ACEI have looked at this issue. A recent meta-analysis has shown the benefi cial effects of this therapeutic approach, with an average of 65% less risk of developing proteinuria and a threefold increase in the likelihood of regression to normoalbuminuria.11 Almost all of this effect was independent of changes in systemic BP, being attributed to intraglomerular effects of ACEI.12 These fi ndings reinforce the idea that the antiproteinuric effect of ACE inhibitors and ARBs is independent of BP control. Treatment of Diabetic Nephropathy P: 53.5% L: 46.5% I=P=A I 300: 20% I 150: 27% P: 18.9% 20% V: A: 17% ↓ 67 Cardiovascular: similar 35% Proteinuria: L Cardiovascular: similar Proteinuria: I <33%, P<10% and A<6% Changes in level of albuminuria I 300: <38% I 150: <24% P: 2% Regression to normoalbuminuria I 300: 34% I 150: 24% P: 21% Regression to normoalbuminuria 30% V: A: 14.5% 1º endpoint 2º endpoint Withdrawal Doubling of sCr<25% ESRD <28% Death: similar Doubling of sCr <33% (I vs P) y <37% A) (I vs ESRD <23% (I vs both groups) Death: similar to onset of Time overt nephropathy I 300: 5.2% I 150: 9.7% P: 14.9% Changes in level of albuminuria <44% V: A: <8% up Follow- 42 months 32 months 24 months 6 months Design Losartan (L) 50- 100 mg/d Placebo (P) Irbesartan 75-300 mg/d (I) Amlodipine 2.5-10 mg/d (A) Placebo (P) Irbesartan 150 mg/d (I 150) Irbesartan 300 mg/d (I 300) Placebo (P) Valsartan 120 mg/d (V) Amlodipino 8 mg/d (A) Table 2. Studies evaluating angiotensin receptor antagonists in patients with diabetic nephropathy Table patients Number of 1513 1715 590 300 (12) (13) (10) (14) Study RENAAL RENAAL IDNT IRMA MARVAL The Diabetic Patient and Chronic Kidney Disease

On the other hand, a post hoc analysis of RENAAL study showed that the most important risk factor for progression of nephropathy is the degree of proteinuria, both at baseline and residual proteinuria observed after 6 months of treatment. Thus, one of the most important goals of treatment in patients with DN is to achieve maximum possible reduction of 68 proteinuria.13-15 Finally, the DETAIL study has shown that administration of an ARB (telmisartan 80 mg/day) was accompanied by a similar effect in preventing the progression of renal failure compared with enalapril (20 mg/day) in a group of 250 type 2 diabetics with microalbuminuria.16 Therefore, we recommend the use of ACEI or ARBs therapy of choice in both type 1 diabetic patients with microalbuminuria and type 2, even with normal levels of BP.

Combination Blockage The combined blockage of RAS could be done in various ways, with different drugs and different levels, but the most studied to date has been based on the combination of ACEI and ARBs. When initiating treatment with an ACEI, we see a reduction of plasma A-II. However, in the long-term, there has been a loss of effect, so that A-II concentrations return to baseline. This concept has been called “escape phenomenon”.17 Dual therapy using both an ACEI and ARBs, would minimize or neutralize the “escape phenomenon” previously described, and could have an additive or even synergistic effect in protecting target organs. The mechanisms of action of both drugs are somewhat different in some ways even complementary, and it has been speculated that the combination of both would be superior to monotherapy in the treatment of various situations.18 Several studies, both in diabetic patients type 1 and type 2, have explored the effect of combination therapy ACEI + ARB. Overall, this therapeutic approach has been partnered with Treatment of Diabetic Nephropathy respect to monotherapy, with greater antihypertensive and antiproteinuric effects.19, 20 Recently published results of the ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), which included more than 25,000 patients with established vascular disease or with diabetes and target organ damage, were randomized to receive telmisartan, ramipril or a 69 combination of both. This is the largest study to date comparing dual blockage of RAAS blockage compared with ACE inhibitors or individual ARA. The results showed that the development of stroke was similar to ramipril and telmisartan, while the branch of combination therapy showed no superiority over any other two branches of separate treatment.21

Very high doses of RAS blockers In recent years, another strategy for SRA blockers, and speciﬁ cally with the ARA, is the use of much higher doses than recommended in clinical practice. Several studies show that supramaximal doses of these drugs are associated with a greater decrease in proteinuria than that obtained with standard doses.22, 23

Antagonists of aldosterone Numerous studies have demonstrated the role of aldosterone as a mediator in the progression of renal damage and cardiovascular disease through its direct haemodynamic effects and cellular mechanisms. Experimental studies in rats have shown aldosterone may contribute to the progression of renal disease, while the use of aldosterone antagonists can reduce proteinuria and slow the progression of renal disease independent of BP values. On the other hand, the use of ACE inhibitors or ARBs is unable to reduce aldosterone levels in the long term, this so called “phenomenon of aldosterone escape” perpetuates the harmful effects on the progression The Diabetic Patient and Chronic Kidney Disease

of nephropathy.24 In the last decade, many studies in which patients with chronic proteinuric nephropathies treated with receptor antagonists, aldosterone (spironolactone, eplerenone) in addition to the usual treatment (ACEI/ARBs) have signiﬁ cantly lower proteinuria levels. There are studies that show how combination therapy of ACEI and/or ARB 70 inhibitors with aldosterone is more effective in reducing proteinuria that the use of these drugs individually.25

Direct renin inhibitors In the context of RAAS blockage, the groups of newer antihypertensive drugs which are direct renin inhibitors, aliskiren is the sole representative today. The antihypertensive effectiveness of this new drug appears to be similar to that seen with ACE inhibitors or ARA. When added to an ARB, aliskiren blocks the compensatory activation of RAS and further reduces BP.26 Recently, published studies examining the antihypertensive and antiproteinuric effect of this drug observed similar effects with ACEI or ARBs.27

Special considerations relating to the blockage of the RAAS Following the initiation of treatment with drugs that block the RAAS, certain precautions must be taken, particularly related to the potential deterioration of the RF and the development of hyperkalemia, see Figure 1. These drugs should be introduced gradually and in increasing doses, and it would be advisable to carry out checks of renal function and serum potassium after initiating treatment, especially in patients with associated risk factors. Treatment of Diabetic Nephropathy

Figure 1

New therapeutic targets In recent years, the therapeutic use of vitamin D has been tested, and how its metabolites may reduce the progression of chronic kidney disease and improve cardiovascular prognosis of renal disease population. Vitamin D defi ciency is common among patients with chronic kidney disease and is associated with other cardiovascular risk factors such as albuminuria, diabetes mellitus and lower glomerular fi ltration rate. Vitamin D and its metabolites have not only proven to be effective drugs in the treatment of secondary hyperparathyroidism but also due to other pleiotropic effects. From the experimental point of view, studies show that vitamin D or its metabolites can prevent interstitial fi brosis, mesangial proliferation and loss of podocytes. Among the proposed mechanisms are benefi cial haemodynamic and non-haemodynamic effects (apoptosis, The Diabetic Patient and Chronic Kidney Disease

angiogenesis, anti-inﬂ ammatory effects, anti-thrombotic and anti-atherogenic).28 Finally, several emerging studies note the role of the use of vitamin D or its derivatives through its effect on the renin- angiotensin-aldosterone antiproteinuric effect, slows the progression of kidney disease.29 72

Anaemia Treatment DN patients usually present a greater degree of anaemia related to renal insufﬁ ciency than those found in other renal diseases. Also anaemia in diabetic patients may appear earlier than other aetiologies.

Causes of anaemia in diabetic patients: • The main cause of anaemia in patients with chronic renal failure (CRF) is inadequate renal production of erythropoietin (EPO). Lower levels of EPO have been detected in anaemic patients with diabetes (without CRF) compared with anaemic patients without diabetes. It has been speculated that the lower erythropoietic response in patients with diabetes without nephropathy could be an early or interstitial damage mechanisms of glycosylation.30

• In patients with diabetes type 1 anaemia was detected even with neuropathy associated with incipient nephropathy. Most of these patients have low levels of EPO. The exact mechanism has not been elucidated but renal denervation secondary to autonomic neuropathy in the presence of damage to the EPO-producing cells of the renal cortex could be the cause.31

• Normocytic normochromic anaemia has been observed in patients with newly diagnosed diabetes. The Treatment of Diabetic Nephropathy

explanation could be the “glucotoxicity” on erythroid precursors or oxidative stress mature erythrocytes.31

• Patients with nephrotic syndrome, including also those with DN, have a marked urinary excretion of EPO, with a decrease in plasma concentration. They also have higher urinary loss of transferrin. These losses may 73 reduce plasma concentrations of iron and cause iron deﬁ ciency and microcytic anaemia. Recent studies have linked the presence of anaemia as a risk factor for the progression of renal disease. However, early treatment of anaemia can slow the progression of renal failure. Anaemia has a negative impact on patient survival and has been considered an important cardiovascular risk factor associated with the chronic kidney disease. For all these reasons, the treatment of anaemia in diabetic patients is necessary in order to optimize the clinical course in these subjects. However, in two large prospective randomized studies in patients with CKD (CHOIR, CREATE), Hb above 12 g/dL was associated with increased cardiovascular complications and mortality. Some of the conclusions of the developer TREAT study, in which there was no treatment effect of anaemia in relation to death or cardiovascular events but there was a signiﬁ cant increase in risk of stroke in patients treated with darbepoetin.32, 33 A key aspect of these studies is not the levels of haemoglobin achieved by the patients but the dose of EPO required to achieve these levels. For this reason, it is recommended, in the interest of safety, treatment with EPO to achieve target Hb 10-12 g/dl. In light of these considerations, correcting anaemia in patients should be treated cautiously. The objectives of Hb for patients depend on the stage of CKD, the association of cardiovascular disease, prothrombotic factors, age, gender, race or geographic area. The Diabetic Patient and Chronic Kidney Disease

Key Points • The amount of proteinuria is an important prognostic data in most renal diseases.

• There is a strong correlation between proteinuria 74 reduction induced by ACEI/ARA and the renoprotective effect of these drugs.

• The antiproteinuric effect of RAAS inhibition is observed even in the ﬁ rst weeks/months of treatment.

• These drugs should be introduced gradually and in increasing doses, and it would be advisable to check renal function and serum potassium after initiating treatment.

• Patients with DN usually present a greater degree of anaemia related to kidney failure found in other renal diseases.

• We need to correct anaemia in patients with diabetes (after correcting for other factors, such as iron deﬁ ciency) but with some caution (haemoglobin between 10-12 g/dL), and monitoring the dose required to achieve target haemoglobin. Treatment of Diabetic Nephropathy

References

1. Praga M, Hernandez E, Montoyo C, Andres A, Ruilope LM, Rodicio JL. Long-term beneﬁ cial effects of angiotensin converting enzyme inhibitors in patients with nephrotic proteinuria. Am J Kidney Dis 1992; 20:240-248. 2. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. A 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359:1577-1589. 75 3. Gross JL, De Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention and treatment. Diabetes Care 2005; 28:164-176. 4. Asociación Española de Nefrología Pediatrica, Sociedades Españolas de Diabetes, Endocrinología y Nutrición, Medicina Familiar y Comunitaria, Medicina Rural y Generalista y Nefrología. Documento Consenso sobre la detección y tratamiento de la nefropatía diabética en España. Nefrología 2002; 22:521-530. 5. Koitka A, Tikellis C. Advances in the renin-angiotensin-aldosterone system: relevance to diabetic nephropathy. Scientiﬁ c World Journal 2008;8:434-5. 109. 6. Bakris GL. Protecting renal function in the hypertensive patient: clinical guidelines. Am J Hypertens 2005; 18:112S-9S. 7. Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, et al. Diabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004; 351:1952-61. 8. Matchar DB, McCrory DC, Orlando LA, Patel MR, Patel UD, Patwardhan MB. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med 2008; 148:16-29. 9. The ACE inhibitors in Diabetic Nephropathy Trial Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors?. A metaanálisis of individual patient data. Ann Intern Med 2001; 134:370-379. 10. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P. Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345:870-8. The Diabetic Patient and Chronic Kidney Disease

1 1.ACE inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive ACE inhibitors: a meta-analysis of individual patient data. Ann Intern Med 2001; 144:370-9. 12. Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002; 106:672-678. 76 13. Brenner BM, Cooper ME, De Zeew D, Keane WF, Mitch WE, Parving HH, et al. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. RENAAL study investigators. N Engl J Med 2001; 345:861-9. 14. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al.; Collaborative Study Group. Renoprotective effect of the angiotensin- receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851-60. 15. de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65:2309-20. 16. Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, et al. Diabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004; 351:1952-61. 17. Azizi M, Ménard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 2004; 109:2492-9. 18. Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 2002; 89:A3-9. 128. 19. Jacobsen P, Andersen S, Jensen BR, Parving HM. Additive effect of ACE inhibition and angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. J Am Soc Nephrol 2003; 14:992-9. 20. Rossing K, Jacobsen P, Pietraszek L, Parving HH. Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomised double-blind crossover trial. Diabetes Care 2003; 26:2268-74. 21. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al.; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547-59. Treatment of Diabetic Nephropathy

22. Schmieder RE, Klingbeil AU, Fleischmann EH, Veelken R, Delles C. Additional antiproteinuric effect of ultrahigh dose candesartan: a double-blind, randomized, prospective study. J Am Soc Nephrol 2005; 16:3038-45. 136. 23. Rossing K, Schjoedt KJ, Jensen BR, Boomsma F, Parving HH. Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria. Kidney Int 2005; 68:1190-8. 77 24. Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an agiotensin converting enzyme inhibitor: implications for therapy. Cardiovascular Drugs Ther 1995; 9:145-149. 25. Crysostomou A, Pedagogos E, MacGregor L, Becker G. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol 2006; 1:256-262. 26. Gradman AH, Pinto R, Kad R. Current concepts: renin inhibition in the treatment of hypertension. Curr Opin Pharmacol 2008; 8:120-6. 27. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008; 358:2433-46. 28. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Andress DL. Prevalence of abnormal serum vitamin D, PTH, calcium and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 2006; 71:31-38. 29. Agarwal R, Acharya M, Tian J, Hippensteel RL, Melnick JZ, Qiu P, Williams L, Batlle D. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int 2005; 68:2823-2828. 30. Bosman DR, Winkler AS, Marsden JT, et al. Anaemia with erythropoietin deﬁ ciency occurs early in diabetic nephropathy. Diabetes Care 2001; 24:495-499. 31. Craig KJ, Williams JD, Riley SG, Smith H, Owens DR, Worthing D, Cavill I, Phillips AO. Anaemia and diabetes in the absence of nephropathy. Diabetes Care 2005; 28:1118-1123. 32. Singh AK, Himmelfarb J, Szczech LA. Resolved: Targeting higher haemoglobin is associated with greater risk in patients with CKD anaemia. J Am Soc Nephrol 2009; 20: 1436-1443. 33. Singh AK. Does TREAT give the boot to ESAs in the treatment of CKD anaemia? J Am Soc Nephrol 2010; 21: 1-13.

Oral 79 Anti-diabetics and Insulin in Patients with Diabetic Nephropathy The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To become familiar with the different types of oral anti- diabetics • To become familiar with the different types of insulin 80 • The use of oral anti-diabetics, emphasizing whether or not they are used in the presence of nephropathy

ORAL ANTI-DIABETICS At the moment, there are several groups of oral hypoglycaemic medications for the treatment of patients with diabetes mellitus (DM), and they are only indicated for those with type 2 diabetes mellitus. Treatment with these medications is recommended when lifestyle changes do not achieve or maintain acceptable glycaemic control. These medications are used as a monotherapeutic measure and starting with lower doses. Depending on the HbA1c control, the dose can be increased or combined with another drug from a different group. If the desired results are not achieved, a third drug can be added or insulin treatment can be started. The choice of one drug or the other depends on the characteristics of the patient, tolerance, efﬁ ciency, proven safety and cost. Recommendations for the use of hypoglycaemic drugs to treat DM have been established for patients without renal problems. The majority of oral anti-diabetics are metabolised and eliminated by the kidney. In the presence of altered renal function, the drug can accumulate and therefore increase the risk of hypoglycaemia and its adverse effects. In some cases, it is necessary to take into account the patient’s renal failure state and the drug’s characteristics when adjusting the dose or Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy avoiding it all together. In patients on haemodialysis it is best to avoid the use of any oral anti-diabetic, although the drugs meglitinide and pioglitazona can be used. This section includes the most important aspects in relation to oral anti-diabetics, emphasizing whether or not they are used in the presence of nephropathy (Tables 1 and 2) as well as the action mechanism and characteristics of each drug family.

1. MEDICATIONS THAT STIMULATE THE RELEASE OF 81 INSULIN: SULFONYLUREAS AND MEGLITINIDES 1.1 Sulfonylureas These are medications that are derived from sulfamides. They act on the pancreatic beta cells increasing the secretion of stored insulin, both basal and when stimulated by eating, and slightly decrease the release of glucagon. Therefore, in order for them to work correctly the basal cell needs to function. Moreover, they improve the capture and use of glucose mediated by insulin in peripheral tissues. They also decrease insulin clearance in the liver.1 They have a hypoglycaemic effect independent of the glucose plasma levels. In patients with DM they reduce glucose plasma levels during fasting at an average of 60-70 mg/dl and the HbA1c by 0.8%-2%. There are various sulfonylureas on the market, all with a different potency, onset and duration. They are all metabolised in the liver giving way to metabolites that are active (glipizide), partially active (glibenclamide, glimepiride, gliquidone) and inactive. These metabolites are eliminated in signiﬁ cant quantities by way of the kidney. Biliary excretion is important for gliquidone and glimepiride, but less for glipizide. Patients in stages 4 and 5 of CKD should avoid the use of sulfonylureas due to the increased risk of hypoglycaemia. It is The Diabetic Patient and Chronic Kidney Disease

advisable to use gliquidone in patients with stage 3 CKD because of its elimination through the liver and low doses of glimepiride and glipizide due to their lower half-lives. The most frequent side effect of sulfonylureas is hypoglycaemia. They can also cause gastrointestinal problems, anorexia, headaches, nausea and paresthesia. Several medications interact with sulfonylureas. They increase the hypoglycaemic effect of alcohol, aspirin, beta blockers, sulfonamides, 82 phenylbutazone, dicumarol, ﬁ brates, MAO inhibitors, tricyclic antidepressants, ACE inhibitors, NSAIDs,

allopurinol, antihistamines, H2 and anabolic steroids (Table 3). They decrease the hypoglycaemic action of rifampicin, barbiturates, oral contraceptives, thiazides, corticosteroids, and thyroid hormones.

1.2. Meglitinides analogues These are not insulin secreting sulfonylurea drugs; however they do stimulate the secretion of a hormone similar to that of the sulfonylureas. They have a quicker onset and a shorter duration of action, which is why their administration is recommended for 15 minutes before each meal. Their indication is based on the ability to reduce the oscillation in levels of postpandrial glucose.2 They decrease glucose levels during fasting at an average of 60-75 mg/dl and HbA1c by 0.8%-2%. Included in this group of drugs are repaglinide (0.5 to 2 mg dose3) and nateglinide (60 to 120 mg dose). They are both metabolised in the liver. Nateglinide is metabolised to active metabolites that are excreted through the kidney, while repaglinide is metabolised to inactive metabolites. Therefore with repaglinide it is not necessary to adjust the dose, except in cases of stage 4 renal failure.4 Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

The most important side effect is induced hypoglycaemia.

2. METAFORMIN Metaformin is a member of the biguanide family; however, if used properly it does not present the lactic acidosis risk associated with these types of medications. Its mechanism of action is based on reducing the liver production of glucose and increasing the use of glucose by the muscular and adipose 83 tissue. It also decreases intestinal absorption of glucose and sensitizes the peripheral tissues to the action of insulin, and in this way, decreases the resistance to insulin in patients with DM. Metaformin also increases the metabolism of glucose, especially in the spleen. It is considered to be a drug that induces weight loss or stabilizes weight.5 It decreases glucose levels during fasting at an average of 50-70 mg/dl and HbA1c by 1.4%-1.8%. Adverse reactions are mild, frequent and transient and are usually related to the dose. They include digestive symptoms that can be reduced by initiating treatment in lower doses, preferably taken at meals, speciﬁ cally dinner. The most serious adverse reaction is lactic acidosis, although its frequency is low. It mostly occurs in patients with renal, liver or heart failure. It usually begins with a general feeling of malaise, myalgia, dyspnea and abdominal pain. In the most serious cases hypothermia, hypotension and bradycardia can be observed, and it can evolve to coma or death. Other adverse reactions are headaches and muscle cramps. It rarely produces hypoglycaemia except when used in combination with another hypoglycaemic drug. Metaformin is not recommended for patients with altered kidney function (plasmic creatinine greater than 1.5 in men and 1.4 in women or a clearance of less than 60 mL/min), congestive heart failure, chronic hepatopathy, and in general in the presence of The Diabetic Patient and Chronic Kidney Disease

a serious illness due to the risk of lactic acidosis.6 It should be used with precaution when it is administered with cimetidine, ranitidine and trimethoprime because they decrease its elimination from the body, as well as with the administration of drugs that antagonize insulin secretion or its action; like beta blockers, corticosteroids, diuretics and calcium antagonists.

3. ALFA-GLUCOSIDASE INHIBITORS 84 These drugs slow down the digestion of complex carbohydrates at the intestinal level by suppressing the intestinal enterocyte enzymes that are implicated in the hydrolysis of polysaccharides and oligosaccharides. They reduce the postpandrial levels of glucose.7 In addition, they decrease the levels of glucose during fasting an at average of 35-40 mg/dl and HbA1c by 0.4% to 0.7%. There are two alfa-glucosidase inhibitors: acarbose and miglitol. Their pharmacological proﬁ les are similar with the main difference being that acarbose is practically not absorbed and is eliminated by the intestine, while miglitol is absorbed but not metabolised and eliminated by the kidney. Neither is recommended for patients in stages 3, 4 and 5 of CKD. Due to their mechanism of action they should be taken before eating. The most frequent adverse effect of these drugs is digestive intolerance. To reduce these symptoms to a minimum treatment should begin with a low dose (25-50 mg at a time) and increase gradually according to the patient’s tolerance. They do not usually produce hypoglycaemia, except in cases that are associated with the use of sulfonylureas or insulin.

4. THIAZOLIDINEDIONES (GLITAZONES) These are drugs that reduce the peripheral resistance to insulin and increase its action without increasing its secretion. Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

They act at the muscular, fatty tissue, and liver levels. They act by binding to the PPAR (peroxisome proliferator-activated receptors). They decrease the levels of HbA1c by 0.5% to 1.5%. Several drugs from this group have been studied, and several of them have been taken off the market due to hepatopathy or increased cardiovascular risk. At the moment the only one commercially available is pioglitazona. It is indicated 85 as a monotherapeutic oral drug for patients with DM type 2, especially for those that are overweight, do not control their lifestyle, and cannot take metaformin due to intolerance or because it is contraindicated. The glitazonas present a gradual effect in the reduction of glucose at the beginning of treatment, reaching a maximum effect after about 8 weeks. Glitazonas are metabolised in the liver, giving way to various metabolites. Pioglitazona is not indicated for patients with hypersensitivity to the drug and those with heart or liver failure. In patients with renal failure the plasmic concentration of pioglitazona and its metabolites are lower than observed in patients with normal renal function. However, clearance of the drug is independent of renal function. Therefore, the concentration of free pioglitazona remains unaltered in nephropathic patients, and its use is not contraindicated and there is no need for dose adjustment. In cases of patients with CKD stages 2 and 3 it can produce liquid retention, which is why those patients with associated heart failure should be closely monitored. In stages 4 and 5 of CKD it is not necessary to adjust the pioglitazona dose.10 In patients on dialysis there is no ﬂ uid overload problem,11 since the management of water and salt elimination by dialysis is not affected. The drug can produce anaemia and increased body weight due to increased water retention. The Diabetic Patient and Chronic Kidney Disease

The side effects of pioglitazona are mild and infrequent. They include diarrhoea, increased appetite, ﬂ atulence, headache, aneamia, vision problems especially at the beginning of treatment. Vision problems are probably caused by temporary changes in the clarity and refractive index in the ocular lens due to change in glucose levels.

5. DRUGS WITH AN INCRETIN EFFECT 86 The glucagon like peptide 1 (GPL-1) is a protein secreted in the intestinal L-cells, which stimulates the release of insulin and inhibits the release of glucagon by the pancreas. It also decreases gastric emptying and reduces food intake. Native GLP-1 has a half-life of less than 10 minutes. It is quickly metabolised by dipeptidyl peptidase IV (DPP-IV). There are two commercially available types of these drugs; GLP-1 analogues12 and DPP-IV inhibitors.13 Drugs with an incretin effect are recommended for obese diabetic patients with poorly controlled lifestyles, and those that cannot take metaformin due to intolerance or contraindication. This is due to the fact the GLP-1 analogues signiﬁ cantly decrease weight and DPP-IV inhibitors do not compared with other oral anti-diabetics which increase weight. They also lower the levels of Hb1Ac to 0.6%-1.1% and basal glucose by an average of 25 mg/dl. 5.1 GLP-1 Analogues They directly activate the GLP-1 receptor, increasing its physiological actions. They reduce glucose level and induce quick satiation and a weight loss of about 5 kg after two years of treatment. Although various types of these drugs are being studied, the only commercially available drug is exenatide. It has a longer half-life than native GLP-1. The recommended dose is two subcutaneous doses of 5-10 μg per day. Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

It is eliminated from the body by the kidney. If GFR is greater than 30mL/min it is not necessary to adjust the dose, and is contraindicated when renal function is lower than this. Exenatide causes nausea in a great number of patients at the beginning of the treatment. This effect is transitory and decreases with a gradual increase of the dose. The recommended starting dose is 5μg increasing it to 10μg twice daily. 87

5.2 DPP-IV Inhibitors They act by increasing the endogenous concentration of native GLP-1, impeding its inactivation by the DPP- IV enzyme. They improve glycaemic control with a neutral effect on body weight. There several drugs of this type: sitagliptin, vildagliptin and saxagliptin. It is administered orally in a single daily dose of 100 mg, 100 mg and 5 mg respectively. They are all eliminated by the kidney. In patients with a creatinine clearance of 30-50mL/min the recommended dose is half of the normal dose.14 These drugs are generally well tolerated and the undesirable side effects are rare. Side effects include adverse gastrointestinal symptoms, very infrequent anaphylactic reactions, angioedema and Steven- Johnson Syndrome. The Diabetic Patient and Chronic Kidney Disease Should be introduced at a low dose Contraindicate if CCr < 30mL/min Used glyquidone if CCr 30–60mL/min Contraindicated if CCr < 15 mL/min Used repanglinide if CCr 15–60mL/min Contraindicated if CCr < 60mL/min Contraindicated if CCr < 60mL/min

88 Hypoglycaemia gain Weight Uncommon sensitivity reactions Hypoglycaemia gain Weight Uncommon sensitivity reactions Gastrointestinal effects effects Rare lactic acidosis Gastrointestinal Bile 50 % Urine 80 % Urine 70 % Bile 95 % Urine 65 % Bile Bile Gastrointestinal Urine Active Active Inactive Inactive Inactive Active Inactive Not absorbed Not metabolised Not metabolised Urine Metabolism Excretion Side effects Use in renal failure Table 1: non insulin hypoglicemic agents Table 2.5-15mg oral 1-6mg oral 2.5-10mg oral 15-180mg oral 30-120mg oral 0.5- 4mg taken about 15–30min before meals oral 25–50mg taken about 15–30min before meals oral 500 – 2000mg oral Dose 0.8 - 2% 60 – 120mg 0.4 – 0.7% 1.8% HbA1c decrease 0.8 - 2%. 1.4 – Repanglinide Acarbose Miglitol Antidiabetic agent Glymepiride Glypizine Glyquidone Glcazide Meglitinidas Nateglinide α -glucosidase inhibitors Biguanides Metformin Sulphonylureas Glybenclamide Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy Thiazolidinediones Inhibit DPP-IV or gliptins GLP-1 analogues

89 Fluid retention. gain Weight Gastrointestinal effects Should assed liver function test Caution in heart disease, anaemia and hepatic failure effects Anaphylaxis, angioedema, and Steven-Johnson syndrome Gastrointestinal introduced at a low dose Gastrointestinal effects Should be Bile Urine Urine Metabolism Excretion Side effects Use in renal failure inactive Active Active Dose 15 – 45mg oral Active and 100 mg oral 100 mg oral 5 mg oral 5 – 10 microg two sc doses DPP-IV = Dipeptidil peptidasa IVGLP-1 Glucagon like peptide HbA1c decrease 1.5% 0.6 – 1.1% 0.5 – 1.1% 0.6 – Antidiabetic agent Pioglitazone Sitagliptin Vildagliptine Saxagliptine Thiazolidinediones Inhibit DPP-IV or gliptins GLP-1 analogues Exenatide The Diabetic Patient and Chronic Kidney Disease No Yes Yes Glitazones Incretins No Yes Yes 90 Yes Yes Warning Warning Alpha-glucosidase inhibitors Warning No No No Yes No Yes Yes CrC--creatine clearance. Table 2: Selection of oral anti-diabetics in CKD Table Yes No Yes Yes Glipizide Gliquidone Yes 29–15 Warning< 15 Warning No No No 59–30 Gliquidone CrC Sulfonylureas Meglitinides Metformin > 9089–60 Yes Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

Table 3: Drugs that can potentiate the anti-hyperglycaemic effect of sulphonylureas

Mechanism Example

Displacement from Salicylates, sulphonamides, proteins warfarin, plasma phenylbutazone, ﬁ bric acid derivatives

Decreased hepatic Warfarin, monoamine oxidase inhibitors, metabolism chloramphenicol, phenylbutazone 91

Decreased renal Salicylates, probenecid, allopurinol excretion

Intrinsic Salicylates, alcohol (ethanol), hypoglycaemic monoamine oxidase inhibitors activity

INSULIN In healthy individuals 50% of insulin is secreted without stimulation and independent of glucose levels. The other 50% is secreted in answer to postprandial glucose stimulation. Endogenous insulin is directly secreted in the portal system. The liver metabolises approximately 75%, while the other 25% is metabolised in the kidney. 60% of arterial insulin is ﬁ ltered in the kidney in the glomerural and 40% is secreted actively in the tubules. The majority of the insulin that is in the tubules is metabolised into amino acids and only 1% is secreted intact.15 Once creatinine clearance drops below 20mL/min insulin clearance also decreases. Insulin is one of the best studied drugs. It is recommended as mono-therapy in patients with DM type 1 and can be The Diabetic Patient and Chronic Kidney Disease

combined or not with oral hypoglycaemics in type 2 patients that do not control their lifestyle. It must be taken into account in patients with diabetic nephropathy that because insulin is cleared through the kidney, the half-life is lengthened and their requirements can decrease.16 Given that the majority of oral hypoglycaemic drugs are contraindicated in patients in stages 4 and 5 of CKD, in the presence of diabetic nephropathy insulin is the best therapeutic option as long as there is no further scientiﬁ c evidence contraindicating it. When creatinine clearance 92 reaches a range of 10-30 mL/min the dose of insulin should be reduced. Later, when the patient begins renal replacement therapy the dose should again be reduced to half.

Types of Insulin Traditionally, insulin has been classiﬁ ed according to its quickness and duration; rapid, intermediate and long acting. NPH and human insulin are used the most. Over the years analogues to rapid-acting insulin (lispro, aspart and glulisine) and long acting analogues (glargine and detemir) have been developed, which have an improved pharmacokinetic proﬁ le (Table 4), but increase treatment costs.18 They are clear in color, do not require shaking before injection and cannot be mixed with other insulins.

Table 4: Types of Insulin Duration of Type of Insulin Action Onset Action Peak Action Lispro 5-10 min 1-2 h 3-4 h

Aspar 5-10 min 1-2 h 3-4 h

Glulisine 5-10 min 1-2 h 3-4 h

Regular 30-60 min 2-4 h 6-8 h

NPH 1-3 h 5-7 h 13-16 h Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

Duration of Type of Insulin Action Onset Action Peak Action Detemir 2-4 h Variable 20-24 h

Glargine 2-4 h Variable 20-24 h

Reduce the insulin dose by 25% what GFR is 10-30 ml/min and by 50% when GFR is <10ml/min.

Long-acting insulin analogues are characterised by having a greater reproducibility of their effect with lower glycaemic 93 variability due to a pharmacodynamic profi le without the peaks and valleys characteristic of NPH insulin.19 However, when compared with glargine or determir there are no observable differences in relation to HbA1c levels, in fact some studies have shown reductions of 0.1%-0.5% in favor of the analogue.20,21,22 Therefore, they do not provide advantages related to the reduction of HbA1c. They do, however, have a lower incidence of hypoglycaemic episodes; nocturnal episodes are almost non-existant or signifi cantly reduced.23,24 The long-acting insulin analogues have a longer duration of action: between 18-23 hours for detemir and 22-27 hours for glargine. The duration depends on the dose, and the greatest advantage is that these can be administered just once a day. Detemir is associated with lower weight gain. At the moment the differences between the use of one or the other is unknown with regards to effi cacy. The commercially available fast-acting insulin analogues are: lispro, aspart and glulsine. They have similar pharmacokinetic and pharmacodynamic properties. They aim to simulate the quick, powerful and short duration response of endogenous postprandial insulin. One advantage is that they improve the patient’s quality of life due to their quick onset of 5-10 minutes compared with 30 minute onset of regular insulin. This allows them to be administered in the necessary dose just before and right after meals (Figure 1).27 They also decrease the incidence of late onset hypoglycaemia. The Diabetic Patient and Chronic Kidney Disease

Although there is no scientiﬁ c evidence regarding the beneﬁ ts of using analogues compared to using traditional insulin in patients with renal failure, at the moment it is better to use analogues due to the lower risk of hypoglycaemia.

Figure 1

Types of Insulinas aspart, lispro, glulisina (4-6 h)

94 regular (6-10 h) NPH (12-20 h)

glargina, detemir (20-24 h) Insulin plasma levels

Time (h)

Insulin Administration Systems Insulin is available in three different systems: vials, cartridges, and prepared syringes or pens. Vials and cartridges are used in hospitals, and syringes and pens are almost never used. The pen system allows for better conservation and greater ease of use, which allows for greater patient autonomy and better quality of life.

Insulin Administration Modalities Insulin can be administered in two different types of therapies; conventional or intensive. This classiﬁ cation is based on the complexity and degree of similarity to the physiological endogenous secretion of insulin. 1. Conventional Therapy It includes the most simple insulin administration regimens and it has two guidelines: Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

• One or two doses of intermediate/long actin insulin per day like NPH, glargine or detemir (Figure 2, 3). • One or two doses of intermediate/long acting insulin per day (NPH, glargine or detemir) with fast-acting insulin like regular insulin or rapid-acting analogues, mixed in the same syringe or premixed in biphasic insulin form.

When metabolic control deteriorates or treatment with oral 95 anti-diabetics is contraindicated, insulin treatment can begin with either one or two doses in combination or not with oral hypoglycaemics. Another alternative is to start with rapid- acting insulin mixed with long-acting insulin. Therefore, when regular insulin and NPH is administered every 12 hours, with the onset of action at about 30 minutes after, it will cover the insulin needs for breakfast and dinner, while NPH starts to work 2 hours after and will cover the basal needs and the postprandial peak. The two types of insulin can be administered separately or premixed. The administration of premixed insulin is more comfortable for the patient since it reduces the number of injections and avoids possible patient errors in the mixture. Every premixed insulin has a ﬁ xed proportion of long-acting and rapid-acting insulin. There are mixtures of NPH insulin with regular insulin and mixtures of long and rapid-acting insulin analogues. The mixes are considered to be less ﬂ exible and present a greater risk of hypoglycaemia. The main advantage to conventional therapy is the simplicity of the regimens. It requires less daily glycaemic control and therefore less dose variation, improving patient education and compliance. However, this therapy achieves poorer glycaemic control and requires a strict control of insulin-meal-exercise schedules. In addition to an overlapping effect of rapid and long-acting insulin, many patients might need carbohydrate supplements at mid-morning or late afternoon to prevent hypoglycaemia. The Diabetic Patient and Chronic Kidney Disease

At the moment, it is considered an alternative to intensive therapy for patients with a scarce necessity for insulin, those who cannot comply with regimens and those that do not require strict control; for example patients who are over 80 years of age and terminal patients. A variation of this type of therapy consists of regular insulin at dinner and NPH before

Figure 2. Conventional Therapy. Non-physiological Indications. 96 Breakfast Lunch Dinner Bedtime Breakfast Lunch Dinner Bedtime

Total Total insulin effect insulin effect Insulin Effect

Glargina NPH NPH

Figure 3. Conventional Therapy. Physiological Indications.

Breakfast Lunch Dinner Bedtime

Total insulin effect Insulin Effect

NPH NPH Regular Regular Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy going to bed.41 Intensive therapy is necessary in the case of poor glycaemic control with conventional therapy. 2. Intensive Therapy (Figure 4) This therapy consists of basal-prandial or basal-bolus insulin which attempts to reproduce the endogenous insulin secretion pattern in a more precise way than conventional therapy. It separates the basal insulin needs from the prandial requirements. It includes two types: 97 • Multi-doses; the basal component is covered by long- acting insulin injections every 12 or 24 hours, which the postprandial component is covered with multiple injections of quick-action insulin. • Continuous infusion (CSII): the basal component is covered by a continuous infusion of rapid-acting insulin administered by a pump, while the postprandial component is covered with extra bolus of rapid-acting insulin, as needed.

The fundamental requisite for this type of therapy is patient’s ability to control their glucose, a basic factor for diabetic care. With intensive therapy the doctor should recommend an appropriate regimen, defi ne the objectives and instruct the patient on how to modify the insulin dose according to capillary glucose levels, physical activity and diet.4,5 The patient should be motivated, accept their illness, implicate themselves in their treatment and receive the appropriate diabetic education. Intensive therapy is currently the fi rst choice for diabetic patients, especially those that have an irregular life and those that have a high risk for hypoglycaemia like nephropathic patients on renal replacement therapy. The advantages include improved glucose control with lower glucose oscillations, lower risk for hypoglycaemia, decreased microvascular complications, and the possibility to have a more fl exible way of life in relation to diet, schedules and physical activity. The Diabetic Patient and Chronic Kidney Disease

Figure 4. Intensive Therapy.

Breakfast Lunch Dinner Bedtime Breakfast Lunch Dinner Bedtime

Total Total insulin effect insulin effect Insuline Effect

Lispro Lispro Lispro Glargina NPH Lispro NPH 98 Aspart Aspart Aspart Lispro Aspart Lispro Aspart Aspart

Insulin Treatment Guidelines Treatment should be started at 0.2 U/kg of prolonged action insulin per day (approximately 10 U/day) in patients with DM type 2. The patient should be instructed on how to self-adjust the dose which consists of an increase of 2U every 3 days, if the average basal glucose level is greater than 100mg/dl. The prandial dose adjustments are done according to the prepandial glucose level. The total insulin dose is usually 0.4-0.9U/kg. The transition from oral anti-diabetics to insulin can be done in a variety of ways. One possible strategy is to add 10U/day of long-acting insulin to the oral anti-diabetic, adjusting the dose weekly according to the patients self-control.29 If good metabolic control is not achieved with a risk of hypoglycaemia and NPH has been chosen but not glargine or detemir, the required doses should be split into two. In those cases where acceptable basal glucose levels are achieved, but postprandial hyperglycaemia persists, an extra dose of rapid-acting insulin should be added before meals. Rapid-acting insulin can be used 30 minutes before meals or a rapid-acting insulin analogue immediately following meals. This type of insulin should start at 0.1-0.15U/kg. The dose should be increased, according to the established objective, to 1U per day for each Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

50 mg/mL above the glucose level objective or for every 10-15g of carbohydrate intake. An uncommon insulin treatment option is to prescribe an intensive regimen from the beginning.30 Independent of the chosen therapeutic option, the majority of patients with DM require two or more doses of insulin as their illness progresses.

To summarize, diabetic nephropathy is a microvascular 99 complication that some patients with DM develop. Strict control of glucose, blood pressure, lipid profi le, body weight and quitting tobacco can slow the development of renal problems. Insulin has been shown to be the most effi cient tool to control diabetes. Although for DM type 1 it is the only option, in DM type 2 it should be considered patients that meet necessary requirements. There is no universal treatment for type 2 diabetics. In every case the most effi cient method should be used. In general, there is a preference to use oral anti-diabetics at the beginning of treatment. With time the pancreatic beta cells deteriorate which leads to the insuffi ciency of oral anti- diabetics and the necessity to use insulin. The use of an oral anti-diabetic in combination with a single dose of prolonged- action insulin is the simplest therapy. At the moment prolonged-action insulin analogues are preferred over NPH due to their more predictable action profi le and because of a lower hypoglycaemic risk. When the combination of an oral anti-diabetic and a single insulin dose fails, it is necessary to introduce prandial insulin doses before meals. Nowadays it is preferred to use prolonged-action insulin analogues with various doses of quick-action insulin analogues with meals, instead of premixed insulin because of its greater effi ciency and safety. In any case the objective should be to achieve and maintain a good glucose control to slow down the deterioration of renal function and prevent the appearance of other DM complications. The Diabetic Patient and Chronic Kidney Disease

Also in patients with diabetic nephropathy, as the majority of oral anti-diabetics are metabolised and eliminated through the kidney, when GFR is lower than 30mL/min insulin treatment should be started. In these moment diet, exercise and pharmacological treatment can be modiﬁ ed according to the patient’s characteristics, especially their renal function. Insulin doses should be cut in half when creatinine clearance is lower than 10mL/min.

100 Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

Key Points • Optimise glucose and blood pressure control, to reduce the risk and/or slow the progression of nephropathy. • Glycaemic control and monitoring in end-stage renal disease (ESRD) are complex. • The targets of therapy in ESRD are a HbA1c value of less than 7%, a fasting blood glucose level less than 101 140 mg/dl, and a postprandial glucose level less than 200 mg/dl. • ESRD patients need ongoing diabetes education, with an emphasis on how to recognize and treat hypoglycaemia. • In ESRD patients we must insist about lifestyle modiﬁ cations, such as weight loss, reduction of protein, salt, alcohol intake and exercise. • With the onset of overt nephropathy, initiate protein restriction to 0.8g/kg body/day (10% of daily calories) and to 2400 g/day salt intake. Further restrictions may be useful in slowing the decline of glomerular ﬁ ltration range (GFR) in selected patients. • Diabetic pharmacotherapy in ESRD should be individualised. Most diabetes drugs are metabolised and/or excreted at least in part by the kidney, so that patients in ESRD are at greater risk of hypoglycaemia. • Glipizide, GLP-1 analogues and gliptins, pioglitazone and meglitiinides could be used in patients with ESRD in state 3 or 4. The doses of oral diabetes drugs should be lowered in those patients. The Diabetic Patient and Chronic Kidney Disease

• Long-acting insulin (glargine, detemir or NPH) for basal requirements, along with rapid-acting insulin before meals two or three times daily. • The newer basal insulin (glargine or detemir) and rapid- acting insulin analogues (lispro, aspart or glulisina insulin) are more favorable than NPH and regular

102 insulin, but their higher cost could be an issue. • For ESRD patients with type 1 diabetes, insulin therapy should be started at 0.5U/kg, which is half the calculated dose in patients without renal failure. For ESRD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25U/kg. Further adjustments to the regimen should be individualised based on self- monitored blood glucose patterns. • When the GFR drops to between 10 and 50 mL/min, the total insulin dose should be reduced by 25%; once the ﬁ ltration rate is below 10 mL/min, the insulin dose should be decreased by 50% from the previous amount. Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

References

1. Ritz E, Rychlik I, Locatelli F, Halimi S. End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimentions. Am J Kidney Dis 1999; 34:795-808. 2. American diabetes association. Nephropathy in Diabetes. Diabetes Care 2004; 27:579-83. 3. Fagerudd J, Forsblom C, Pettersson-fernholm K, Groop PH. Implementation of Guidelines for the prevention of diabetic nephropathy. Diabetes Care 2004; 27:803-4. 4. Remuzzi G, Schiemppati A, Ruggeneti P. Nephropathy in patients 103 with type 2 diabetes. N Engl J Med 2002; 346:1145-51. 5. Nacional Kidney Foundation- Kidney Disease Outcome and Quality Initiative. Clinical practice guidelines for nutrition in chronic renal failure: K/DOQI National Kidney Foundation. Am J Kidney Dis 2000;35(suppl 1):S1-S140. 6. Bantle JP, Wylie-Rosett J, Albright AL, Apovian CM, Clark NG, Franz MJ, Hoogwerf BJ, Lichtenstein AH, Mayer-Davis E, Mooradian AD, Wheeler ML. Nutrition Recommendations and Interventions for Diabetes-2008. Diabetes Care 2008; 31(Suppl 1):S61-S78. 7. Rigalleau V, Raffaitin C, Gin H, Lasseur C, Chauveau P, Aparicio M, Combe C. The effect of a low-protein diet for diabetic nephropathy is underestimated. Am J Clin Nutr 2009; 89:1277-8. 8. Kopple JD. Do low-protein diets retard the loss of kidney function in patients with diabetic nephropathy?. Am J Clin Nutr 2008; 88:593-4. 9. Executive Summary: Standards of Medical Care in Diabetes-2010. Diabetes Care 2010;33: S4-S10. 10. Lebovitz HE: Oral therapies for diabetic hyperglycaemia. Endocrinol Metab Clin North Am 2001; 30:909-33. 11. Black C, Donnelly P, McIntyre L, Royle PL, Shepherd JP, Thomas S. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007; 18:CD004654. 12. Cheatham WW: Repaglinide: a new oral blood-glucose lowering agent. Clin Diabetes 1998; 16:70-2. 13. Schumacher S, Abbasi I, Weise D, Hatorp V, Sattler K, Sieber J, Hasslacher C: Single – and multiple dose pharmacokinetics of repaglinide in patients with type 2 diabetes and renal impairment. Eur J Clin Pharmacol 2001; 57:147-52. 14. Bailey CJ, Turner RC: Drug therapy: metformin. N Engl J Med 1996; 334:574- 9. The Diabetic Patient and Chronic Kidney Disease

15. McCormack J, Johns K, Tildesley H: Metformin’s contraindications should be contraindicated. JAMC 2005; 173: 502-4. 16. Balfour JA, MacTavish D: Acarbose: an update of its pharmacology and therapeutic use in Diabetes Mellitus. Drugs1993; 46: 1025-54. 17. Charpentier G, Riveline JP, Varroud-Vial M: Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab 2000; 26 (Supl. 4):73-85. 18. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004; 351:1106-18. 19. Budde K, Neumayer HH, Fritsche L, Sulowicz W, Stompor T, Eckland D: Tha pharmacokinetics of pioglitazone in patients with impaired 104 renal function. Br J Clin Pharmacol 2003; 55:368-74. 20. N. R. Robles, R. Alcázar, O. González Albarrán, J. Honorato, J. Acha, F. de Álvaro y cols. Manejo práctico de antidiabéticos orales en pacientes con enfermedad renal. Nefrología 2006; 26:538-58. 21. Monami M, Marchionni N, Mannucci E. Glucagon like peptide 1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol 2009;160:909-17. 22. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; Sitagliptin Study 035 Group. Efﬁ cacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007; 9:733–45. 23. Bergman AJ, Cote J, Yi B, et al. Effect of renal insufﬁ ciency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 2007; 30:1862–4. 24. Rabkin R, Simon NM, Steiner S, Colwell JA. Effects of renal disease on renal uptake and excretion of insulin in man. N Engl J Med 1970; 282:182–7. 25. Pearson JG, Antal EJ, Raehl CL, Gorsch HK, Craig WA, Albert KS, Welling PG: Pharmacokinetic disposition of 14Cglyburide in patients with varying renal function. Clin Pharmacol Ther 1986; 39:318-24. 26. Shrishrimal K, Hart P and Michota F. Managing diabetes in hemodialysis patients: observations and recommendations. Clevelan Clin J Med 2009; 76:49-55. 27. Siebenhofer A, Plank J, Berghold A, Jeitler K, Horvath K, Narath M, et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database Syst Rev 2006; 19: CD003287. 28. Scholtz HE, Pretorius SG, Wessels DH, Becker RHA. Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia 2005; 48:1988–95. Oral Anti-diabetics and Insulin in Patients with Diabetic Nephropathy

29. Ratner RE, Hirsch IB, Neiﬁ ng JL, Garg SK, Mecca TE, Wilson CA. Less hypoglycaemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care 2000; 23:639–43. 30. Chase HP, Dixon B, Pearson J, Fiallo-Scharer R, Walravens P, Klingensmith G, et al. Reduced hypoglycaemic episodes and improved glycaemic control in children with type 1 diabetes using insulin glargine and neutral protamine hagedorn insulin. J Pediatr 2003; 143:737–40. 31. Garg SK, Gottlieb PA, Hisatomi ME, D’Souza A, Walker AJ, Izuora KE, et al. Improved glycaemic control without an increase in severe hypoglycaemic episodes in intensively treated patients with type 1 diabetes receiving morning, evening, or split dose insulin glargine. 105 Diabetes Res Clin Pract 2004; 66:49–56. 32. Ratner RE, Hirsch IB, Neiﬁ ng JL, Garg SK, Mecca TE, Wilson CA. Less hypoglycaemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care 2000; 23:639–43. 33. Yki-Jarvinen H, Dressler A, Ziemen M, for the HOE 901/ 3002 Study Group. Less nocturnal hypoglycaemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000; 23:1130–6. 34. Heise T, Nosek L, Ronn BB, Endahl L, Heinemann L, Kapitza C, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 2004; 53:1614-20. 35. Rosenstock M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetologia 2008; 51:408-16. 36. American Diabetes Association. Insulin administration (Position Statement). Diabetes Care 2002; 25 (Suppl. 1): S112–S115. 37. Sáez de la Fuente J, Granja Berna V, Ferrari Piquero JM, Valero Zanuy MA, Herreros de Tejada López-Coterilla A. Tipos de insulina. Rev Clin Esp 2008; 208:76-86. 38. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26:3080-6. 39. Li Y, Xu W, Liao Z, Yao B, Chen X, Huang Z, et al. Induction of long- term glycaemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function. Diabetes Care 2004; 27:2597-602.

Diabetes Mellitus 107 and Renal Transplantation The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To review the indications of kidney transplantation in diabetic patients • To review the cardiology studies in this group of patients • To understand the fundamental post-transplant care 108 that can improve graft and recipient survival • To know the beneﬁ ts of kidney transplantation

INTRODUCTION Although there are cases described in medical literature of patients with type 2 Diabetes Mellitus (DM) who received a pancreas-kidney transplant, such transplants should be performed primarily in patients with type 1 DM. No benefi ts have been shown conclusively in type 2 DM patients because of the peripheral insulin resistance and pre-existing C-peptide secretion. Renal transplantation alone is indicated in patients with type 2 DM and those with type 1 DM who do not meet criteria for a pancreas-kidney transplant.1 Although graft and patient survival in the long run is lower among diabetics than compared to non-diabetics, renal transplantation is the best treatment due to the improved quality of life and the survival rate in transplant patients compared to those remaining on dialysis. There must be a rigorous study done for all potential renal transplant recipients, due to the high incidence of cardiovascular Diabetes Mellitus and Renal Transplantation complications as well as potential technical diffi culties that may exist for the presence of severe calcifi cations in the iliac territory.

SELECTION AND EVALUATION OF CANDIDATE The major objective of the pre-transplant recipient evaluation is to identify factors which increase the risk of death, graft loss or major morbidity after renal transplantation. The following factors that increase risk must be considered for potential renal transplant recipients: • Increased age: At present, there is no age contraindi- 109 cation • Obesity • Pre-existing cardiovascular disease • Chronic viral infection (hepatitis B or C, HIV) • Gastrointestinal disorders • Chronic pulmonary disease • Previously treated malignancy • Adverse psychosocial factors

The survival of kidney transplant recipients is lower than that of the general population,2 however; patient survival after transplantation is clearly higher than those who remain on dialysis.3 Therefore, it can be stated that kidney transplantation has achieved the landmark of being the best form of therapy for patients with end-stage renal disease. As the population of patients with chronic kidney disease becomes older and the proportion of patients with DM increases,4 thus; compared to patients without DM, recipients with DM contribute disproportionately to morbidity and mortality that may follow renal transplantation.5 The impact of DM on the outcomes of kidney transplantation is very important; compared to non DM, recipients with DM had a signiﬁ cantly increased risk of post- transplant cardiovascular (CV) events, all-cause mortality and The Diabetic Patient and Chronic Kidney Disease

CV mortality.6 The results of different studies strongly suggest the need to study and treat the CV disease in kidney transplant recipients. As is well known, CV disease is the leading cause of death in diabetic end-stage renal disease, probably due to the acceleration of atherosclerosis caused by diabetes itself. In patients with DM, current protocols are needed to prevent the development of CV disease before transplantation, to identify patients at risk and treat patients with CV disease detected. It is also well established that patients with end stage renal disease, and especially those with diabetic nephropathy, have 110 a markedly increased prevalence of coronary artery disease. Some studies have included a coronary angiography as part of the protocol of all potential diabetic kidney and kidney- pancreas transplant recipients. The results have showed that almost half of the patients had signifi cant coronary artery stenosis, and half of those underwent revascularization.7 The main problem is that most patients with coronary stenosis did not have symptoms of myocardial ischemia. This fact makes it very diffi cult to establish protocols for diagnostic and therapeutic approaches. One study showed that 36% had signifi cant coronary disease, but only one fourth of these patients had angina.8 It is very important to identify transplant candidates with signifi cant coronary artery disease. All patients require basic cardiac evaluation including an electrocardiogram, an echocardiogram and a stratifi cation of risk for a cardiovascular event (age, smoking history, ST-T wave changes on electrocardiogram, prior coronary disease, peripheral vascular disease, etc.). A signifi cant percentage of patients require a non-invasive cardiac stress evaluation; an angiography should be performed in selected high-risk patients. Patients who have undergone angioplasty or coronary artery bypass can be accepted if they have adequate left ventricular function without demonstrable ischemia9(Algorithm 1). Diabetes Mellitus and Renal Transplantation Follow-up Negative Stress test** Low risk (<2 factors) cant # fi 111 Positive Normal stenosis Renal Transplant or non signi > 20 years DM Prior CV disease High risk (>2 factors*) Symptoms cant stenosis fi revascularisable Renal Transplant Signi Diabetic renal transplant candidate Angioplasty or Surgery **Dobutamine stress echocardiography or Thallium stress test) **Dobutamine stress echocardiography or YES Coronary Angiography Not a candidate cant stenosis non- dysfunction fi Severe ventricular revascularisable • Signi Algorithm 1: Approach to cardiac evaluation before renal transplantation Algorithm 1: • (*Hypertension, cigarette smoking, left ventricular hypertrophy, dyslipidemia, > 1 year on dialysis, age>60, family CV disease… (*Hypertension, cigarette smoking, left ventricular hypertrophy, The Diabetic Patient and Chronic Kidney Disease

The presence and extent of peripheral vascular calcifi cations are strong predictors of cardiovascular events and cause mortality in end-stage renal disease patients on haemodialysis.10 DM has been noted as a risk factor for valvular calcifi cation, peripheral vascular calcifi cations and coronary artery calcifi - cation in haemodialysis patients. In all diabetics patients it is necessary to do an Angio-Tomography to assess vascular calcifi cation of the aorto-iliac territory. Patients with severe vascular calcifi cations may not be candidates to receive a kidney transplant because of the impossibility to perform the arterial anastomosis (Figure 1). 112

Severe vascular calciﬁ cation

Figure 1: Angio-Tomography showing severe vascular calciﬁ cation. The radiographic examination is essential in all renal transplant candidates with diabetes.

Peripheral vascular disease is evaluated by clinical examination and usually by arterial duplex ultrasound.

SURGICAL PROCEDURE Surgical technique does not differ from that used in other transplants. However, complications and surgical difﬁ culties may be greater due to the usual vascular calciﬁ cation; hence, the importance of an Angio-CT with coronal sections to evaluate the calcium-free zones. Diabetes Mellitus and Renal Transplantation

INMUNOSUPPRESSION Inmunosuppressive therapy does not differ from that used routinely in patients without diabetes. The maintenance inmu- nossuppressant is prednisone, tacrolimus (or less commonly cyclosporine) and mycophenolate mofetil (or rarely azathioprine). However, due to the diabetogenic effect of steroids, these patients might benefi t from their early withdrawal. The introduction of two new anti-IL2 receptor monoclonal antibod- ies (basiliximab and daclizumab) may facilitate combination therapies for early reduction of steroids. A variety of strategies have been used to reduce steroid usage by either low-dose, 113 alternate-day dose, or complete steroid withdrawal regimens. The rationale for minimizing exposure to steroids is based on the need to avoid its well-known side effects: osteoporosis, avascular necrosis, cataracts, weight gain, diabetes, hypertension and dyslipidaemia. Randomised controlled studies have shown that withdrawal of steroids in maintenance therapy may increase the risk of acute rejection and secondarily worsen graft survival.11 Therefore, it is essential to identify those patients who can benefi t from the reduction of immunosuppressive therapy without increasing the immune risk. The mechanisms of action of both cyclosporin and tacrolimus are similar, but tacrolimus is 10 to 100 times more potent than cyclosporin. In the European and American randomised trials comparing tacrolimus and cyclosporin, the overall incidence of hyperglycaemia and DM were higher in the tacrolimus group.12,13 Compared to cyclosporine, tacrolimus reduces the risk of acute rejection and improves graft survival during the fi rst year of transplantation. Low-dose tacrolimus minimises the risk of new-onset diabetes after transplantation compared to higher doses of tacrolimus. Although the diabetogenic effect is less than that of calcineurin inhibitors, the European study demonstrated that sirolimus also had a deleterious effect on glucose metabolism. The Diabetic Patient and Chronic Kidney Disease

In summary, it is necessary to use an immunosuppressive regimen with a good metabolic proﬁ le without increasing the incidence of acute rejection.

POST-TRANSPLANT COMPLICATIONS

Surgical complications Due to the increased incidence of obesity in patients with type 2 DM, there may be more complications in the surgical wound. In addition, transplant patients with DM are an increased risk 114 of soft tissue infections. Sometimes, it is necessary to stop mycophenolate mofetil and replace it with azathioprine. Severe vascular calciﬁ cation may cause lower limb ischemia where the renal transplant is located.

Metabolic complications Obtaining correct metabolic control has been and remains a priority in the clinical management of diabetic patients. However, after performing a kidney transplant metabolic control can worsen. Good metabolic control is essential to reduce CV risk. • Obesity: In kidney transplant recipients, obesity is associated with CV events and mortality. Obesity is also associated with hypertension, dyslipidaemia and diabetes.14 After renal transplantation, there is evidence of signiﬁ cant weight gain in most patients. Diet and increased physical activity may help to sustain weight reduction and reduce CV disease risk. • Dyslipidaemia: The incidence and prevalence of dyslipidaemia is high in diabetic kidney transplant recipients; in large part due to the fact that immunosuppressive agents cause or contribute to dyslipidaemias. The main agents involved in the development are cor- Diabetes Mellitus and Renal Transplantation

ticosteroids, cyclosporine and sirolimus/everolimus. The overall prevalence of dyslipidaemia during the ﬁ rst year after transplantation is higher than 50%.

• Diabetes mellitus: The cumulative incidence of new- onset diabetes after renal transplantation at the end of the fi rst year is around 10-30% of patients on cyclosporine or tacrolimus and corticosteroids.15 The use of these immunosuppressants and the use of high doses of corticosteroids in the treatment of acute rejection signifi cantly worsens glycaemic control in these patients. Tacrolimus and cyclosporine may 115 cause DM by directly decreasing the insulin secretion of pancreatic beta cells. As mentioned previously, the risk of diabetes is higher with tacrolimus than cyclosporine. The choice of immunosuppressive medications should be individualised. Obesity, aging and hepatitis C make glycaemic control diffi cult in this transplant group (Table 1). Poor glycaemic control may increase the risk of metabolic complications, graft failure, CV disease and mortality.16,17 The United Kingdom Prospective Study (UKPDS) and Diabetes Control Complications Trial in the general diabetic population reported that strict glycaemic control reduces the development of microalbuminuria, proteinuria and renal failure (doubling serum creatinine).18,19 However, recent data (ACCORD study) suggests that mortality may be increased in type 2 diabetic patients by targeting HbA1c levels lower than 6%.20 In general, balanced metabolic control is recommended, taking into account the diffi culty in managing diabetes in patients with diabetogenic drugs and macrovascular and microvascular involvement (advanced autonomic neuropathy causing gastroparesis and hypoglycaemic unawareness). The Diabetic Patient and Chronic Kidney Disease

Table 1: Risk factors for worsening of DM

• Tacrolimus • Cyclosporine • Corticosteroids • Sirolimus / Everolimus • Acute Rejection • Obesity • Older Age • Hepatitis C 116 EVOLUTION AND CARE Kidney transplantation is considered the treatment of choice for all patients with renal failure and DM. The risk of death for these recipients is less than half of that for dialysis patients.3 This requires a thorough study of the possible candidate, considering the benefi ts and drawbacks. Renal transplantation leads to a notable improvement of a patient’s general condition, but does not affect metabolic control or prevent the subsequent development of chronic complications associated with diabetes, especially CV events. The frequency of CV events dramatically increase during the peri-transplantation period and remained high throughout the fi rst year after transplantation. The annual rate of fatal or non-fatal CV events is 3.5-5% in kidney transplant recipients; at 36 months after transplantation, nearly 40% of patients have suffered a CV event.21,22 According to American Registry, patient and graft survival is around 95% and 89% in the fi rst year, and 80% and 60% respectively after 5 years. For all these reasons, it is essential that patients have a healthy lifestyle with exercise, proper diet and weight loss as needed. Randomised trials in the general population suggest Diabetes Mellitus and Renal Transplantation that aspirin prophylaxis may prevent CV disease in patients with DM; aspirin (65-100 mg/day) should be used as primary prophylaxis of cardiovascular events in kidney transplants, even though there are no confi rmatory studies.23 Optimal blood pressure control and smoking cessation are necessary, cigarette smoking is an independent risk factor for patient survival, graft survival and CV disease24 (Table 2).

Table 2: Management of diabetic kidney transplants 117 Optimise glycemic control (target HbA1c< 7%) Optimal control of blood pressure - < 130/85 mmHg - < 125/75 mmHg, if proteinuria > 1g/24h

Close monitoring of lipids - LDL < 100 mg/dl - HDL > 45 mg/dl in men; > 55 mg/dl in women - Triglycerides < 150 mg/dl

Monitoring of urinary albumin excretion Smoking cessation Physical exercise Weight control Drugs: Aspirin prophylaxis, blockade of the renin angiotensin system (RAS)*

* Before demonstrating the absence of renal artery stenosis graft The Diabetic Patient and Chronic Kidney Disease

Key Points • Kidney transplantation is considered the treatment of choice in all patients with renal failure and DM. The risk of death for these recipients is less than half for those patients that remain on dialysis. • The medical evaluation prior to transplantation is crucial since many patients have pre-existing cardiac disease and other complications of diabetes. 118 • Cardiovascular evaluation is very important to prevent morbidity and mortality post-transplant. • Inmunosuppressive therapy does not differ from that routinely used in patients without diabetes. However, it is essential to identify those patients who can beneﬁ t from the reduction of immunosuppressive therapy without increasing the immune risk. • Rigorous metabolic control is essential after transplantation. Diabetes Mellitus and Renal Transplantation

References

1. Sampaio MS, Kuo HT, Bunnapradist S. Outcomes of simultaneous pancreas-kidney transplantation in type 2 diabetic recipients. Clin J Am Soc Nephrol 2011; 6: 1198-1206. 2. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998; 32: 853-906. 3. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a ﬁ rst cadaveric transplant. N Engl J Med 1999; 341: 1725-1730. 119 4. 2006 annual data report. Am J Kidney Dis 2006; 49 (Suppl 1): S1-S234. 5. Jardine AG, Fellstrom B, Logan JO, et al. Cardiovascular risk and renal transplantation: Post hoc analyses of the Assessment of Lescol in Renal Transplantation (ALERT) Study. Am J Kidney Dis 2005; 46: 529-536. 6. Cosio FG, Hickson LJ, Grifﬁ n MD, et al. Patient survival and cardiovascular risk after kidney transplantation: The challenge of diabetes. Am J Transplant 2008; 8: 593-599. 7. Witczak BJ, Hartmann A, Jenssen T, et al. Routine coronary angiography in diabetic nephropathy patients before transplantation. Am J Transplant 2006; 6: 2403-2408. 8. Koch M, Gradaus F, Schoebel FC, et al. Relevance of conventional cardiovascular risk factors for the prediction of coronary artery disease in diabetic patients on renal replacement therapy. Nephrol Dial Transplant 1997; 12: 1187-1191. 9. Friedman SE, Palac RT, Zlotnick DM, et al. Clin J Am Soc Nephrol 2011; 6: 1185-1191. 10. Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999; 10: 1606-1615. 11. Pascual J, Quereda C, Zamora J, et al. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: A meta-analysis of randomised, controlled trials. Transplantation 2004; 78: 1548-1556. 12. European FK506 Multicenter Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporine in prevention of liver allograft rejection. Lancet 1994; 344: 423-428. The Diabetic Patient and Chronic Kidney Disease

13. The US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110-1115. 14. Eckel RH, Krauss RM. American Heart Association call to action: obesity as a major risk factor for coronary heart disease. AHA Nutrition Committee. Circulation 1998; 97: 2099-2100. 15. Cosio FG, Pesavento TE, Osei K, et al. Post-transplant diabetes mellitus: Increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int 2001; 59: 732-737. 16. Cosio FG, Pesavento TE, Kim S, et al. Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int 2002; 62: 1440-1446.

120 17. Kasiske BL, Snyder JJ, Gilbertson D, et al. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003; 3: 178-185. 18. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837-853. 19. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993; 329: 977-986. 20. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-2559. 21. Ojo AO. Cardiovascular complications after renal transplantation and their prevention. Transplantation 2006; 82: 603-611. 22. Kasiske BL, Maclean JR, Snyder JJ. Acute myocardial infarction and kidney transplantation. J Am Soc Nephrol 2006; 17: 900-907. 23. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 (Suppl 3): S1-S157. 24. Kasiske BL, Klinger D. Cigarette smoking in renal transplant recipients. J Am Soc Nephrol 2000; 11: 753-759. Diabetes Mellitus and Renal Transplantation

121

Diabetes Mellitus and 123 Pancreas-Renal Transplantation The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To review the indications of pancreas transplantation • To know the main surgical techniques and complications • To understand the fundamental post-transplant care that can improve graft and recipient survival • To know the beneﬁ ts of simultaneous pancreas-kidney transplantation

124

INTRODUCTION The history of pancreas transplantation is intertwined with the evolution of diabetes mellitus treatment. Diabetes is one of the most severe illnesses that exists. Not only does it shorten the survival of those suffering but it also dramatically worsens their quality of life. The ﬁ rst successful pancreas transplant in humans was performed by Kelly and Lillehei on 17 December 1966 in the De- partment of Surgery at the University of Minnesota.1 The initial results were very disappointing with pancreatic survival rate less than 50%. However, further evolution has been very positive. Nearly 80% are simultaneous pancreatic-kidney transplantation (SPK) although today, pancreas transplantation alone (PTA) or pancreas transplantation after kidney transplantation (PAK) is increasingly common. The steady improvement in the outcome of pancreas transplants has been documented by the International Pancreas and Islet Transplant Registry.2 However, pancreatic transplantation is a complex technique that should be reserved for centers with greater experience. Diabetes Mellitus and Pancreas-Renal Transplantation

INDICATIONS FOR PANCREAS TRANSPLANTATION The new immunosuppressant agents will contribute to improve graft survival in patients with SPK, PAK and PTA and increase the rate of transplantation in these patients as well. The indications for SPK are well stratiﬁ ed and are relatively straighforward3 (Table 1). The medical evaluation prior to transplantation is crucial since many arrive with pre-existing cardiac disease and other complications of diabetes, which may substantially increase the

Table 1: Indications for pancreas transplantation (adapted from American Diabetes Association3)

Indications for pancreas transplantation 125 Simultaneous kidney and pancreas transplant (SPK) - Endstage renal disease or near endstage renal disease with type 1 diabetes with other diabetic complications. - Prior kidney transplant which is failing in a type 1 diabetic. *Pancreas graft survival is better when done simultaneously with a kidney transplant Pancreas after kidney transplant (PAK) - Prior to kidney transplant in type 1 diabetic with other diabetic complications. Pancreas transplant alone (PTA) - History of frequent acute severe metabolic complications - Clinical and emotional problems with insulin therapy - Consistent failure of insulin-based management to prevent acute complications. risk of graft loss and death. The medical evaluation for the potential SPK transplant candidate is similar to that of the kidney transplant alone, although the cardiac workup is more extensive. The best candidates for transplantation are younger than 50 years of age and have a limited number of major complications of type 1 diabetes with advanced renal failure or end- stage renal disease (ESRD). Additional complications such The Diabetic Patient and Chronic Kidney Disease

as vascular disease and severe gastroparesis put patients at higher risk of post-transplant complications, but none of them exclude a patient from transplantation. All potential candidates must undergo a cardiovascular evaluation as well as the risk of coronary heart disease. The correct selection of donor and recipient is the fundamental factor that inﬂ uences survival. The major objective of the pre-transplant recipient evaluation is to identify factors which increase the risk of death, graft loss or major morbidity after SPK transplantation (Table 2). Cardiovascular disease is the leading cause of death in diabetic ESRD patients. There is no consensus on what the best cardiovascular assessment of a possible candidate for SPK transplantation, because the prevalence of silent ischemia 126 and cardiomyophathy is high. All patients require noninvasive cardiac stress evaluation; angiography should be performed in selected high-risk patients. Patients who have undergone angioplasty or coronary artery bypass can be accepted if they have adequate left ventricular function without demonstrable ischemia. Peripheral vascular disease is evaluated by clinical

Table 2: Contraindications to a simultaneous pancreas-kidney transplantation

Absolute contraindications Severe cardiac disease - Recent myocardial infarction - Cardiomyopathy with low ejection fraction - Angiography indicating non-correctable artery disease Severe peripheral vascular disease - Aortoiliac disease without possibility of surgical correction Cerebral vascular disease Intestinal ischemia Malignancy (recently diagnosis, metastatic and untreatable) Age over 60 years Active infection Major psychiatric illness Ongoing drug or alcohol abuse Diabetes Mellitus and Pancreas-Renal Transplantation examination and usually by arterial duplex ultrasonography. In general, the pancreatic transplant candidate should undergo a thorough pre-transplant study (Table 3).

SURGICAL PROCEDURE Pancreatic transplantation is a solid organ transplant with a

Table 3: Evaluation of the pancreas transplant candidate

History and physical examination by nephrologist, endocrinologist and transplant surgeon. Psychological evaluation (when indicated) - Ophthalmology evaluation - Dental evaluation - Gynecology consultation for all females 127 Cardiovascular evaluation - Doppler arterial studies (carotid and lower limb) - Echocardiography, exercise treadmill, stress thallium. Angiography (according to results and background) - Aortoiliac scanner Genitourinary evaluation - Cystourethrogram and urodynamics study - Prostate study over 40 years Evaluation of neuropathy - Electromyography and gastric emptying scan (gastroparesis) Serology and immunology studies Laboratory tests Mammography in females over 35 years high incidence of surgical complications. However, in experienced centers, these complications have been decreasing progressively with a consequent improvement in graft and recipient survival. Several factors including donor management and selection, organ procurement and preservation, and advances in immunosuppressive medications have resulted The Diabetic Patient and Chronic Kidney Disease

in these improved outcomes. In addition to these factors, the refi nements in surgical techniques and prophylactic measure shows have also contributed to this improvement in results.4 The various surgical techniques can be classifi ed according to the type of exocrine drainage performed. The usual practice is to transplant the whole pancreas with a cuff of duodenum, which provides a means to drain exocrine secretions into either the small bowel or the bladder. From 2000 to present, the majority of the transplants were enterically drained. • Bladder drainage (BD): This drainage was initially used for its technical simplicity and because it allows monitoring for rejection by measurement of urinary 128 amylase and also avoids enterotomy-associated risks of infection and leaks. Although, very rarely, it also allows renal biopsy. The main disadvantages of BD include no physiological drainage with high susceptibility to dehydration, metabolic acidosis, refl ux pancreatitis and frequent urologic complications (hematuria, cysti- tis, urethritis, urinary tract infection). • Enteric drainage (ED): This drainage allows physiological drainage of exocrine pancreatic secretion, thus avoiding urologic complications. ED with a Roux-en-Y loop has a higher risk of an anastomotic leak. Almost invariably anastomotic leaks are complicated with serious intra-abdominal infection. The pancreatic graft is placed in the right iliac fossa, intraperitoneally, while the renal graft is then placed in the left iliac fossa. The preferred method of venous drainage remains controversial: • Systemic venous (SV): It is the most widely used method (above 90% of centers). SV is an established surgical technique that is associated with excellent long-term results.5 The SV drainage involves the anastomosis of the donor portal vein to the recipient iliac (common or external) vein o vena cava. Anastomosis is preferred Diabetes Mellitus and Pancreas-Renal Transplantation

CAVA VEIN

PORTAL VEIN

Figure 1: Porto-caval anastomosis (Courtesy of Dr. Manrique). to the vena cava as we have seen a dramatically reduction of pancreatic graft thrombis6 (Figure 1). 129 • Portal venous (PV): PV drainage is a more physiological method that eliminates hyperinsulinaemia. The technique involves the portal vein anastomosis with the superior mesenteric vein. • Arterial reconstruction: In the majority of cases, a donor Y-iliac artery extension graft is used to join the superior mesenteric and splenic arteries on the pancreas. Arterial reconstruction with the donor Y graft is anastomosed to the iliac artery (usually common) (Figure 2).

INMUNOSSUPPRESION Most centers use quadruple therapy with antibody induction during the fi rst week (thymoglobulin currently). The maintenance inmunossuppresion is prednisone, tacrolimus (or less commonly cyclosporine) and mycophenolate mofetil (or rarely azathioprine). The incidence of acute rejection with the quadruple therapy decreased signifi cantly (36% vs 76%, p< 0,01) but there was an increase of cytomegalovirus infection.7 Our center uses azathioprine during the fi rst month post-transplant The Diabetic Patient and Chronic Kidney Disease

PORTAL VEIN

ILIAC GRAFT

Figure 2: Arterial reconstruction, donor Y-iliac artery extension graft is used to join the superior mesenteric and splenic arteries on the pancreas (Courtesy of Dr. Manrique). 130 due to the decrease in the incidence of anastomotic leaks with this immunosuppressive therapy. The use of tacrolimus has improved the survival of pancreatic graft (vs. cyclosporine), without imposing a factor for a worse glycemic control (diabetogenic).8

POST-TRANSPLANT COMPLICATIONS SPK recipients may fall victim to severe post-transplant complications in the early recovery period. Meticulous care is required to treat and prevent potential complications. Thrombosis Early pancreatic allograft thrombosis (ﬁ rst week) is the most feared complication since it often assumes graft loss. This problem occurred in up to 5 to 10% of recipients. This is clinically manifested by a sudden rise in serum glucose usually associated with pain over the graft area. Venous thrombosis is more frequent than arterial thrombosis. If this occurs, surgical intervention is indicated to attempt a thrombectomy but the most common is the graft excision. Anticoagulation Diabetes Mellitus and Pancreas-Renal Transplantation therapy and/or antiplatelet agents are used by many centers to reduce the incidence of pancreatic graft thrombosis. As discussed above, in Hospital Doce de Octubre in Madrid, Spain, the portocava venous bypass has reduced the incidence of thrombosis.

Infections The antimicrobial prophylaxis is very important in this type of transplant. Trimethoprim-sulfamethoxazole is used during the fi rst 6-9 months to prevent Pneumocystis infections; fl uconazole is using during 40 days for prophylaxis of intra- abdominal fungal infections and oral valgancyclovir is given for 3 months following transplantation to all patients to prevent cytomegalovirus infection. Also, prophylaxis for bacterial 131 infection was performed for 40 days, usually with ciprofl oxacin. The occurrence of intra-abdominal infection is an extremely serious complication that reduces signifi cantly both patient and graft survival. Pancreatitis, anastomotic leaks and graft necrosis have all been associated with the development of intra-abdominal infections.

Pancreatitis The diagnosis is based on the presence of hyperamylasae- mia in combination with severe abdominal pain and distension. The confi rmatory diagnosis is made by ultrasonography or CT scan showing radiological evidence of pancreatic oedema and infl ammation. It is more common in patients with BD, urinary retention causing refl ux pancreatitis. Placement or Foley catheter and use of octreotide can usually achieve the cure. However, sometimes, enteric conversion of the graft is needed for recurrent refl ux pancreatitis. In patients with ED it is often more serious because it is complicated by intra- abdominal infections requiring treatment with octeotride and parenteral nutrition.10 It is necessary to make a correct differ- ential diagnosis between acute rejection and pancreatitis. The Diabetic Patient and Chronic Kidney Disease

Anastomotic leak Anastomotic leak is a highly morbid complication of pancreas transplantation. The incidence of duodenal leak is 10-12% in patients with BD and around 5% in ED.11 The clinical presentation is severe abdominal pain and distension as well as fever in about half of the cases. In BD, elevated creatinine in the drained ﬂ uid is suggestive of the diagnosis; in ED, the presence of high amylase or the increase in the drained ﬂ uid is suspected leak. The CT scan with bladder contrast establishes the diagnosis in most cases. Anastomotic leak from BD could be treated conservatively with placement of Foley catheter; if the clinical course is poor is decided to perform a enteric conversion. The patients with ED can be rarely managed with 132 conservative measures and exploratory laparotomy is needed to repair the leak and usually the duodenoenterostomy.

IMPACT ON DIABETIC COMPLICATIONS Pancreas transplantation is performed to eliminate the need for exogenous insulin, avoid acute metabolic complications (hypoglycaemia, hyperglycaemia with ketoacidosis) and try to improve the microvascular and macrovascular disease. A diabetic patient, after a successful pancreas transplantation, has blood glucose and glycosilated hemoglobin in normal range without needing insulin or dietary restrictions. Adequate metabolic control can prevent the development of vascular complications. On the other hand, some studies have shown a lower cardiovascular mortality in patients who receive a simultaneous pancreas-kidney transplantation compared to those receiving a kidney transplant alone.12

Retinopathy There is no hard evidence that successful pancreas transplantation and normalization of metabolic stage has a beneﬁ cial effect on diabetic retinopathy after 5 years of follow-up. Only Diabetes Mellitus and Pancreas-Renal Transplantation in a prospective fundoscopic study of SPK recipients over 45 months was there a decreased need for post-transplant laser therapy and the diabetic retinopathy showed stabilization in 62%.13

Nephropathy Fioretto et al. published the fi rst study in diabetic patients who received pancreas transplant alone. They studied renal function and performed renal biopsies before pancreas transplantation and 5 and 10 years later in eight patients with type 1 diabetes but without uremia who had mild to advanced lesions of diabetic nephropathy at the time of transplantation. They demonstrated statistically signifi cant improvements in different histological parameter when kidney biopsies were performed 133 10 years post-transplantation. These observations established for the fi rst time that pancreas transplantation could improve chronic lesions of diabetic nephropathy.14

Neuropathy Sensory-motor polyneuropathy usually improves quickly after pancreas transplantation. Recovery is more complete in sensory than in motor nerves.15 Improvement in autonomic reactivity and stabilization or improvement in gastric emptying is noted in SPK compared to kidney transplant alone in diabetic patients.

Macrovascular disease There are few studies that examine the beneﬁ ts of successful pancreas transplantation on macrovascular disease. Studies show a worsening of the coronary heart disease or in progression of peripheral vascular disease.16 On the other hand, Fiorina et al. has reported beneﬁ cial effects of pancreas transplantation. These patients showed a lower atherosclerotic risk and normalization of endothelial dysfunction.17 The Diabetic Patient and Chronic Kidney Disease

Quality of life In general terms, SPK recipients with well-functioning allografts report an increased global quality of life and frequently return to work. The success of SPK is insulin-independence.

ISLET TRANSPLANTATION At present, the results are not very encouraging. Further studies are required to recommend their use.

134 Diabetes Mellitus and Pancreas-Renal Transplantation

Key Points • The best candidates for simultaneous pancreas-kidney transplantation are younger than 50 and have a limited number of major complications of type 1 diabetes with advanced renal failure or end-stage renal disease (ESRD).

• The medical evaluation prior to transplantation is crucial since many patients arrive with pre-existing cardiac disease and other complications of diabetes.

• All potential candidates must undergo a cardiovascu- 135 lar evaluation as well as the risk of coronary heart disease.

• The correct selection of donor and recipient is the fundamental factor that inﬂ uences survival.

• Early pancreatic allograft thrombosis (ﬁ rst week) is the most feared complication since it is often assumed graft loss.

• The antimicrobial prophylaxis is very important in this type of transplant.

• Pancreas transplantation is performed to eliminate the need for exogenous insulin, avoid acute metabolic complications and try to improve the microvascular and macrovascular disease. The Diabetic Patient and Chronic Kidney Disease

References 1. Kelly W, Lillehei R, Merkel F, et al. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery 1967; 61: 827-837. 2. Gruessner DC, Sutherland DE. Pancreas trasnplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant 2005; 19: 433-455. 3. American Diabetes Association. Pancreas transplantation for patients with type 1 diabetes. Diabetes Care 2003; 26: S120. 4. Humar A, Kandaswamy R, Granger D, et al. Decreased surgical risks of pancreas transplantation in the modern era. Ann Surg 2000; 231: 269-275. 5. Sollinger HW, Odorico JS, Knechtle SJ, et al. Experience with 500 136 simultaneous pancreas-kidney transplants. Ann Surg 1998; 228: 284-296. 6. Jiménez C, Manrique A, Herrero ML, et al. Incidence of páncreas graft thrombosis in portoiliac and portocaval venous anastomosis. Transplant Proc 2005; 37: 3977-3978. 7. Cantarovich D, Karam G, Giral-Classe M, et al. Randomized comparison of triple therapy and antithymocyte globulin induction treatment after simultaneous pancreas-kidney transplantation. Kidney Int 1998; 54: 1351-1356. 8. Waki K, Terasaki PI, Kadowaki T. Long-term pancreas allograf survival in simultaneous pancreas-kidney transplantation by era: UNOS registry analysis. Diabetes Care 2010; 33: 1789-1791. 9. Muthusamy AS, Giangrande PL, Friend PJ. Pancreas allograft thrombosis. Transplantation 2010; 90: 705-707. 10. Jiménez C, Manrique A, Morales JM, et al. Conversion from bladder drainage to enteric drainage for complications after pancreas transplantation. Transplant Proc 2009; 41: 2469-2471. 11. Pirsch JD, Odorico JS, D´Alessandro AM, et al. Post-transplant infection in enteric versus bladder-drained simultaneous pancreas- kidney transplant recipients. Transplantation 1998; 66: 1746-1750. 12. Smets YFC, Westendorp RGJ, Van Der Pjil JW, et al. Effect of simultaneous páncreas-kidney transplantation on mortality of patients with type-1 diabetes mellitus and end stage renal failure. Lancet 1999; 353: 1915-1919. Diabetes Mellitus and Pancreas-Renal Transplantation

13. Koznarova R, Saudek F, Sosna T, et al. Beneﬁ cial effect of pancreas and kidney transplantation on advanced diabetic retinopathy. Cell Transplant 2000; 9: 903-908. 14. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339: 69-75. 15. Allen RD, Al Harbi IS, Morris JG, et al. Diabetic neuropathy after pancreas transplantation: Determinans of recovery. Transplantation 1997; 63: 630-638. 16. Biesenbach G, Margreiter R, Konigsrainer A, et al. Comparison of progression of macrovascular diseases after kidney or pancreas and kidney transplantation in diabetic patients with end-stage renal disease. Diabetologia 2000; 43: 231-234. 17. Fiorina PLRE, Massimo V, Minicucci F, et al. Effects of kidney –pancreas transplantation on atherosclerotic risk factors and endothelial dysfunction in IDDM uremic patients. Diabetes 2000; 49: A30. 137 SECTION II CARING FOR DIABETICS WITH CHRONIC KIDNEY DISEASE Assessment of Glycaemic Control in the Dialysis 139 Population The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To understand the importance of controlling diabetes in dialysis patients • To understand that HbA1c is a sensitive parameter in the general population, but is not very speciﬁ c, as a diabetes marker

INTRODUCTION The American Drug Administration (ADA) and the European 140 Association for the Study of Diabetes (EASD) propose the use of HbA1c as the preferred diagnostic test for diabetes. They suggest that HbA1c >7% is strongly correlated with increased mortality.2 Moreover, K/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease say that “Target HbA1c for people with diabetes should be <7.0%, irrespective of the presence or absence of CKD.”6 Lowering HbA1c to below or around 7% has been shown to reduce microvascular and neuropathic complications of diabetes, and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease.6 However, a long evaluation of patients from a large national dialysis organization resulted in a higher mortality rate in those with lower HbA1c levels, which seems to have been related to malnutrition.7 Furthermore, multiple studies have recently reported that HbA1c may not provide a relevant assay for glycaemic control in haemodialysis patients. Assessment of Glycaemic Control in the Dialysis Population

Metabolic parameters accepted as efﬁ cient for diabetes detection and control: • Fasting plasma glucose- FPG-Fasting is deﬁ ned as no caloric intake for at least 8 hours • Glycated haemoglobin - haemoglobin A1c, HbA1c, A1c. • Glycated proteins.

1. Diabetes Diagnosis For decades, the diagnosis of diabetes was based on plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-h value in the 75g oral glucose tolerance test (OGTT). In 2009, an International Expert Committee that included representatives of the ADA, the International Diabetes Federation (IDF), and the EASD recommended the use of the 141 HbA1c test to diagnose diabetes, with a threshold of ≥6.5%1, and ADA adopted this criterion in 2010.2 ADA recommendations for diagnosis include: • HbA1c ≥6.5%, FPG ≥126mg/dl (7.0mmol/l). • Post-Prandial 2-h plasma glucose ≥200mg/dl (11.1 mmol/l) during an OGTT.2

2. Assessment of Glycaemic Control Two primary techniques are available for health providers and patients to assess the effectiveness of the management plan for gylcaemic control: patient self-monitoring of blood glucose (SMBG) or interstitial glucose, and HbA1c. Tight control means getting as close to a normal (non-diabetic) blood glucose level as you safely can. Ideally, this means levels between 70 and 130 mg/dl before meals, and less than 180mg/dl two hours after starting a meal, with a HbA1C level less than 7%. The Diabetic Patient and Chronic Kidney Disease <180 mg/dL (<10.0 mmol/L) <180 mg/dL glucose should not exceed <140mg/dl (<7.8mmol/l) as long as hypoglycaemia is avoided Peak Post-prandial glucose (1-2 hours after beginning a meal)

142 70–130mg/dl (3.9–7.2mmol/l) (FPG fasting plasma glucose no caloric intake for at least 8 h) glucose <100 mg/dl (<5.5mmol/l) post-meal plasma Two-hour Pre-prandial capillary ed and standardized to Twice per year in stable patients Twice who achieved goals Quarterly after change in treatment or if goal not achieved HbA1C <7.0 % (non-pregnant adults) The test should be performed in a laboratory using a method that is certi ﬁ NGSP assay the DCCT • • <7.0 % Individual approach <6.5%

2 2 3 International Diabetes Federation (IDF) European Association for the Study of Diabetes (EASD) American Diabetes Association (ADA) Assessment of Glycaemic Control in the Dialysis Population

2.1 Self-monitoring of blood glucose (SMBG) SMBG should be done three or more times daily for patients using multiple insulin injections or insulin pump therapy.2 Continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens can be a useful tool to lower HbA1c in selected adults (age ≥25 years) with type 1 diabetes. CGM may be a supplemental tool to SMBG for those with hypoglycaemia unawareness and/or frequent hypoglycaemic episodes.2

2.2 Haemoglobin A1c – (HbA1c / A1c) The percent HbA1c of glycated haemoglobin provides an estimation of blood glucose levels over a three to four month 143 period. Typically, HbA1c is measured via high performance liquid chromatography and immunoassay. Glycated haemoglobin has became the basis for evaluating long-term glycaemic management as both a screening and diagnostic tool, and appears to be on the brink of ofﬁ cial recognition as the preferred diagnostic test for diagnosing diabetes.4 The ADA published a new term in diabetes management, estimated average glucose, or eAG, derived from HbA1c. The relationship between HbA1c and eAG is described by the formula5,6:

28.7 X A1c – 46.7 = eAG The Diabetic Patient and Chronic Kidney Disease

HbA1c eAG % mg/dl mmol/l 6 126 7.0 6.5 140 7.8 7 154 8.6 7.5 169 9.4 8 183 10.1 8.5 197 10.9 9 212 11.8 9.5 226 12.6 10 240 13.4

A calculator for converting HbA1c results into estimated 144 average glucose (eAG), in either mg/dl or mmol/l, is available on the ADA website.5

HbA1c in Dialysis patients can have important variations:

1. The uraemic environment, blood loss during dialysis and frequent blood sampling contribute to the decreased life span of erythrocytes in those on haemodialysis. 2. The HbA1c is also lower due to the reduced red blood cell survival, red blood cell transfusions and erythropoietin treatments in those on haemodialysis. 3. The HbA1c levels are also theoretically suppressed by the resulting anaemia associated with the shorter life span of erythrocytes. These factors establish the argument that HbA1c underestimates glycaemic control in haemodialysis patients and that HbA1c is not a reliable test. Therefore, one should not use HbA1c as a guideline in patients with diabetes and renal disease who are on dialysis.8-10 Assessment of Glycaemic Control in the Dialysis Population

Table 1. Factors inﬂ uence HbA1c and its measurement10: 1. Erythropoiesis • Increased HbA1c: iron, vitamin B12 deﬁ ciency, decreased erythropoiesis. • Decreased HbA1c: administration of erythropoietin, iron, vitamin B12, reticulocytosis, chronic liver disease.

2. Altered Haemoglobin - Genetic or chemical alterations in haemoglobin may increase or decrease HbA1c.

3. Glycation • Increased HbA1c: alcoholism, chronic renal failure, decreased intra-erythrocyte pH. • Decreased HbA1c: aspirin, vitamin C and E, certain haemoglobinopathies, increased intra-erythrocyte pH.

4. Erythrocyte destruction • Increased HbA1c: increased erythrocyte life span after Splenectomy. • Decreased A1c: decreased erythrocyte life span: 145 haemoglobinopathies, splenomegaly, rheumatoid arthritis or drugs such as antiretrovirals, ribavirin and dapsone.

5. Assays • Increased HbA1c: hyperbilirubinemia, carbamylated haemoglobin, alcoholism, large doses of aspirin, chronic opiate use. • Decreased HbA1c: Hypertriglyceridemia • Variable HbA1c: haemoglobinopathies. HbA1c levels are underestimated in haemodialysis patients, especially in correlation with low haematocrit and those treated with higher doses of erythropoietin. One study recommended a more accurate means to estimate glycaemia control9:

Haematocrit is ≥30% HbA1c x 1.14

Haematocrit is <30% and treated with low dosages HbA1c x 1.19 of erythropoietin Haematocrit is <30% and treated with high dosing HbA1c x 1.38 of erythropoietin The Diabetic Patient and Chronic Kidney Disease

Serum Glycated Albumin (GA) It was previously suggested that HbA1c may not be a reliable measure of glycaemic control in dialysis patients. Also, many proteins other than haemoglobin undergo non-enzymatic glycation, leading to formation of products that play a role in the development of diabetic vascular complications. Therefore, serum glycated albumin (GA) and fructosamine are now under investigation, and researchers have hypothesized it to be an alternative marker for glycaemic control in patients with diabetes, including those with ESRD.8 HbA1c and albumin-corrected fructosamine (AlbF) levels were highly correlated and both were signifi cantly associated with serum glucose. AlbF, however, was more highly correlated with mean glucose values, when less than 150 mg/dl, and were a more useful predictor of morbidity. AlbF, but not HbA1c, was a 146 signifi cant predictor of hospitalization.8 The advantage of fructosamine and glycated albumin is that their levels are not affected by haemoglobin. They refl ect estimated glucose over a shorter period (2-3 weeks). However, GA and fructosamine are not readily available in most clinical laboratories. There are not many reference levels, and can be affected by conditions that alter protein metabolism such as proteinuria, dysproteinemia, malnutrition, thyroid abnormalities and liver disease. In this case, GA and fructosamine values must be adjusted to albumin concentration.11 Assessment of Glycaemic Control in the Dialysis Population

Key Points • HbA1c alone is not a deﬁ nitive parameter when diagnosing diabetes.

• An HbA1c >7% is correlated to higher risk of mortality.

• Lowering HbA1c to <7% reduces microvascular and neuropathic complications.

• HbA1c levels are underestimated in haemodialysis patients especially in correlation with low haematocrit.

147 The Diabetic Patient and Chronic Kidney Disease

References

1. The International Expert Committee. International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes. Diabetes Care 2009 July;32( 7):1327-1334.

2. Standards of Medical Care in Diabetes—2011. American Diabetes Association. Diabetes Care 2011 January; 34(S1).

3. Guideline for Management of Post-meal Glucose. International Diabetes Federation, 2007 (www.idf.org)

4. Mitka M. Hemoglobin A1c poised to become preferred test for diagnosing diabetes. JAMA 2009 Apr 15;301(15):1528.

5. http://professional.diabetes.org/glucosecalculator.aspx

6. KDOQI Clinical Practice Guidelines and Clinical Practice Recommen- dations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007 Feb:49( 2), Suppl 2. 148 7. Kalantar-Zadeh K, Kopple JD, Regidor DL, Jing J, Shinaberger CS, Aronovitz J, McAllister CJ, Whellan D, Sharma K. A1C and survival in maintenance hemodialysis patients. Diabetes Care 2007 May;30(5):1049-55.

8. Mittman N, Desiraju B, Fazil I, Kapupara H, Chattopadhyay J, Jani CM, Avram MM. Serum fructosamine versus glycosylated hemoglobin as an index of glycemic control, hospitalization, and infection in diabetic hemodialysis patients. Kidney Int Suppl. 2010 Aug;(117):S41-5.

9. Uzu T, Hatta T, Deji N, Izumiya T, Ueda H, Miyazawa I, Kanasaki M, Isshiki K, Nishio T, Arimura T. Target for glycemic control in type 2 diabetic patients on hemodialysis: effects of anemia and erythropoietin injection on hemoglobin A(1c). Ther Apher Dial 2009 Apr;13(2):89-94.

10. Gallagher EJ, Le Roith D, Bloomgarden Z. Review of hemoglobin A(1c) in the management of diabetes. J Diabetes 2009 Mar;1(1):9-17.

11. Kovesdy CP, Sharma K, Kalantar-Zadeh K. Glycemic control in diabetic CKD patients: where do we stand? Am J Kidney Dis 2008 Oct;52(4):766-77. Assessment of Glycaemic Control in the Dialysis Population

149

Chronic Complications in Diabetic Patients

151 The Diabetic Patient and Chronic Kidney Disease

1.- Diabetic foot.

Diabetic foot deﬁ nition1 The foot of a diabetic patient that has the potential risk of pathologic consequences, including infection, ulceration, and/or destruction of deep tissues associated with neurologic abnormalities, various degrees of peripheral vascular disease, and/or metabolic complications of diabetes in the lower limb. (Based upon the World Health Organization [WHO] deﬁ nition.)

Charcot Foot deﬁ nition1 Arthropathy, osteoarthropathy, neuroarthropathy: Noninfectious destruction of bone and joint associated with neuropathy.

Gangrene deﬁ nition1 The death or necrosis of a part of the body secondary to injury, infection, and/or lack of blood supply. This indicates irreversible damage where healing cannot be anticipated without loss of some part of the extremity.

152 Neuropathy deﬁ nition1 Nerve dysfunction affecting sensory, motor, and/or autonomic ﬁ bers with varying degrees of impairment, symptoms, and signs. Diabetic peripheral neuropathy is the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes.

Ulceration (Ulcer) deﬁ nition1 A partial- or full-thickness defect in the skin that may extend to subcuticular tissue, tendon, muscle, bone, or joint. Chronic Complications in Diabetic Patients

Risk factors (Interna onal Working Group on the Diabe c Foot)7 − Group 0 - no evidence of neuropathy − Group 1 - neuropathy present but no evidence of foot deformity or peripheral vascular disease − Group 2 - neuropathy with evidence of deformity or peripheral vascular disease − Group 3 - history of foot ulceration or lower extremity amputation

Key components of the diabe c foot exam 1 Vascular Examina on Dermatologic Examina on − Palpa on of pulses (dorsalis pedis, − Skin appearance: posterior bial, popliteal, femoral) • Color, texture, turgor, quality − Subpapillary venous plexus ﬁ lling me • Dry skin (normal ≤3 seconds) − Calluses: Discolora on/subcallus − Venous ﬁ lling me (normal ≤20 seconds) haemorrhage − Color changes: − Fissures (especially posterior heels) − • Cyanosis Nail appearance: • • Onychomycosis, dystrophic Dependent rubor • • Erythema Atrophy • Hypertrophy − Presence of oedema • Paronychia − Temperature gradient • Presence of hair − Dermal thermometry − Ulcera on, gangrene, infec on (Note − Integumentary changes consistent with loca on, size, depth, infec on status, etc.) ischemia: − Interdigital lesions • Skin atrophy − Tinea pedis • Nail atrophy − Markers of diabetes: • Abnormal wrinkling • Skin spots — diabe c dermopathy • Diminished pedal hair • Necrobiosis lipoidica diabe corum • Bullosum diabe corum • Granuloma annulare 153

Musculoskeletal Examina on Neurologic Examina on − Biomechanical abnormali es: − Vibra on percep on: • Orthopedic deformi es • Tuning fork 128 cps • Hammertoes • Measurement of vibra on • Bunion(s) or Tailor’s bunion(s) percep on threshold • Flat or high-arched feet (Biothesiometer) • Charcot deformi es − Light pressure: Semmes–Weinstein 10-gram • Iatrogenic deformi es (e.g., monoﬁ lament amputa ons) − Light touch: co on wool • Limited joint mobility • Tendo-Achilles contractures/ − Two-point discrimina on equinus − Pain: pinprick − Gait evalua on − Temperature percep on: hot and cold − Muscle group strength tes ng: − Deep tendon reﬂ exes: ankle, knee • Passive and ac ve, − Clonus tes ng nonweightbearing and − Babinski test weightbearing • Foot drop − Rhomberg’s test • Atrophy — intrinsic muscle atrophy − Plantar pressure assessment: • Computerized devices • Harris ink mat

Footwear Examina on − Type of shoe − Lining wear − Fit − Foreign bodies − Shoewear, pa erns of wear − Insoles, orthoses The Diabetic Patient and Chronic Kidney Disease

“Figure 1. - Screening form for diabetes foot disease. Adapted from NIDKK diabetic foot screening form.

154

Chronic Complications in Diabetic Patients

Vascular and neurologic examination of the lower extremity 1,4,7-9 Evaluation Parameters Normal Values Vascular • Palpation of pulses Present • Dependent rubor Absent • Venous ﬁ lling time <20 s • Capillary reﬁ ll <3 s • Arterial Doppler exam for ankle-brachial index (ABI) 1.1 • Toe pressures >40 mm Hg • Transcutaneous oxygen tension (TcPO2) >40 mm Hg

Neurologic • Semmes-Weinstein 5.07 monoﬁ lament (10 g) Detected • Biothesiometer (vibration perception threshold) <25 V • Vibration perception — 128 cps tuning fork Detected • Deep tendon reﬂ exes Present

Modifi ed Wagner Classifi cation System 1,10-12 Grade Lesion 0 No open lesions: may have deformity or cellulitis A Ischemic B Infected 1 Superfi cial ulcer A Ischemic B Infected 2 Deep ulcer to tendon, or joint capsule A Ischemic B Infected 155 3 Deep ulcer with abscess, osteomyelitis, or joint sepsis A Ischemic B Infected 4 Localized gangrene — forefoot or heel A Ischemic B Infected 5 Gangrene of entire foot A Ischemic B Infected

University of Texas Wound Classiﬁ cation System1,13-14 Stage Grade 0 I II III

Pre- or Superﬁ cial wound, Wound Post-ulcerative Wound not involving penetrating to A lesion penetrating tendon, capsule, bone or joint completely to tendon or bone or capsule epithelialized

B Infected Infected Infected Infected C Ischemic Ischemic Ischemic Ischemic

Infected and Infected and Infected and Infected and D ischemic ischemic ischemic ischemic The Diabetic Patient and Chronic Kidney Disease

Charcot pathogenesis1,15,16

Long-standing NEUROPATHY Neuropathic diabetes disease

Injury, Ligamentous sprain laxity joint Infection or fracture instability

Painless ambulation

Joint degeneration and subluxation

Ulcer ACUTE Continued Infection CHARCOT FOOT weightbearing

156 Figure 2.- Sanders/Frykberg Classiﬁ cation of Diabetic Neuropathic Osteoarthropathy. (From Sanders L.J., Frykberg, R.G. Diabetic neuropathic osteoarthropathy: the Charcot foot. In: The High Risk Foot in Diabetes Mellitus, p. 297 (edited by R.G. Frykberg, Churchill Livingstone, New York, 1991))1. Chronic Complications in Diabetic Patients

Diabetic Foot Disorders CHARCOT FOOT: A Clinical Practice Pathway1

HISTORY • Onset of Changes ◦ Progressive / Static ◦ Erythema ◦ Swelling • Trauma - Type, When, Repetitive? • Pain / Sensation • Previous Ulcer and/or Charcot • Arthropathy • Diabetes Duration / Control

See infection pathway EXAMINATION See ulcer pathway • Dermatologic ◦ Erythema, Warmth, Cellulitis/Ulcer • Musculoskeletal ◦ Swelling, Deformation, “Rockerbottom” • Neurologic ◦ Degree of Neuropathy Assessed by Semmes- Weinstein Fiber, Vibratory, Proprioception Va sc ular • Vascular ◦ Pulses, Swelling

• Plain X-Ray • Site(s) Involved • Osteolysis, Fractures, Dislocation • Soft-Tissue Oedema • Medial Arterial Calciﬁ cation

ADDITIONAL DIAGNOSTIC 157 PROCEDURES AS INDICATED • Imaging Studies ◦ CT Scan ◦ MRI ◦ Bone Scan - e.g., Leukocyte Scan • Serologic Tests ◦ CBC with Differentials ◦ ESR ◦ Blood Glucose ◦ HbA1c ◦ Bone Biopsy and Culture ACUTE CHRONIC TREATMENT

• Absolute Restriction on Foot Unstable Weightbearing Refer to Podiatrist for Orthopedic or Foot Stable ◦ Crutches Molded Foot Wear, Bracing, Insoles Refer to Podiatrist for Supportive ◦ Wheelchair Measures, Patient Education, Timely • Immobilization of Foot Re-Evaluations to Prevent Recurrence ◦ Splint, cast, removable cast until hyperaemia resolved ◦ 4-6 months until quiescence (Chronic) Foot unstable, not responsive to special foot wear or prostheses If ulcer occurs see ulcer pathway refer for podiatric surgery and/or refer for podiatric surgery consult Once quiescent treat as chronic

Foot Stable The Diabetic Patient and Chronic Kidney Disease

Diabetic Foot Disorders CHARCOT FOOT: A Clinical Practice Pathway1

Diabetic Foot Disorders Ulcer

See infection Pathaway Noninfected

HISTORY ◦ Duration ◦ Prior ulcer ◦ Pain/Sensation ◦ Prior treatment ◦ Vascular history

GENERAL FOOT EXAM CLINICAL SENSORY Ulcer examination Probe to bone See infection Vascular EXAM Neurologic Semmes-Weinstein Filament Ulcer size/depth Structural deformity Gangrene present Amputation likely Vibratory (measurement) Propioperception Other as needed Pulses (+) Location Non-weigthbearing, Pulses (-) weigthbearing, bony Intact deformity No further studies Noninvasive exam indicated Ulcer appearance Doppler PVR Granulation tissue, Segmental, TcPO2 necrotic, ﬁ brotic 158 and toe pressures Impaired tissue EMG, NCS, Normal other studies indicated Ulcer periphery prn Undermining, Abnormal hyperkeratosis, erythema

Vascular consult

Positive for Consider X-ray Negative for osteomyelitis See infection osteomyelitis pathway Consider further imaging, bone scan, MRI, leukocyte scan

WOUND CARE Debridement, drainage, +/- cultures from TREATMENT AS Immobilization of Foot base of ulcer, dressings, topical Rx: e.g. APPROPIATE Casts, braces, surgical growth factors (becaplermin) shoes, wheelchair, crutches, etc.

Healed Not Healed

Follow-up and frequent re-evaluation Repeat evaluation and treatment to prevent recurrence, patient as necessary education

Consider Surgical Not Healed Healed Correction of Deformity Chronic Complications in Diabetic Patients

Infec on: A Clinical Prac ce Pathway16

Diabetic foot disorders: INFECTION

History ◦ Trauma, puncture wound, foreign body ◦ Fever, chills, nausea, malaise ◦ Ulcer duration? ◦ Drainage, swelling, erythema ◦ Pain / sensation ◦ Diabetes duration / control

Examination

LIMB-THREATENING INFECTION NON-LIMB-THREATENING INFECTION ◦ >2 cm cellulitis ◦ Lymphangitis ◦ ≤ 2 cm cellulitis ◦ Superfi cial ulcer ◦ Oedema ◦ Does not probe to bone ◦ Fever +/- ◦ No bone, joint involvement ◦ Odour from wound ◦ Mild infection ◦ Deep ulcer ◦ No systemic toxicity ◦ Purulent drainage ◦ No signifi cant ischemia ◦ Hypotension, cardiac arrhythmia (systemic toxicity) ◦ Ischemic changes DIAGNOSTIC PROCEDURES • Cultures from base of ulcer/wound ◦ (tissue specimen If possible) DIAGNOSTIC PROCEDURES • Diagnostic imaging • Deep cultures from base of ulcer / ◦ x-ray, mri, nuclear scans as indicated wound (tissue specimen if possible) • Serologic testing • Diagnostic imaging ◦ CBC with differentials ◦ - x-ray, mri, nuclear / bone / leukocyte ◦ ESR scans, arteriography ◦ Blood glucose 159 • Serologic testing ◦ C BC with differentials ◦ Renal profi le ◦ Blood cultures ◦ ESR TREATMENT ◦ Blood glucose ◦ Renal and hepatic profi le as • Debridement of all necrotic tissue and callus appropriate • Appropriate off-loading • Oral temperature • Wound care / dressing • Empiric antibiotic coverage, modifi ed by culture fi ndings TREATMENT • Outpatient management, with follow-up in 24-72 hours • Hospital admission • Surgical debridement by podiatric surgeon, with • Wound care continued - e.g., pack, dressings, resection of all necrotic soft tissue and bone • Debridement as needed • Exploration and drainage of deep abscess • Hospital admission if infection progresses or systemic • Wound packing and wound care signs / symptoms develop • Empiric antibiotic coverage, modifi ed as per • If infection improves but ulcer remains - see ulcer clinical Pathway • Response and/or culture fi ndings • Refer to podiatrist for follow-up care, patient education, • Long-term antibiotics as necessary, pending • Special shoes and prostheses as needed degree of resolution after debridement/resection • Surgical resection of osteomyelitis • Continued wound care, debridement as needed • If infection improves but ulcer remains - see ulcer pathway • Refer to podiatrist for follow-up care, patient education, special shoes and prostheses as needed • Foot-sparing reconstructive procedures The Diabetic Patient and Chronic Kidney Disease ow fl MACROVASCULAR -Atherosclerosis -Ischaemia 1-5 ow fl Vascular Disease Vascular AMPUTATION Reduced nutrient capillary blood MICROVASCULAR -Structural: Capilary BM thickening -Functional: Increased blood Neuropathic oedema

160 Trauma DIABETES MELLITUS DIABETIC FOOT ULCERATION DIABETIC FOOT Impaired response to infection ow AUTONOMIC -Anhydrosis -Dry skin -Fisures -Decreased sympathetic tone (altered blood ﬂ regulation) Contributing factors in the pathogenesis of ulceration AMPUTATION SENSORY -Loss of protective sensation Neuropathy Osteoarthropathy MOTOR -Weakness arthropy -Deformity -Abnormal stress -High plantar pressure -Callus formation Chronic Complications in Diabetic Patients

Assessment objectives for foot ulcerations 1,5,12

Classiﬁ cation Grade, depth, site, clinical descriptors of wound

Aetiology Mechanical, thermal, chemical trauma

Vibration perception, light touch (10g monoﬁ lament), Neuropathy deep tendon reﬂ exes

Vascular Pulses, ankle-brachial index, toe pressures, TcPO2

Infection Cultures, radiographs, probe, scans, MRI

Deformity/High Pressure Callus, hammertoes, bunion, Charcot, amputation

Ulcer Treatment Guidelines1

• Debridement of necrotic tissue: surgical, mechanical, autolytic, enzymatic

• Pressure reduction: crutches, healing sandal, contact cast, walking brace, foot cast, felt aperture padding, etc.

• Wound care: topical saline gauze dressings, antiseptics, special dressings, growth 161 factors (becaplermin), bioengineered tissues, HBO, etc.

• Infection: incision and drainage, empiric and culture directed antibiotics, soft tissue/ bone/joint resection, amputations

• Vascular: pedal or proximal bypass, endovascular procedures

• Medical management: hyperglycaemia, hypertension, nutritional status, renal status

• Reduce the risk of recurrence: − Regular podiatric care and evaluation − Patient preventative education − Protective footwear − Pressure reduction − Surgery to reduce bony prominence / chronic pressure points The Diabetic Patient and Chronic Kidney Disease

Diabetic foot prevention program1 1. Podiatric Care Regular visits, examinations, and footcare. Risk assessment. Early detection and aggressive treatment of new lesions.

2. Protective Shoes Adequate room to protect from injury; well cushioned walking sneakers, extra depth, custom-molded shoes special modiﬁ cations as necessary.

3. Pressure Reduction Cushioned insoles, custom orthoses, padded hosiery, pressure measurements — computerized or Harris mat. 4. Prophylactic Correct structural deformities — hammertoes, bunions, Charcot. Surgery Prevent recurrent ulcers over deformities. Intervene at opportune time.

5. Preventive Patient education — need for daily inspection and necessity for early Education intervention. Physician education — signiﬁ cance of foot lesions, importance of regular foot examination, and current concepts of diabetic foot management.

Patient education and routine foot care 17-20 Diabetic foot ulcers are extremely preventable if the patient and carers are aware of the risks and take good care of the feet. Eighty percent of ulcers are caused by trauma, often unnoticed due to neuropathy. Patients should be encouraged to: • Wear comfortable, supportive footwear • Avoid walking ‘barefoot’ 162 • Wash the feet once a day in warm (not hot) soapy water • Check for problems every day and report any ﬁ ssuring or other loss of skin integrity • If the skin is dry, use a regular emollient to reduce risk of ﬁ ssuring • Never fail to remove a foreign body from the shoe immediately after it is noticed • Do not warm the feet using hot water bottles or by direct contact with a radiator • Never attempt to ‘self-manage’ callosities using sharp paring instruments • Do not apply adherent dressings such as corn plasters to the feet

2.- Diabetic retinopathy

Diabetic retinopathy

Diabetic retinopathy is largely a microvascular complication, involving disease in the small vessels particularly of the basement membrane. Damage to these vessels results in increased permeability and leakage of blood or plasma into the extravascular space, with secondary thickening of the basement membrane. Disruption of the blood supply causes localised tissue hypoxia, triggering release of vascular growth factors. It is these that promote the proliferation of new vessels during the later stages in both the retina and vitreous humour. Vascular insufﬁ ciency due to atheroma of the larger vessels supplying the eye, or micro-emboli from carotid artery disease may further reduce tissue perfusion and oxygenation. Exudation and haemorrhage lead to ﬁ brosis, further damaging visual function and predisposing to retinal detachment. Chronic Complications in Diabetic Patients

Retinopathy screening and treatment: ADA recommendations 21

General recommendations ● To reduce the risk or slow the progression of retinopathy, optimize glycaemic control. ● To reduce the risk or slow the progression of retinopathy, optimize blood pressure control.

Screening ● Adults and children aged 10 years or older with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes. ● Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist shortly after the diagnosis of diabetes. ● Subsequent examinations for type 1 and type 2 diabetic patients should be repeated annually by an ophthalmologist or optometrist. Less frequent exams (every 2–3 years) may be considered following one or more normal eye exams. Examinations will be required more frequently if retinopathy is progressing. ● High-quality fundus photographs can detect most clinically signiﬁ cant diabetic retinopathy. Interpretation of the images should be performed by a trained eye care provider. While retinal photography may serve as a screening tool for retinopathy, it is not a substitute for a comprehensive eye exam, which should be performed at least initially and at intervals thereafter as recommended by an eye care professional. ● Women with preexisting diabetes who are planning pregnancy or who have become pregnant should have a comprehensive eye examination and be counseled on the risk of development and/or progression of diabetic retinopathy. Eye examination should occur in the ﬁ rst trimester with close follow-up throughout pregnancy and for 1 year postpartum.

Treatment ● Promptly refer patients with any level of macular oedema, severe NPDR, or any PDR 163 to an ophthalmologist who is knowledgeable and experienced in the management and treatment of diabetic retinopathy. ● Laser photocoagulation therapy is indicated to reduce the risk of vision loss in patients with high-risk PDR, clinically signiﬁ cant macular oedema, and in some cases of severe NPDR. ● The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection, as this therapy does not increase the risk of retinal hemorrhage. The Diabetic Patient and Chronic Kidney Disease

References

1. Frykberg RG, Armstrong DG, Giurini J, Edwards A, Kravette M, Kravitz S et al. Diabetic foot disorders. A Clinical Practice Guideline. American College of Foot and Ankle Surgeons. Brooklandville (USA): Data Trace Publishing; 2000. 2. Reiber, G.E., Vileikyte, L., Boyko, E.J., Del Aguila, M., Smith, D.G., Lavery, L.A., Boulton, A.J.M. Causal pathways for incident lower- extremity ulcers in patients with diabetes from two settings. Diabetes Care 22:157–162, 1999. 3. Boulton, A.J., Meneses, P., Ennis, W.J. Diabetic foot ulcers. a framework for prevention and care. Wound Rep. Reg. 7:7–17, 1999. 4. International Working Group on the Diabetic Foot. International Consensus on the Diabetic Foot, Amsterdam, The Netherlands, 1999. 5. Frykberg, R.G. Diabetic foot ulcerations. The High Risk Foot in Diabetes Mellitus, p. 151, edited by R.G. Frykberg, Churchill Livingstone, New York, 1991. 6. Apelqvist, J, Bakker, K, Van Houtum, WH, et al. International Consensus on the Diabetic Foot. The International Working Group 164 on the Diabetic Foot. Amsterdam, The Netherlands, John Wiley & Sons. 1999; p67. 7. McNeely, M.J., Boyko, E., Ahroni, J.H. The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration: How great are the risks? Diabetes Care 18:216–219, 1995. 8. Pecoraro, R.E., Ahroni, J., Boyko, E.J. Stensel, V.L. Chronology and determinants of tissue repair in diabetic lower-extremity ulcers. Diabetes 40:1305–1313, 1991. 9. Kalani, M., Brismar, K., Fagrell, B., Ostergren, J., Jorneskog, G. Transcutaneous oxygen tension and toe blood pressure as predictors for outcme of diabetic foot ulcers. Diabetes Care 22:147–151, 1999. 10. Wagner, W.F. The dysvascular foot: a system for diagnosis and treatment. Foot Ankle 2:62–122, 1981. 11. Young, M.J. Classiﬁ cation of ulcers and its relevance to management. The Foot in Diabetes, 3rd ed., pp. 61–72, edited by A.J.M. Boulton, H. Connor, P.R. Cavanagh, John Wiley & Sons, Chichester, UK, 2000. 12. Frykberg, R.G. Diabetic foot ulcers: current concepts. J. Foot Ankle Surg. 37:440–446, 1998. Chronic Complications in Diabetic Patients

13. Lavery, L.A., Armstrong, D.G., Harkless, L.B. Classiﬁ cation of diabetic foot wounds. Foot Ankle Surg. 35:528–531, 1996. 14. Armstrong, D.G., Lavery, L.A., Harkless, L.B. Validation of a diabetic wound classiﬁ cation system; the contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 21:855–859, 1998. 15. Sanders, L.J., Frykberg, R.G. Diabetic neuropathic osteoarthropathy. The Charcot foot. The High Risk Foot in Diabetes Mellitus, p. 297, edited by R.G. Frykberg, Churchill Livingstone, New York, 1991. 16. Frykberg, R.G., Kozak, G.P. Neuropathic arthropathy in the diabetic foot. Am. Fam. Phys. 17:105, 1978. 17. McCulloch D. Evaluation of the diabetic foot. In: UpToDate, Mulder JE (Ed), UpToDate, Post TW, 2010. 18. Litzelman, DK, Marriott, DJ, Vinicor, F. The role of footwear in the prevention of foot lesions in patients with NIDDM. Conventional wisdom or evidence-based practice? Diabetes Care 1997; 20:156. 19. Uccioli, L, Faglia, E, Monticone, G, et al. Manufactured shoes in the prevention of diabetic foot ulcers. Diabetes Care 1995; 18:1376. 20. Lavery, LA, Vela, SA, Fleischli, JG, et al. Reducing plantar pressure in the neuropathic foot. A comparison of footwear. Diabetes Care 1997; 20:1706. 21. American Diabetes Association. Standards of Medical Care in Diabe- 165 tes 2010. Diabetes Care 2010;33(Suppl 1):S11-S61.

Acute Complications in Diabetic Patients

167 The Diabetic Patient and Chronic Kidney Disease

1.Hypoglycaemia

Deﬁ nition 1 Plasma glucose less than 70 mg/dl in diabetic patients and less than 50mg/l in non-diabetic patients. It is the most frequent complication in diabetic patients with pharmacological therapy.

Types 1 Hypoglycaemia grade I or mild: mild adrenergic clinical signs: - Sweating - Tremors - Restlessness - Pale skin - Tachycardia - Anxiety - Hunger - Nausea

Hypoglycaemia grade II or moderate: important adrenergic and / or neuroglycopenic clinical signs: - Sweating - Acute Tremors - Disorientation 168 - Change of behavior - Difﬁ culty concentrating - Confusion - Weakness - Drowsiness - Changes in vision - Difﬁ culty speaking - Headache - Dizziness

Hypoglycaemia grade III or severe: Plasma glucose level is usually less than 50 mg/dl. Serious neuroglycopenic clinical signs: - Confusion - Seizures - Decreased level of consciousness

Pseudohypoglycaemia: Symptoms of hypoglycaemia with normal levels of blood glucose. It usually ocurrs in people with chronic hyperglycaemia due to inadequate control of blood glucose levels. Acute Complications in Diabetic Patients

Hypoglycaemia Clinical Pathway2

169

Patient should have his scheduled meal or snack. If the patient is needs more than 1 hour for lunch, administer 15 g carbohydrate and protein source. After stablizing the patient, teach patient and family about: The Diabetic Patient and Chronic Kidney Disease

Hypoglycaemia in CKD patients3

Frequent or persistent hypoglycaemia in diabetic dialysis patients is often due to severe underdialysis with poor caloric intake or hidden disease, such as infection or malignancy. Frequent adjustment of insulin dose and evaluation of blood glucose diaries are essential in this setting as is the provision of an adequate dialysis dose. Drugs that interfere with the counter-regulatory response to hypoglycaemia (such as beta blockers) and long-acting insulin and oral hypoglycaemic agents should be discontinued, if possible, until more stable glycaemic control is achieved.

2.- Diabetic ketoacidosis and hyperosmolar hyperglycaemic state

Deﬁ nition 4-8

Diabetic ketoacidosis (DKA) is characterized by the triad of hyperglycaemia, anion gap metabolic acidosis, and ketonemia. Metabolic acidosis is often the major ﬁ nding. The serum glucose concentration is usually greater 170 than 500mg/dL (27.8mmol/L) and less than 800mg/dL (44.4mmol/L). How- ever, serum glucose concentrations may exceed 900mg/dL (50mmol/L) in patients with DKA who are comatose. In certain circumstances, such as DKA in of starvation or pregnancy, or treatment with insulin prior to arrival to the emergency department, the glucose may be only mildly elevated.

Hyperosmolar hyperglycaemic state (HHS), there is little or no ketoacid accumulation, the serum glucose concentration frequently exceeds 1000 mg/dL (56mmol/L), the plasma osmolality may reach 380mosmol/kg, and neurologic abnormalities are frequently present (including coma in 25 to 50 percent of cases). Most patients with HHS have an acceptable pH >7.30, a serum bicarbonate >20 meq/L, a serum glucose >600 mg/dL (33.3 mmol/L), and test negative for ketones in serum and urine, although mild ketonamia may be present. Acute Complications in Diabetic Patients 4-8 >18 HHS >600 >7.30 >12 Variable >250 >12 >10 Mild Moderated Severe Alert Alert/drowsy Stupor/coma Stupor/coma >250 >250 15-18 10 to <15 <10 PositivePositive Positive Positive Positive Positive Small Small Variable Variable Variable >320 7.25-7.30 7.00-7.24 <7.00

171 DKA Δ Table 1.- Diagnostic criteria for diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS) Table Urine ketones* Serum ketones* Effective serum osmolality (mOsm/kg)• Anion gap Alteration in sensorial or mental obtundation Serum bicarbonate (mEq/L) Arterial pH Plasma glucose (mg/dL) Calculation: (Na+) - (Cl- + HCO3-) (mEq/L). See text for details. * Nitroprusside reaction method. • Calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18. Δ Association American Diabetes Copyright © 2006 Protocol for the management of adult patients with DKA4,6,8

% %

is resolved.

% Acute Complications in Diabetic Patients

DKA management in adults 4-8 Clinical features

• DKA usually evolves rapidly over a 24-hour period. • Common, early signs of ketoacidosis include nausea, vomiting, abdominal pain, and hyperventilation. The earliest symptoms of marked hyperglycaemia are polyuria, polydipsia, and weight loss. • As hyperglycaemia worsens, neurological symptoms appear, and may progress to include lethargy, focal deﬁ cits, obtundation, seizure, and coma. • Common causes of DKA include: infection; noncompliance, inappropriate adjustment, or cessation of insulin; new onset diabetes mellitus; and myocardial ischemia.

Evaluation and laboratory ﬁ ndings

• Assess vital signs, cardiorespiratory status, and mental status. • Assess volume status: vital signs, skin turgor, mucosa, urine output. • Obtain the following studies: serum glucose, urinalysis and urine ketones, serum electrolytes, BUN and creatinine, plasma osmolality, mixed venous blood gas, electrocardiogram; add serum ketones if urine ketones present. • Diabetic ketoacidosis (DKA) is characterized by hyperglycaemia, an elevated anion gap metabolic acidosis, and ketonemia. Dehydration 173 and potassium deﬁ cits are often severe. • Serum glucose is usually greater than 250mg/dL (13.9mmol/L) and less than 800mg/dL (44.4mmol/L). In certain instances (eg, insulin given prior to ED arrival), the glucose may be only mildly elevated. • Additional testing is obtained based on clinical circumstances and may include: blood or urine cultures, lipase, chest x-ray.

Management

• Stabilize the patient’s airway, breathing, and circulation. • Use a large bore IV (≥16 gauge) access; monitor patient using a cardiac monitor, capnography, and pulse oximetry. • Monitor serum glucose hourly, and basic electrolytes, plasma osmolality, and venous pH every two to four hours until the patient is stable. • Determine and treat any underlying cause of DKA (eg, pneumonia or urinary infection, myocardial ischemia). The Diabetic Patient and Chronic Kidney Disease

DKA management in adults 4-8 Management Replete fl uid defi cits: • Give several liters of isotonic (0.9%) saline as rapidly as possible to patients with signs of shock. • Give isotonic saline at 15 to 20mL/kg per hour, in the absence of cardiac compromise, for the fi rst few hours to hypovolemic patients without shock. • After intravascular volume is restored, give one-half isotonic (0.45%) saline at 4 to 14mL/kg per hour if the corrected serum sodium is normal or elevated; isotonic saline is continued if the corrected serum sodium is reduced. • Add dextrose to the saline solution when the serum glucose reaches 200mg/dL (11.1mmol/L).

Replete potassium (K+) defi cits: • Regardless of the initial measured serum potassium, patients with DKA have a large total body potassium defi cit. • If initial serum K+ is below 3.3mEq/L, hold insulin and give K+ 20 to 30 mEq/hour IV until K+ concentration is above 3.3mEq/L. • If initial serum K+ is between 3.3 and 5.3mEq/L, give K+ 20 to 30mEq per liter IV fl uid; maintain K+ between 4 to 5 mEq/L. • If initial serum K+ is above 5.3mEq/L do not give K+; check K+ every 2 174 hours. Give insulin: • Do not give insulin if initial serum K+ is below 3.3mEq/L; replete K+ fi rst. • Give all patients with K+ below 3.3mEq/L regular insulin.Either of two regimens can be used: 0.1units/kg IV bolus, then start a continuous IV infusion 0.1units/kg per hour; OR do not give bolus and start a continuous IV infusion at a rate of 0.14units/kg per hour. • Continue insulin infusion until ketoacidosis is resolved, serum glucose is below 200 mg/dL (11.1 mmol/L), and subcutaneous insulin is begun.

Give sodium bicarbonate to patients with pH below 7.00: • If the arterial pH is between 6.90 and 7.00, give 50mEq of sodium bicarbonate plus 10mEq of potassium chloride in 200mL of sterile water over two hours. • If the arterial pH<6.9, give 100mEq of sodium bicarbonate plus 20mEq of potassium chloride in 400mL sterile water over two hours. Protocol for the management of adult patients with HHS4,6,8 The Diabetic Patient and Chronic Kidney Disease

DKA and HHS in CKD patients3,9,10 • Severe hyperglycaemia with serum glucose concentrations occasionally greater than 1000mg/dL (55mmol/L) may be observed amongst dialysis patients with diabetes. Unlike those without renal failure, however, hypovolemia and marked hypernatremia do not occur since glucosuria is absent in anuric individuals. The net effect is minimal symptoms, even among those with extreme hyperglycaemia. However, these patients may have marked hyperkalemia due to potassium fl ux from cells in response to extracellular fl uid hypertonicity. Patients with type 1 diabetes may also develop diabetic ketoacidosis. • Instead of fl uid replacement, management is principally dependent upon the administration of low doses of intravenous insulin (commonly beginning at a dose of 2 units/hour). As with nondialysis patients with severe hyperglycaemia and diabetic ketoacidosis, serum glucose and potassium concentrations must be closely monitored.

Hypoglycaemia and Hyperglycaemia in CKD patients3,11 • These patients often have gastroparesis, which complicates the timing of insulin injections. Gastric emptying studies will conﬁ rm the diagnosis, which can often be effectively treated with metoclopramide, or bethanechol (urecholine). Improvement in 176 glycaemic control may also improve gastric motility. Cisapride, previously used for gastric emptying disorders, is now restricted per the manufacturer’s and Federal Drug Administration’s recommendations due to the risk of arrhythmias. As of August 2000, prescriptions for the drug can only be ﬁ lled directly through the manufacturer after providing documentation as to need for the drug and assessment of risk factors for cardiac arrhythmias in the individual patient (including a prolonged QTc on the EKG or use of medications known to alter the drug’s metabolism such as macrolide antibiotics, antifungals and phenothiazines). Cisapride is no longer listed in the Physicians Drug Reference (PDR) and is technically removed from the market. • Other causes of brittle blood glucose include patient misunderstanding of the timing of insulin injections, poor compliance with dietary restrictions and insulin therapy, erratic eating habits, and poor timing of CAPD exchanges. These problems can often be corrected with patient reeducation. Noncompliance, impaired vision, and a depressive illness should also be investigated. Acute Complications in Diabetic Patients

Key Points • Hypoglycaemia is the most frequent complication in diabetic patients; it is deﬁ ned as plasma glucose less than 70mg/dl. • Signs and symptoms of hypoglycaemia can also be evident with higher blood glucose levels when the person is accustomed to increased basal levels of glucose and a sharp decrease is induced. • Signs and symptoms of hypoglycaemia are produced by the adrenergic response and neuroglycopenia, highlighting fatigue, tachycardia, sweating, confusion and behavior changes in severe cases. • There are three different types of hypoglycaemia: mild, moderate and severe. To reverse it, administer a rapidly absorbed carbohydrate by the rule of 15mg every 15

minutes. 177 • Both, diabetic ketoacidosis and hyperosmolar hyperglycaemic states are caused by an insulin deﬁ ciency and incomplete metabolism of fat and protein as a secondary process whilst the body attempts to obtain needed energy. • Both are characterized by severe hyperglycaemia, with diabetic ketoacidosis being the most common in type 1 diabetes and hyperosmolar hyperglycaemic state the most common in type 2 diabetes. For both cases treatment will be aimed at controlling blood glucose levels and treating the triggers. The Diabetic Patient and Chronic Kidney Disease

• In CKD patients different parameters need to be considered and evaluated before acute complications of diabetes can be treated, these are: deﬁ ning CKD stage, residual diuresis, electrolytes imbalance, other medications and dialysis treatment.

178 Acute Complications in Diabetic Patients

References

1. Childs BP, Clark NG, Cox DJ, Cryer PE, Davis SN, Dinardo et al. Deﬁ ning and reporting hypoglycaemia in diabetes: a report from the American Diabetes Association Workgrup on Hypoglycaemia. Diabetes Care 2005; 28(5): 1245-9. 2. Servicio Andaluz de Salud. Protocolos de urgencias y emergencias más frecuentes en el adulto. Junta de Andalucia; Sevilla 1999. 3. Berns JS. Management of hyperglycaemia in diabetics with end-stage renal disease. In: UpToDate, Rose, BD (Ed), UpToDate, Post TW, 2010. 4. Kitabchi AE, Rose BD. Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycaemic state in adults. In: UpToDate, Rose, BD (Ed), UpToDate, Mulder JE, 2010. 5. Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York, 2001, pp. 809-815. 6. Kitabchi, AE, Umpierrez, GE, Murphy, MB, Kreisberg, RA. Hyperglycaemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006; 29:2739. 7. Kitabchi, AE, Umpierrez, GE, Fisher, JN, et al. Thirty years of personal experience in hyperglycaemic crises: diabetic ketoacidosis and hyperglycaemic hyperosmolar state. J Clin Endocrinol Metab 2008; 93:1541. 179 8. Kitabchi, AE, Umpierrez, GE, Miles, JM, Fisher, JN. Hyperglycaemic crises in adult patients with diabetes. Diabetes Care 2009; 32:1335. 9. Mak, RH. Impact of end-stage renal disease and dialysis on glycaemic control. Semin Dial 2000; 13:4. 10. Montoliu, J, Revert, L. Lethal hyperkalemia associated with severe hyperglycaemia in diabetic patients with renal failure. Am J Kidney Dis 1985; 5:47. 11. Daniels, ID, Markell, MS. Blood glucose control in diabetics: II. Semin Dial 1993; 6:394.

Haemodialysis and the Diabetic Patient

181 The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To gain an understanding of the impact of haemodialysis on diabetes • To gain insight into the complications of diabetes and the effect on the diabetic haemodialysis patient

INTRODUCTION Diabetic renal patients form the largest group of patients starting haemodialysis, probably fuelled by the global epidemic of type 2 diabetes. 40% of diabetic patients with renal disease undergo haemodialysis as their renal replacement therapy.1 Haemodialysis provides unique challenges for diabetic patients: • Diabetes control 182 • Mortality • Complications of diabetes

Diabetic control Patients are known to have extremes of hyper and hypoglycaemia caused by:

• Reduction of blood glucose due to diffusion during dialysis therapy. • Removal of hypoglycaemic medications by the dialysis process. Haemodialysis and the Diabetic Patient

• Altered pharmacological response to hypoglycaemics as a result of uraemia and possible vitamin D abnormalities.

Patients frequently have a gradual reduction of blood glucose during haemodialysis, followed by post haemodialysis hypoglycaemia (due to removal of hypoglycaemic medication during the haemodialysis treatment). In addition, many patients have lost the ability to determine these swings in glycaemic control, resulting in a marked impact on mortality.

Hyperglycaemic agents Diabetes becomes harder to control in the context of renal failure as the medications available to manage diabetes become more limited due to the altered pharmacological excretion of these drugs. Metformin is avoided due to the risk of developing lactic acidosis, particularly if creatinine clearance is less than 30mLs/min. Other medications are used with caution, and often at reduced dosages due to reduction in clearance related to a reduced glomerular ﬁ ltration rate. Insulin regimens should be tailored to haemodialysis therapy, using newer insulin regimens. One innovation in therapy is to have separate insulin regimens for haemodialysis days 183 and non-haemodialysis days; with reduced insulin being administered on the haemodialysis day to avoid complicating the hypoglycaemic effects of haemodialysis therapy. To detect variations in diabetic control, patients should have regular assessments of blood glucose level during the haemodialysis process. This, however, will not detect hypoglycaemia experienced outside of the haemodialysis setting. Continuous glucose monitoring devices have shown real beneﬁ ts in diabetic haemodialysis,2,3 particularly in detecting those patients who experience post haemodialysis hypoglycaemia. The Diabetic Patient and Chronic Kidney Disease

Transition phase There should be frequent evaluation and adjustment of hypoglycaemic therapy when a patient commences haemodialysis: commencement of renal replacement therapy is frequently associated with a rapid decline in glomerular ﬁ ltration rate, further exacerbating insulin resistance and reducing renal gluconeogenesis (renal synthesis of glucose) combined with the effect of a new haemodialysis treatment altering glycaemic control. Self-management and education are paramount in enabling patients to manage the variability of their glucose levels.

Dietary input Patients are advised to eat little and more often to enable optimal diabetic control.4 Dietary intake on haemodialysis days can be effected by: • Access to food whilst traveling to and from dialysis and waiting for transport • Substandard of nutritional input during dialysis therapy

184 • Post haemodialysis lethargy

Exercise Exercise is an important aspect of glycaemic control, with its glucose burning properties, and is being actively encouraged during haemodialysis, with many units offering structured exercise programmes.

Mortality Many patients undergoing renal replacement therapy with diabetes exhibit co-morbidities (particularly cardiovascular) Haemodialysis and the Diabetic Patient and the presence of these contribute to the high mortality rate (20%). The risk is felt to be higher in females with type 2 diabetes.5 Diabetic patients often have a higher risk of long term poor health due to: • Cardiovascular disease • Peripheral vascular disease – especially affecting the blood supply to the feet • Micro-vascular disease – especially affecting the blood supply to the eye • Neuropathy – particularly affecting sensation in the feet • Delayed healing and increased risk of infection in wounds

These are well known complications of diabetes, but have been found to be more prevalent in the haemodialysis diabetic population. The nature of diabetic renal failure itself makes these patients more prone to complications as their diabetes may have been poorly controlled leading to diabetic nephropathy; and renal failure and the dialysis processes lead to poorly controlled diabetes exacerbating the risk of complications. 185 Cardiovascular complications amongst diabetic renal patients are understandably common: • Blood vessel damage • Impaired left ventricular compliance • Loss of autonomic regulation • High susceptibility to over-hydration in the intra-dialytic interval Patients who develop hypoglycaemia related to dialysis, are also more likely to develop intra-dialysis hypotension, and vice versa.6 High frequency intra-dialytic hypotension makes it more The Diabetic Patient and Chronic Kidney Disease

difﬁ cult to reach the target dry weight of patients, ultimately leading to worsened blood pressure control, and therefore further antihypertensive therapy. Antihypertensive therapy prior to haemodialysis sessions frequently exacerbates intra- dialytic hypotension. Poor glycaemic control is strongly associated with sudden cardiac death, increased cardiac events and increased mortality,7 and is a signiﬁ cant predictor of the emergence of cardiovascular disease in diabetic haemodialysis patients,8 causing a higher burden of micro-vascular complications.9

Diabetic complications & Haemodialysis Diabetes can create issues related to haemodialysis treatment itself: • Vascular access problems – vascular disease makes long term vascular access harder to achieve • Increased intra-dialytic weights gain, related to thirst caused by hyperglycaemia • Increased instability during haemodialysis treatments due to: 186 1. The affect of neuropathy on the autonomic nervous system10 2. Hypoglycaemia6 3. Cardiovascular instability

Duration of therapy Avoiding of intra-dialytic hypotension may be achieved with longer dialysis sessions with lower ultraﬁ ltration rates,11 which may enable target dry weight to be achieved. The DOPPS12 study showed that treatment times longer than 240 minutes were associated with a lower risk of all-cause mortality Haemodialysis and the Diabetic Patient compared with standard treatment. Short daily dialysis and nocturnal dialysis are both associated with improved mortality amongst all haemodialysis patients, but there is no conclusive evidence in diabetic patients. Many haemodialysis machines are now equipped with integral blood volume monitoring systems; which, when nurses are appropriately trained, can be utilised to predict and prevent intra-dialysis hypotension. Repeated electrocardiogram assessment of cardiac rhythm may be helpful, as the absence of sinus rhythm is a risk indicator for cardiovascular events, stroke and all-cause death.13

Dialysate Glucose forms an integral constituent of dialysate; historically added to create an osmotic gradient across the membrane to facilitate fl uid removal, provision of nutritional support, and to prevent hypoglycaemic episodes, as glucose readily moves across the dialysate membrane. Hyperglycaemia secondary to glucose intake during haemodialysis can activate infl ammatory pathways, and contribute to a pro-infl ammatory state,14 resulting in reduced erythropoiesis, accelerated destruction 187 of erythrocytes, leading to iron defi ciency, and resistance to erythropoiesis-stimulating agents (ESAS). Recent RCT suggest that a level of 100mg/l glucose would be appropriate for diabetic and non-diabetic patients, whilst higher glucose levels and glucose free dialysate should be avoided.15

Dialyser Choice of dialyser may also be signifi cant, with majority of dialysers available either composed of or coated with biocompatible material less likely to trigger infl ammatory response, which may amplify infl ammatory processes already The Diabetic Patient and Chronic Kidney Disease

activated in diabetic patients, accelerating atherosclerosis and malnutrition. Recent studies have looked at potential benefi ts on mortality with high fl ux dialyser use; predominantly in a selection of the more unwell patients on dialysis, which often includes a high percentage of diabetic patients. Initial results seem to indicate a signifi cant survival benefi t, with the Membrane Permeability Outcome study16 showing an improvement in mortality only in patients with diabetes. Krane13 found that death was signifi cantly lower for diabetic patients treated with high fl ux synthetic dialysers, compared with low fl ux synthetic membranes.

Type 1 & Type 2 Type 1 diabetes appears to provide the biggest challenge for haemodialysis patients. These patients are more likely to have diabetes as the primary cause of renal failure and are more likely to develop other complications of diabetes.16 They are also more likely to manage using insulin therapy, which provides more risk of hypoglycaemia during haemodialysis.12 However, whilst Type 2 diabetes is more likely to present as a co-morbidity, the management, risks and haemodialysis 188 treatment still need to be managed in a similar way to minimise the risks to these patients.

Management of Complications Whilst the complications of diabetes in the context of haemodialysis is complex and the outlook appears bleak, it is thought that good glycaemic control and management of these complications, along with early detection, leads to the best possible outcomes for diabetic haemodialysis patients. This is an area being well researched within the renal community at present and a debate is occurring as to which approaches to management provide the best outcomes for these patients. In Haemodialysis and the Diabetic Patient particular, McIntyre17 found, through a multi-centre study, that good diabetes practice and management of the complications of diabetes within the context of dialysis were associated with improved outcomes for diabetic haemodialysis patients. Below, are the best recommendations for haemodialysis diabetic patients, which also incorporate some practice patterns identiﬁ ed in previous studies.17 Manage the diabetes and haemodialysis treatment as one entity, rather than 2 separate issues. This requires good links between diabetes and renal teams to allow:

• Timely referral of patient with detected complications of diabetes. • Management of the haemodialysis treatment within the context of diabetes.

These links are not easy to forge and to provide seamless care for the patient may be impossible. However, the following approaches may improve links between the 2 specialities:

• Joint haemodialysis/diabetes clinics. • Good communication between diabetes and renal consultants. 189 • Referral pathways between diabetes and renal multi- disciplinary teams, both in hospital and in community. This should include nurses, dieticians, pharmacists, podiatrists. • Review of diabetes control during and after the haemodialysis session, as well overall management. • Speciﬁ c consideration of the challenges diabetic patients face in relation to their haemodialysis – ﬂ uid gains, vascular access etc. • Creating healthcare professionals that work in one speciality and have an understanding of the other e.g. The Diabetic Patient and Chronic Kidney Disease

diabetic link nurses from the haemodialysis nursing staff. • Fostering knowledge and understanding between the 2 specialities. This will help to bridge the gaps between the 2 specialties and help the patient integrate both their diabetes and haemodialysis treatments into their life, maintaining optimum diabetes control.

2) Monitor the complications of diabetes Haemodialysis nurses can also develop skills to detect complications; taking advantage of the links developed between the 2 specialties and providing the best opportunity for good outcomes for these patients. In particular, haemodialysis nurses are best placed to do this, as they see the patient regularly; helping to reduce the burden of treatment for these patients, who are not then required to attend separate appointments, but can have their diabetes monitored whilst in for haemodialysis. Haemodialysis nurses are best placed to perform the following: 190 • 6-12 monthly foot checks – checking for sensation, vascular complications and ulceration. • Monitor glycaemic control – through blood glucose and HbA1c measurement. • Encourage the patient to attend annual eye checks.

For this approach to be successful, good links and referral pathways are required between the diabetes and renal teams. If early detection of complications occurs, then the patient requires the appropriate support to be in place to manage these complications. Detection itself will not prevent the complications from occurring. Haemodialysis and the Diabetic Patient

Key Points • Diabetic patients commencing haemodialysis therapy should be rigorously evaluated for further deterioration of GFR, which will impact on glycaemic control.

• Diabetic patients on haemodialysis should have regular blood glucose assessment, at least pre and post dialysis therapy.

• Attempts should be made to investigate whether patients experience post haemodialysis hypoglycaemias.

• Close links should be forged with diabetic teams, so that seamless care is provided where possible.

• Nurses within the haemodialysis team have to have reasonable knowledge and awareness of diabetes and its complications.

• Monitoring for complications should be performed where possible during or around haemodialysis appointments to minimise need for patients to attend multiple appointments. 191 • Dialysis nurses should competently use all monitoring available to predict and prevent intra-dialysis hypotension.

• Dialysis nurses should have an awareness of the severity of cardiovascular complications and facilitate cardiovascular assessment of these patients.

• Dialysis nurses should be able to assess and monitor the haemodialysis prescription in the context of diabetes, and adjust relevant factors, e.g. dialysate content, duration and frequency in response to patient need. The Diabetic Patient and Chronic Kidney Disease

References

1. NEPHRON Clinical Practice 114/S1/10. UK Renal Registry 2009. 12th Annual Report of the Renal Association. Ansell.D, Feehally.J, Fogarty.D, Inward.C, Tomson.C, Warwick.G and Williams.A. UK Renal Registry, Bristol, UK. (The data reported here have been supplied by the UK Renal Registry of the Renal Association. The interpretation and reporting of these data are not the responsibility of the Authors and in no way should be seen as an ofﬁ cial policy or interpretation of the UK Renal Registry or the Renal Association). 2. Riveline.J, Teynie.J, Belmouaz.S, Franc.S, Dardari.D, Bauwens. M, Caudwell.V, Ragot.S, Bridoux.F, Charpentier.G, Marechaud.R and Hadjadi.S. Glycaemic control in type 2 diabetic patients on chronic hemodialysis: use of a continuous glucose monitoring system. Nephrology Dialysis Transplantation Sept 2009. 3. Kazempour-Ardebili.S, Lecamwasam.V, Dassanyake.T, Frankle.A, Tam.F, Dornhorst.A, Frost.G and Turner.J. Assessing glycaemic control in maintenance hemodialysis patients with type 2 diabetes. Diabetes Care July 2009. 4. Chamney.M, Pugh-Clarke.K and Kafkai.T. Management of co-morbid diseases in a patient with established renal failure. Journal of Renal Care September 2009. 5. Karame.A, Labeeuw.M, Trolliet.P, Caillette-Beaudoin.A, Cahen.R, Ecochard.R, Galland.R, Hallonet.P, Pouteil-Nobel.C and Villar.E. The impact of type 2 diabetes on mortality in end stage renal disease patients differs between genders. Nephron 2009. 6. Sun.C, Lee.C and Wu.M. Hypoglycaemia in diabetic patients undergoing chronic hemodialysis. Therapeutic Apheresis and 192 Dialysis April 2009. 7. Dreschsler.C, Krane.V, Ritz.E, Marz.W and Wanner.C. Glycaemic control and cardiovascular events in diabetic hemodialysis patients. Circulation December 2009 Volume 120, issue 24. 8. Tsujimoto.Y, Ishimura.E, Tahara.H, Kakiya.R, Koyama.H, Emoto.M, Shoji.T, Inaba.M, Kishimoto.H, Tabata.T and Nishizawa.Y. Poor glycaemic control is a signiﬁ cant predictor of cardiovascular events in chronic hemodialysis patients with diabetes. Therapeutic Apheresis and Dialysis August 2009. Volume 13, issue 4. 9. Tascona.DJ, Morton.AR, Toffelmire.EB, Holland.DC and Iliescu.EA. Adequacy of Glycemic control in hemodialysis patientswith diabetes. Diabetes Care October 2006 Volume 29, issue 10. Haemodialysis and the Diabetic Patient

10. Zitt.E, Neyer.U, Meusburger.E, Tiefenthaler.M, Kotanko.P, Mayer.G and Rosenkranz.A. Effect of dialysate temperature and diabetes on autonomic cardiovascular regulation during hemodialysis. Kidney and Blood Pressure Research 2008. 11. Locatelli.F, Del Veccio.L and Cavalli.A. How can prognosis for diabetic ESRD be improved? Seminars in Dialysis March-April 2010. 12. Dialysis Outcomes and Practice Patterns Study. Canaud.B, Bragg- Gresham.J, Marshall.M, Desmeules.S, Gillespie.B, Depner.T, Klassen. P and Port.F. Mortality risk for patients receiving hemodiaﬁ ltration versus hemodialysis; European results for the DOPPS. Kidney International 2006. 13. Krane.V, Krieter.D, Olschewski.M, Marz.W, Mann.J, Ritz.E and Wanner.C. Dialyzer membrane characteristics and outcome of patients with type 2 diabetes on maintenance hemodialysis. American Journal of Kidney Diseases Feb 2007. 14. Hoenick.N. The composition of dialysate. British Journal of Renal Medicine Autumn 2009. Volume 14, issue 3. 15. Burmeister.j, Scapini.A, da Roasa Miltersteiner.D Generali da Costa. M and Machado Campos.B. Glucose-added dialysis ﬂ uid prevents asymptomatic hypoglycaemia in regular haemodialysis. Nephrology Dialysis and Transplantation 2007. Volume 22, Issue 4. 16. Helve.J, Haapio.M, Grnhagen-Riska.C and Finne.P. Co-morbidity and survival of patients with type 1 diabetes on renal replacement therapy. Diabetologia September 2010. 17. McIntyre N., Thumma J., Fluck R., Greenwood R., Rayner H., King J., Robinson B., Pisoni R., and Ramirez S. ‘Haemodialysis Facility Failure to Deliver Optimal Diabetic Care to Diabetic Haemodialysis Patients is Associated with Increased Mortality: An International Picture from 193 DOPPS III’ in 37th. EDTNA/ERCA International Conference: Improving the quality of renal care in Europe: building a bridge between theory and practice: Abstract Book p.39 Abstract No. O28 2008.

Peritoneal Dialysis in Patients with Diabetic Nephropathy

195 The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To cover the complexities of treating diabetic patients, requiring renal replacement therapy, with peritoneal dialysis

BACKGROUND Diabetes Mellitus is one of the major causes of end-stage renal disease (ESRD) in many countries.1 5 – 10% of type 2 DM patients are likely to develop severe renal disease, requiring renal replacement therapy; this is lower than in type 1 diabetic patients; however the incidence of type 2 diabetes is generally 10 times higher in the general population. 60 – 80% of patients who start dialysis belong to the type 2 group.2 This is signiﬁ cant, as type 2 diabetics have a higher incidence of co-morbidities, particularly cardiovascular disease, tend to be older, and have an increased risk of hospitalisation, all which may have be effected when some commence renal replacement therapy. A small number (10%) of these patients are likely to end up on peritoneal dialysis (PD); probably reﬂ ective of the reducing peritoneal dialysis treatment modality 196 percentage across the renal population as a whole. (Figures from UK Renal registry3) PD is associated with certain negative factors for patients with diabetes: continuous glucose absorption from PD solutions may lead to hyperglycaemia, obesity, hyperlipidaemia, and increased peritoneal permeability because of the accumulation of glucose degradation products (GDPs).4 Glucose is rapidly absorbed from the peritoneal cavity,5 with an average intake of 100-300g of glucose per day; diabetic patients treated with peritoneal dialysis should regularly check blood sugar levels, Peritoneal Dialysis in Patients with Diabetic Nephropathy to detect the adverse effects of this glucose loading. Diabetic patients newly commenced on PD must regularly assess blood glucose levels, and have the support from diabetes physicians, and clinical nurse specialists, who will assist in adapting medication to control blood glucose. Good links between the diabetes service and the PD nurses are essential to facilitate communication over therapy changes. Patients may need to be supported with adapting diabetic medication according to dialysis prescription. It is no longer considered good practice to add insulin into the peritoneal dialysate to alleviate the need for insulin injections.

Patient Outcomes Studies comparing both dialysis modalities suggest that that HD compared with PD offers equal offers equal or better patient survival across all subgroups of patients needing dialysis during the fi rst 2 years.6,7 Although survival rates of diabetic patients on peritoneal dialysis has improved greatly, diabetic patients continue to do signifi cantly worse than non- diabetics. Progressive increase in peritoneal permeability, loss of ultrafi ltration, and peritoneal fi brosis, are exacerbated in patients with diabetes. The study undertaken by Wu1 to evaluate the impact of pre-dialysis glycaemic control on clinical outcomes for type 2 diabetic patients on CAPD suggests 197 that whilst good glycaemic control predicts better survival, it does not change the pattern of mortality in diabetic patients. Ultimately these factors will lead to PD technical failure. Factors effecting long term survival of patients on peritoneal dialysis are; • Co-morbidity at the initiation of dialysis • Age of the patient • Frequency of peritonitis The Diabetic Patient and Chronic Kidney Disease

• Ultraﬁ ltration failure • Increased production of Advanced Glycation End- products (AGE’s) • Dialysis adequacy/use of solutions • Peritoneal dialysate membrane permeability • Residual renal function

Peritonitis Peritonitis is the greatest cause of discontinuation of peritoneal dialysis, and is a potent cause of membrane damage.8 Type 2 diabetic patients have a higher incidence of peritonitis, a lower peritonitis free interval and a lower survival rate, which is inﬂ uenced by the increased age of the patients, and the higher prevalence of cardiovascular disease.2

Ultraﬁ ltration failure Conventional peritoneal dialysate uses glucose as an osmotic agent to assist with ultraﬁ ltration, to allow for the passage of solutes across a gradient. The continuous exposure to the bio- incompatibility of standard solutions including the very high

198 glucose concentrations has contributed to the functional and structural changes of the peritoneum and loss of ultrafi ltration is associated with long-term PD.9 Increasing the number of hypertonic exchanges in patients with failing ultrafi ltration will further increase the cumulative glucose exposure with further worsening peritoneal damage. Their effects include direct cyto- toxicity, stimulation of the infl ammatory process leading to the formation of Advanced Glycation End-products (AGEs) which are deposited in the peritoneal membrane and are responsible for these changes.8 Peritoneal Dialysis in Patients with Diabetic Nephropathy

These structural changes are accelerated in diabetes and are strongly associated with hyperglycaemia.1 AGEs are produced in response to chronic disease; production is high in renal failure,10 caused by oxidative stress of uraemia, and historically it has been accepted that hyperglycaemia caused by diabetes also accelerates the production. AGE production is linked to glycosylation and fi brosis of the peritoneal membrane,11 reducing the use of the membrane for dialysis, and also of diffusion through the membrane into the vascular system, where they may have a negative effect on cardiovascular status.12,13 Non glucose containing dialysate is suggested as an alternative, to prolong the longevity of the peritoneal membrane. 12 A study has been investigating ways of reducing the formation of AGEs; the addition of carnosine and other anti-glycosylation drugs to the peritoneal dialysis fl uid have shown some success in suppression of the formation, which could have a benefi cial application for reducing cardiovascular risk.14

PD Solutions Non-glucose based dialysates, including icodextrin, glycerol and amino acids, as well as double-chamber dialysates with low GDP content and neutral PH, and bicarbonate/lactate buffer formulations have become available for clinical use. Icodextrin 199 is a starch derived glucose polymer that is metabolised to maltose, it has been developed as an alternative to glucose to use in peritoneal dialysis for patients with ultraﬁ ltration failure.15 The use of icodextrin to replace peritoneal dialysis solutions that contain a very high concentration of glucose may itself signiﬁ cantly reduce insulin requirements.16 However icodextrin based lactate buffered PD solution can only be used once daily to avoid an excessive accumulation of lactate2 and Amino- based solutions can only be applied for a limited number of dwells to avoid an excessive nitrogen load. Combined with the The Diabetic Patient and Chronic Kidney Disease

use of an amino acid based solution and the double-chamber dialysates the amount of glucose a patient is exposed to can be signiﬁ cantly reduced. As ultraﬁ ltration failure is associated with by rapid transport of glucose across the peritoneal dialysis membrane, and hence the loss of the osmotic gradient the use of non-glucose based dialysates should be promoted for diabetic and non-diabetic patients. Icodextrin avoids the use of glucose, and contains reduced levels of GDPs compared to conventional solutions. Data from the European APD Outcome Study (EAPOS), suggests that patients using icodextrin at the start of the study had less marked changes in longitudinal membrane function.17 This difference appears to be independent of age, treatment time, or peritonitis during the study period. Results from a two year prospective multicentre study suggest that icodextrin did not affect peritoneal permeability and that it acted in a protective way on the peritoneum.18 Dasgupta19 considers that type 2 diabetes develops through different stages; each of which has different challenges. Treatment with non-glucose based dialysate solutions could reduce the glucose calorie load and glucose toxicity, helping to maintain an optimum blood glucose level. Caution: Icodextrin is hydrolysed in the systemic circulation to oligosaccharides such as maltose, maltotriose, and 200 maltotetraose. These metabolites can have important interactions with some glucose reagent systems.16 The use of icodextrin leads to substantial concentrations of these icodextrin metabolites in the blood, where they are not normally found.20 Therefore, patients with diabetes mellitus treated with icodextrin are at risk of having falsely raised blood glucose measurements with the potential risk of missing the diagnosis of hypoglycaemia depending on the analysis system being used. All blood glucose monitoring kits need to be investigated for interference with icodextrin and altered to a compatible system accordingly. All patients using icodextrin regardless of Peritoneal Dialysis in Patients with Diabetic Nephropathy being diabetic or not should be given information regarding the risk of false glycaemic readings being taken especially in emergency situations.

Changes in modality Changing from CAPD to APD may result in the need to alter the insulin regimen (more at night to limit nocturnal hyperglycaemia, and less by day to limit nocturnal hypoglycaemia) reﬂ ecting the overnight concentration of the glucose load rather than throughout the 24hour period.16 Results from the EAPOS trial17 showed signiﬁ cant detrimental changes in membrane function in anuric patients which appeared to be enhanced by the use of glucose. The use of icodextrin in the long-term dwell was associated with less deterioration in membrane function.

Co-morbid Factors Co-morbid factors that adversely affect long term survival in diabetic peritoneal dialysis patients are; • Cardiovascular disease affecting ability to undertake dialysis activities and tolerate large volume dwells. • Peripheral vascular disease, reducing ability to manage the dexterity required for this treatment. • Cerebrovascular disease effecting ability to manage own condition independently. 201 • Hypoalbuminaemia which will further impact on malnutrition.

Cardiovascular disease A high percentage of patients with diabetes initiating renal replacement therapy have a pre-existing cardiovascular condition; coronary heart disease, previous cerebral vascular accident peripheral vascular disease and amputations.21 The Diabetic Patient and Chronic Kidney Disease

Cardiovascular disease is the most frequent cause of death in patients on peritoneal dialysis; with loss of residual renal function causing over-hydration, glucose loading causing insulin resistance and hyperlipidaemia, in addition to cardiac co-morbidities experienced by patients with established renal disease.22

Malnutrition Malnutrition is a strong predictor of morbidity and mortality; at the start of dialysis many diabetics are already malnourished as a result of decreased intake due to uraemia and gastroparesis, often complicated by socioeconomic condition and depression, and this is aggravated by loss of protein across the peritoneal membrane during dialysis.23 Malnutrition in diabetic peritoneal dialysis patients has been attributed to: • under-dialysis • loss of residual renal function • metabolic acidosis • hyperglycaemia • gastroparesis • the feeling of fullness due to dialysate in the abdomen • suppressed appetite due to glucose absorption from dialysate 202

Conclusion Insulin dose changes will be required when patients change dialysis modalities and regimens especially when using non- glucose based dialysate such as icodextrin and amino-acid based solutions. The effect on capillary blood testing when using icodextrin containing dialysis ﬂ uid must be acknowledged as incorrect blood glucose readings can result if non-compatible glucose monitors are used.16 Peritoneal Dialysis in Patients with Diabetic Nephropathy

Glucose can contribute to peritoneal membrane failure through the generation of GDPs and the formation of AGEs; non- glucose based solutions and dual-chambered solutions reduce the risk of GDPs and AGE production, which can reduce the loss of ultrafi ltration, and peritoneal fi brosis, all of which are exacerbated in patients with diabetes. Early initiation of non- glucose solutions has been proposed to slow the progression of some complications of diabetes, and also optimise albumin and haematocrit levels, which have independent impacts on the mortality of renal patients on dialysis. Some studies suggest that good glycaemic control in pre- dialysis type 2 patients can be benefi cial and further studies to clarify if aggressive glycaemic control after starting dialysis would improve long term survival.1

203 The Diabetic Patient and Chronic Kidney Disease

Key Points • Awareness of the risk of using high glucose concen- trated ﬂ uids for diabetic patients resulting in accelerated changes to the peritoneal membrane.

• Knowledge regarding the use of non-glucose based peritoneal dialysis solutions will reduce glucose load and toxicity and how this will alter insulin requirements.

• Regular routine measurements of blood glucose levels and HbA1c are required.

• Correct usage of glucose regent strips due to the risk of missing hypoglycaemic attacks in patients using icodextrin.

• Patient education regarding the use of high glucose solutions, and their management in dealing with possible hyperglycaemia following use of these solutions.

• Patient education regarding correct blood capillary testing equipment when using icodextrin.

204 Peritoneal Dialysis in Patients with Diabetic Nephropathy

References

1. Wu. M-S, Yu. C-C, Wu. C-H, Herng. J.Y, Leu. M-L and Huang. C-C. Pre-dialysis glycaemic control is an independent predictor of mortality in type II Diabetic patients on continuous ambulatory peritoneal dialysis. Peritoneal Dialysis International Vol 19 (1999), supp 2. 2. Miguel.A, Garcia-Ramon.R, Perez-Contreras. J, Gomez-Roldan.C, Alvarino.J, Escobedo.J, Garcia. H, Lunuza. M, Lopez-Menchero. R, Olivares.J, Tornero.F and Albero.D. Co-morbidity and mortality in peritoneal dialysis: a comparative study of type 1 and 2 diabetes versus non diabetic patients. Nephron November 2002. 3. NEPHRON Clinical Practice 114/S1/10. UK Renal Registry 2009. 12th Annual Report of the Renal Association. Ansell.D, Feehally.J, Fogarty.D, Inward.C, Tomson.C, Warwick.G and Williams.A. UK Renal Registry, Bristol, UK. (The data reported here have been supplied by the UK Renal Registry of the Renal Association. The interpretation and reporting of these data are not the responsibility of the Authors and in no way should be seen as an offi cial policy or interpretation of the UK Renal Registry or the Renal Association). 4. Kuriyama. S. Peritoneal Dialysis in Patients with diabetes: are the benefi ts greater than the disavantages? Peritoneal Dialysis International. Vol. 27 (2007) Supplement 2. S190- S195. 5. Sitter. T. and Sauter. M. Impact of glucose in peritoneal dialysis: saint or sinner? Peritoneal Dialysis International (2005) Vol 25, pp415- 425. 6. Vonesh. E.F, Snyder. J.J, Foley. R.N, Collins. A.J. Mortality studies comparing peritoneal dialysis and hemodialysis: what do they tell us? Kidney Int Suppl 2006; (103): S3-11. 7. Termorshuizen. F, Korevaar. J.C, Dekker F.W, Van Manen. J.G, Boeschoten. E.W, Krediet. R.T. Onbehalf of the Netherlands Cooperative Study on the Adequacy of Dialysis Study Group. Hemodialysis and peritoneal dialysis: comparison of adjusted 205 mortality rates according to the duration of dialysis: analysis of The Netherlands Cooperative Study on the Adequacy of Dialysis 2. J Am Soc Nephrol 2003; 14: 2851-60. 8. Woodrow. G. Can bicompatible dialysis fl uids improve outcomes in peritoneal dialysis patients. Peritoneal Dialysis International (2005) Vol 25, pp230-233. 9. Vriese. A.S. De, Mortier. S. and Lamerire. N.H. Glucotoxicity of the peritoneal membrane: the case for VEGF. Nephrol Dial Transplant 2001 16: 2299-2302. The Diabetic Patient and Chronic Kidney Disease

10. Boulanger. E, Moranne.O, Wautier.M, Witko-Sarsat.v, Descamps- Latscha. B, Kandoussi.A, Grossin.N and Wautier.J. Changes in glycation and oxidation markers in patients starting peritoneal dialysis:a pilot study. Peritoneal Dialysis International March 2006. 11. Boulanger. E, Grossin.N, Wautier.M, Taamma.R and Wautier.J. Mesothelial RAGE activation by AGEs enhance VEGF release and potentiates capillary tube formation. Kidney International 2007. 12. Suliman.M, Stenvinkle.P, Jogestrand.T, Maruyama.Y, Qureshi.A, Baran.y.P, Heimburger.O and Lindholm. B. Plasma pentosidine and total homocysteine levels in relation to change in common carotid intima-media area in the fi rst year of dialysis therapy. Clinical nephrology December 2006. 13. McIntyre.N, Chesterton.L, John.S, Jefferies.H, Burton.C, Taal.M, Fluck.R and McIntyre.C. Tissue-Advanced Glycation End Product Concentration in Dialyssi Patients. American Society of Nephrology 2010. 14. Alhamdani.M, Al-Azzawie.H and Abbas.F. Decreased formation of advanced glycation end-products in peritoneal fl uid by carnosine and related peptides. Peritoneal Dialysis International January 2007. 15. Goldsmith. D, Jayawardene. S, Sabharwal. N, Cooney. K. Allergic reactions to the polymeric glucose-based peritoneal dialysis fl uid icodextrin in patients with renal failure. The Lancet 2000. Vol 355. March 11. 16. Mehmet. S, Quan. G, Thomas. S and Goldsmith. D. Important causes of hypoglycaemia in patients with diabetes on peritoneal dialysis. Diabetic Medicine, 18, 679-682. 17. Davies. S.J, Brown. E.A, Frandsen. N.E, Rodrigues. A.S., Rodriguez- Carmona. A, Vychtil. A, MacNamara. E, Ekstrand. A, Tranaeus. A, Divino Filho. J.C. longitudinal membrane function in functionally anuric patients treated with APD: Data from EAPOS on the effects 206 of glucose and icodextrin prescription. Kidney International, Vol 67 (2005), pp1609-1615. 18. Brown. E.A, Davies. S.J, Rutherford. P, Meeus.F, Borras. M, Riegal. W, et al. Survival of functionally anuric patients on automated peritoneal dialysis: the European APD outcome study. J Am Soc Nephrol 2003; 14: 2948-57. 19. Dasgupta. M. Management of patients with type 2 diabetes on peritoneal dialysis. Advances in Peritoneal Dialysis 2005. 20. Janssen. W, Harff. G, Caers. M, Schellens. A. Positive interference of icodextrin metabolites in some enzymatic glucose methods. Clin Chem 1998; 44: 279-2380. Peritoneal Dialysis in Patients with Diabetic Nephropathy

21. Fang.W, Wang.X, Kothari.J, Khandelwal.M, Naimark.D Jassel.S Bargman.J and Oreopoulos. D. Patient and technique survival on peritoneal dialysis: none0centres experience and review of the literature. Clinical Nephrology 2008. 22. Krediet.R and Balafa. O. Cardiovascular risk in the peritoneal dialysis patient. National Review of Nephrology August 2010. 23. Passadakis.P, Thodis.E, Vargemezis. V and Oreopoulos. D. Long term survival with peritoneal dialysis in ESRF due to diabetes. Clinical nephrology 2001.

207

Diabetes Treatment and CKD

209 The Diabetic Patient and Chronic Kidney Disease

Aims for the treatment of diabetes 1,2 (general population) • Absence of symptoms. • Avoidance of severe hypoglycaemia. • Control of blood glucose to patient-centred targets. • Control of other cardiovascular risk factors. • Prevention, early detection and effective treatment of complications. • Lifestyle sufﬁ ciently ﬂ exible to suit the person’s needs. • Normal life expectancy.

The Alphabet Strategy 2 Education, self-management, compliance. Special Advice focus on exercise, diet, weight reduction, cessation of smoking. Optimal control usually less than 130/80mmHg, in Blood pressure most cases initial treatment will be with an ACE inhibitor/ARB often in combination with a diuretic.

Total cholesterol <4.0mmol/l, LDL <2.0mmol/l, HDL Cholesterol >1.0mmol/l and triglycerides <1.7mmol/l. Statin if treatment cardiovascular disease risk ≥20% over 10 years.

Ideal HbA1c target 6.5% (48mmol/mol), metformin Diabetes control ﬁ rst line in most patients. Early recourse to multiple therapy and insulin if targets not reached.

Detailed yearly examination and appropriate Eye care referral. Aggressive management of vascular risk factors if retinopathy is present. Detailed yearly examination and appropriate referral. Aggressive management of vascular Feet care risk factors if neuropathy and peripheral vascular disease is present. 210 Microalbuminuria/proteinuria patients should be considered for ACE inhibitors or ARB. Statins for Guardian drug secondary prevention and primary prevention in those with cardiovascular disease risk ≥20% over 10 years.

To educate patients, guide treatment and as a Heart disease/ surrogate clinical audit parameter to analyse the CVD score effect of multifactorial intervention. Diabetes Treatment and CKD

Advice for Patients

1. Do not smoke. 2. Maintain ideal body weight for adults (body mass index 20–25kg/m2) and avoid central obesity (waist circumference in white Caucasians <102cm in men and <88cm in women, and in Asians <90cm in men and <80cm in women). 3. Keep total dietary intake of fat to ≤30% of total energy intake. 4. Keep intake of saturated fats to ≤10% of total fat intake. 5. Keep intake of dietary cholesterol to <300mg/day. 6. Replace saturated fats by an increased intake of monounsaturated fats. 7. Increase intake of fresh fruit and vegetables to at least fi ve portions per day. 8. Regular intake of fi sh and other sources of omega-3 fatty acids (at least two servings of fi sh per week). 9. Limit alcohol intake to <21units/week for men or <14units/week for women. 10. Limit intake of salt to <100mmol/l day (<6g of sodium chloride or <2.4g of sodium per day). 11. Regular aerobic physical activity of at least 30 minutes per day, most days of the week, should be taken (for example, fast walking/ swimming).

Administering insulin2

The patient uses a syringe to draw the appropriate dose Insulin from a vial. These plastic insulin syringes are often still administered preferred by patients who have been using them for with a years but are less likely to be chosen by patients who syringe start insulin today. 211

These are quite sophisticated and reliable devices and deliver metered doses of insulin either from a cartridge or Insulin as a pre-loaded disposable pen that is discarded once the ‘pens’ insulin has been fully dispensed. Mixtard 30 is available as an ‘InnoLet’ device, which may be convenient for patients with visual or dexterity problems. The Diabetic Patient and Chronic Kidney Disease

Administering insulin2 There are several types of insulin pumps available and the size has been reduced so that they are quite unobtrusive. These pumps deliver insulin subcutaneously over 24 hours and there are facilities for prandial boosts of insulin. Corrective dose requirements based on carbohydrate intake and the current blood glucose Insulin level (entered by the patient) can be calculated by the pumps device and delivered. Insulin pump therapy should be managed by secondary care centres that provide readily accessible expertise to handle any problem. Pump failure may rapidly lead to insulin deﬁ ciency with risk of ketosis as the formulation used is rapid acting and has a short plasma half life.

Inhaled insulin was recently unsuccessfully launched and has been since withdrawn from the market as it did Inhaled not prove to be as popular as anticipated. These are of insulin value perhaps only in those patients with severe needle- phobia.

Problems with insulin injections2

• Apart from injection site bruises, insulin injections rarely cause problems. Occasionally, insulin allergy may appear and in these cases switching the type of insulin may help. In some cases investigation by skin testing and desensitisation may be needed. • Lipohypertrophy at injection sites may occur and it is important to avoid injecting these areas as absorption is unreliable. • Patients who have commenced insulin therapy sometimes 212 experience blurring of vision due to changes in the amount of water in the lens. This usually corrects itself in a few weeks and the patients should be advised not to change their vision prescription during this time or to purchase new glasses. • Oedema of the feet is also a transient phenomenon and some patients with mild neuropathy may experience a worsening of foot pain when starting insulin. This again will improve with time. Diabetes Treatment and CKD

Figure1:- Insulin injections zones

should be avoided to preserve sensitivity. Choice of site should be rotated.

Alternative areas for blood sampling. These areas are less painful and may improve acceptability particularly in children, but the blood glucose mesasurements respond more slowly following carbohydrate ingestion, particularly at the forearm.

Figure 2.- Sites on the hand suitable for blood sampling

Microvascular and macrovascular disease 213 Tight glycaemic control is particularly effective at reducing microvascular complications (retinopathy, nephropathy, neuropathy), whilst macrovascular disease affecting the larger vessels is more inﬂ uenced by lipids, blood pressure, body fat distribution and exercise. Blood pressure control (and smoking cessation) has a highly beneﬁ cial effect on both micro- and macrovascular disease. So a multifactorial approach addressing all of these factors is extremely important. The Diabetic Patient and Chronic Kidney Disease 300 (can fall) 300 (can fall) Greatly decreased ≥ Anaemia ± oedema, increased blood pressure, uraemic symptoms 300 Decreased ≥ (up to 15g/day) High 120-400 high >400 Very Anaemia ± oedema, increased blood pressure, may be none 300 Normal or decreased ≥ (up to 15g/day) High normal 80-120 Anaemia ± oedema, increased blood pressure, may be none 2 Normal/high 20,300 (microalbuminuria) Normal 60-120 None

ltration

214 Normal (I) Incipient (II) <20 Persistent (III) Clinical (IV) End stage (V) High/ normal High/ normal Hyper ﬁ Normal 60-100 Normal Slightly increased Increased None Increased Increased ltration rate Albuminuria (mg/24 h) Stages of progression diabetic nephropathy Serum creatinine ( μ mol/l) Glomerular ﬁ (mL/min) Blood pressure (mm Hg) Clinical signs Diabetes Treatment and CKD

Minimum surveillance measures for diabetes2

• Weight and body mass index • Blood pressure measurement • Serum cholesterol estimation • Glycosylated haemoglobin (HbA1c) • Estimated glomerular ﬁ ltration rate (e-GFR) • Foot examination • Digital retinal photography • Urinalysis for microalbumin • Depression screening

Treatment targets in diabetic nephropathy2

Treatment targets in diabetic nephropathy should be individually tailored, but generally aim for: • Blood pressure <130/80 • HbA1c <6.5% (48mmol/mol) • Total cholesterol <4.0mmol/l and LDL <2.0mmol/l • Non-smoker status • In established nephropathy with proteinuria, it is safe to assume the patient has widespread microvascular and macrovascular (including coronary artery) disease

215 The Diabetic Patient and Chronic Kidney Disease FAILURE USE IN RENAL USE IN RENAL Used at doses of 2.5-5mg/day if GFR > 50mL/minute Not safe Safe at dosage of 2.5-10mg/day Extended-release form is not safe Not safe Metabolism is by renal affected failure, necessitating dosage reduction and eventually avoidance ADVERSE EFFECTS Hypoglycaemia and weight gain 3 10mg twice daily 20mg twice daily or 20mg/day MAXIMUM DOSE 1mg/day 8mg/day 5mg/day or XL INITIAL INITIAL DOSE 2.5 -5mg/day 5mg/day MECHANISM 216 Increase insulin secretion by pancreatic beta cells Glimeperide (Amaryl) Glipizide (Glucotrol) Non-insulin antihyperglycaemic agents and their use in CKD AGENTS SULFONYLUREAS Glyburide (Micronase) Diabetes Treatment and CKD Can be used May be used with caution, but is best avoided Hepatically metabolised and active metabolites excreted by kidneys; hence, not safe Contraindicated when GFR is < 60mL/minute Not used Not used Hypoglycaemia and weight gain No hypoglycaemia or weight gain 500mg/day 4mg three times a day 180mg three times a day 500mg four times a day 0.5mg three times a day 120mg three times a day 500mg twice daily 100mg/day

Increase insulin secretion by pancreatic beta cells Decrease hepatic gluconeogenesis 217 Meglitinides Repaglinide (Prandin) Nateglinide (Starlix) BIGUANIDES Tolbutamide (Orinase) Chlorpropamide (Diabinese) The Diabetic Patient and Chronic Kidney Disease Metabolism not caution affected; in patients with congestive heart failure Contraindicated because of increased level of parent drug and metabolite Cause weight gain; no hypoglycaemia No hypoglycaemia or weight gain 3 45mg/day 100mg three times daily 850mg three times daily 4mg/day 8mg/day 25mg three times daily 250mg twice daily 15mg/day Prevent digestion of carbohydrates 218 PPAR-gamma agonists; lower insulin resistance and enhance peripheral disposal of glucose Rosiglitazone (Avandia) Pioglitazone (Actos) Alpha-glucosidase inhibitors Acarbose (Precose) Non-insulin antihyperglycaemic agents and their use in CKD Metformin (Glucophage) THIAZOLIDINEDIONES Diabetes Treatment and CKD , <30 mL/min 50mg/day if GFR is 30-50mL/min, or 25mg/day if GFR <30 or in ESRD Contraindicated if GFR is and in ESRD Nausea, vomiting, and weight loss Gastrointestinal risk of effects; hypoglycaemia if used with sulfonylureas 100mg/day 100mg three times daily 10 μ gtwice daily 25mg three times daily 5-10 μ g twice daily 25mg/day Slow gastric emptying, increase postprandial insulin release, reduce glucagon release Inhibit DPP-IV, Inhibit DPP-IV, enhance action of GLP-1 219 GLP-1 ANALOGUES Miglitol (Glyset) Exenatide (Byetta) ‘GLIPTINS’ Sitagliptin (Januvia) The Diabetic Patient and Chronic Kidney Disease 2.5mg/day if GFR <50mL/min and in hemodialysis patients; not studied in peritoneal dialysis Headache, upper respiratory infection, urinary tract infection 3 5mg/day 2.5mg/day

220 ltration rate; ESRD = end-stage renal disease; DPP-IV dipeptidyl peptidase; GLP-1 ﬁ GFR = glomerular Non-insulin antihyperglycaemic agents and their use in renal failure Saxagliptin (Onglyza) glucagon-like peptide-1; PPAR-gamma = peroxisome proliferator-activated receptor gamma glucagon-like peptide-1; PPAR-gamma Diabetes Treatment and CKD

Insulin agents and it use in CKD3

DOSING ONSET INSULIN PEAK EFFECTIVE CHANGE OF PREPARATION ACTION DURATION IN RENAL ACTION FAILURE

RAPID-ACTING

Reduce dose by Regular 30-60min 2-3hr 8-10 hr 25% when Lispro glomerular 5-15min 30-90min 4-6 hr (Humalog) ﬁ ltration rate (GFR) is 10-50mL/min, and by 50% Aspart when GFR 5-15min 30-90min 4-6 hr (NovoLog) <10mL/min

LONG-ACTING

Neutral Reduce dose by 2-4hr 4-10hr 12-18hr protamine 25% when Hagedorn GFR is

(NPH) 10-50 mL/min, and Glargine 2-4hr None 20-24hr by 50% when (Lantus) GFR is less than 10mL/min Detemir 3-4hr 3-14hr 6-23 (19.9) hr (Levemir)

PREMIXED Reduce dose by 221 70/30 human 30-60min 3-12 hr 12-18hr 25% when mix GFR is 70/30 aspart 5-15min 30-90min 12-18hr 10-50mL/min, mix and by 50% when GFR is less than 75/25 lispro mix 5-15min 30-90min 12-18hr 10mL/min The Diabetic Patient and Chronic Kidney Disease Dosing Dialysis 4 Recommendation Avoid Avoid Avoid Avoid Preferred sulfonylurea No dose adjustment necessary Preferred sulfonylurea No dose adjustment necessary Not available in US Avoid Avoid Avoid Dosing Recommendation CKD Stages 3, 4, or Kidney Transplant Reduce dose by 50% when GFR Avoid <70 and .50mL/min/1,73m2 when GFR <50mL/min/1,73m2 Avoid Avoid Preferred sulfonylurea No dose adjustment necessary Preferred sulfonylurea No dose adjustment necessary Not available in USA Avoid Avoid Avoid Initiate at low dose, 1mg daily Avoid Drug Acetohexamide Chlorpropamide Tolazamide Tolbutamide Glipizide 222 Gliclazide Glyburide Gilmepiride Dosing Adjustments by CKD Stage for Drugs Used to Treat Hyperglycaemia Adjustments by CKD Stage for Drugs Used to Treat Dosing Class First-generation sulfonylureas Second- generation sulfonylureas Diabetes Treatment and CKD No dose adjustment necessary No dose adjustment necessary No dose adjustment necessary Avoid Avoid Avoid Avoid No dose adjustment necessary Avoid ned as SCr .1,5mg/dL ned as SCr .1,5mg/dL ﬁ No dose adjustment necessary No dose adjustment necessary Not recommended in patients with SCr >2mg/dL Not recommended in patients with SCr >2mg/dL in women in men or .1,4mg/dL Initiate at low dose, 60mg before each meal No dose adjustment necessary Contraindicated with kidney dysfunction de No dose adjustment necessary Rosigiltazone Exenatide Miglitol Nategilnide Acarbose Pioglitazone Metformin Repaglinide 223 Incretin mimetic Incretin mimetic Alpha- glucosidase inhibitors Thiazolidinediones Biguanides Meglitinides The Diabetic Patient and Chronic Kidney Disease

4 broblastic No data available Reduce dose by 75% (25mg/day) ﬁ There is an additional source of bacterial contamination of dialysate during injection insulin into the bags . Higher total insulin doses are required due to losses of spent dialysate. There is a risk of peritoneal proliferation and perhaps of hepatic subcapsular steatosis. − − − Disadvantages: Reduce dose by 50% (50mg/day) when GFR <50 and by 75% (25mg/ day) when GFR <30ml/min/1.73m2 No dose adjustment necessary for GFR 20-50mL/min/1,73m2 5-11 Sitagliptin 224 Pramlintide Dosing Adjustments by CKD Stage for Drugs Used to Treat Hyperglycaemia Adjustments by CKD Stage for Drugs Used to Treat Dosing It provides a continuous insulin infusion. It eliminates the need for injections. It may provide a more physiologic route of absorption, since the exogenous insulin is absorbed into the portal vein which mimics action of pancreatic insulin. − − − DPP-4 inhibitor Amylin analog Intraperitoneal insulin administration Advantages: Diabetes Treatment and CKD

Toronto Western protocol of intraperitoneal insulin administration5,12

The ﬁ rst three exchanges are performed approximately 20 minutes before each of the major meals and the fourth exchange is an overnight exchange performed at about 11 PM. The blood glucose is measured fasting and one hour after each of the major meals. − On the ﬁ rst day, one-fourth of the total daily subcutaneous insulin dose is given as regular insulin in each of the four exchanges. This insulin is given to help metabolise dietary carbohydrate intake. − An insulin supplement is added to each bag to help metabolise the glucose absorbed from the dialysis solution. Two units are added for each two liter exchange with 1.5% dextrose dialysis solution, four units for each exchange with 2.5% dextrose, and six units for each exchange with 4.25% dextrose.

On the second day, the insulin regimen is adjusted according to the blood glucose levels obtained the previous day. The fasting blood glucose will refl ect the insulin added to the nighttime exchange, while the one-hour postprandial values will refl ect the insulin added to the dialysis solution used before that meal. The insulin dose can be adjusted according to the following sliding scale. For each two liter daily exchange: − Lower the insulin dose by six units if the one-hour postprandial glucose at the same time the previous day was less than 40mg/dL (2.2mmol/L). − Lower the insulin dose by four units if the one-hour postprandial glucose was between 40 and 80mg/dL (2.2 and 4.4mmol/L). − Lower the insulin dose by two units if the one-hour postprandial glucose was between 80 and 120mg/dL (4.4 and 6.7mmol/L). − Do not change the insulin dose if the one-hour postprandial glucose was between than 120 and 180mg/dL (6.7 and 10mmol/L). 225 − Raise the insulin dose by two units if the one-hour postprandial glucose was between 180 and 240mg/dL (10 and 13.3mmol/L). − Raise the insulin dose by four units if the one-hour postprandial glucose was between 240 and 300mg/dL (13.3 and 16.7mmol/L). − Raise the insulin dose by a variable amount if the one-hour postprandial glucose was greater than 300mg/dL (16.7mmol/L). The Diabetic Patient and Chronic Kidney Disease Goal <7.0% 90-130mg/dL (5.0-7.2mmol/L) <180mg/dL (<10.0mmol/L) ciently often to achieve goals 1 fi Frequency Twice per year in stable patients who are achieving goals Twice Every 3 months after change in treatment or if goal not achieved with multiple insulin injections: 3 times daily Treated with fewer insulin injections, oral agents, or medical Treated suf nutrition therapy alone: daily, As needed May be particularly helpful in patients with gastroparesis and those using rapid insulin injections before meals to adjust the dose-meal calculation 226 Measurement HbA1c Preprandial capillary glucose Peak postprandial capillary after glucose (1-2 hr. beginning a meal) ADA Standards for Assessment of Glycaemia Control Standards for ADA Diabetes Treatment and CKD Annually, Annually, more often as needed Annually Annually Annually Frequency Frequency Daily Each visit Each visit 1 Refer high-risk patients to foot and/or vascular specialists Setting digital stereoscopic retinal imaging Health care encounters Health care encounters Ophthalmologist or optometrist who is knowledgeable and experienced in diabetic retinopathy or nonmydriatic Self-management Health care encounters lament fi

227 Comprehensive examination and preventive care Pedal pulses† Visual inspection Visual

Visual inspection Visual Semmes-Weinstein mono Semmes-Weinstein testing, 128-Hz tuning fork Comprehensive dilated eye examination or nonmydriatic digital stereoscopic retinal imaging *High-risk patients include those with CKD, CVD, peripheral vascular disease, neuropathy loss of nail protective sensation, reduced ankle-brachial index, or altered biomechanics, callus, bony deformity, diabetes duration longer than 10 years, and poor glycaemic control. retinopathy, pathology, †Consider obtaining an ankle-brachial index at initial screening for peripheral arterial disease because many patients with peripheral arterial disease are asymptomatic. Foot ulcers*

ADA Standards for Assessment of Retinopathy and Foot Care Standards for ADA Complication Evaluation Retinopathy The Diabetic Patient and Chronic Kidney Disease

Key Points • The CKD stage should be considered before initiating diabetic treatment.

• A therapeutic strategy depends on the patient’s circumstances and abilities and the type of diabetes; for type 2 diabetes a combined therapy with insulin and non insulin anti-hyperglycaemic agents, while for type 1 intensive therapy due to the beneﬁ ts in the short and long term.

• Oral anti-hyperglycaemic drugs (insulin secretagogues sulfonylureas and meglitinides, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors) are used to treat type 2 diabetes. Most of these drugs are contraindicated in CKD patients.

• Treatment will be adjusted according to the patient’s evolution and the appearance of chronic complications. Further adjustments to the regimen should be individualised based on self-monitored blood glucose patterns.

• Patients with CKD are especially susceptible to hypoglycaemia, so diabetic drug therapy requires special 228 caution.

• Diabetic pharmacotherapy in CKD should be individualised. Therapy targets are a HbA1c value between 6% and 7%, a fasting blood glucose level of less than 140mg/dL, and a postprandial glucose level of less than 200 mg/dL. Diabetes Treatment and CKD

• For CKD patients with type 1 diabetes, insulin therapy should be started at 0.5IU/kg, which is half the calculated dose in patients without CKD.

• For CKD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25IU/kg.

• These therapies involve an intensive and continuous health education to manage all the needed techniques accurately and have the appropriate knowledge.

229 The Diabetic Patient and Chronic Kidney Disease

References

1. American Diabetes Association. Standards of Medical Care in Diabetes—2010. Diabetes Care 2010;33(Suppl 1):S11-S61. 2. Holt T, Kumar S. ABC of diabetes. Sixth Edition. Oxford: John Wiley & Sons Ltd; 2010. 3. Shrishrimal K, Hart P, Michota F. Managing diabetes in hemodialysis patients: observations and recommendations. Cleve Clin J Med 2009 Nov;76(11):649-55. 4. National Kidney Foundation. KDOQI™. Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 49:S1-S180, 2007 (suppl 2). 5. Berns JS. Management of hyperglycaemia in diabetics with end-stage renal disease. In: UpToDate, Rose, BD (Ed), UpToDate, Post TW, 2010. 6. Diaz-Buxo, JA. Blood glucose control in diabetics: I. Semin Dial 1993; 6:392. 7. Daniels, ID, Markell, MS. Blood glucose control in diabetics: II. Semin Dial 1993; 6:394. 8. Tzamaloukas, AH, Oreopoulos, DG. Subcutaneous versus intraperitoneal insulin in the management of diabetics on CAPD: A review. In: Adv Peritoneal Dial, Vol 7, Khanna, R, Nolph, KD, Prowant, B, et al (Eds), University of Toronto Press, 1991, pp 81-85. 9. Selgas, R. Comparative study of two different routes for insulin administration in CAPD patients: A multicenter study. Adv Perit Dial 1988; 4:126. 10. Maxwell, DR, Prince, MJ. Blood glucose control in diabetics: III. Semin Dial 1993; 6:397. 11. Selgas, R, Lopez-Riva, A, Alvaro F, et al. Insulin inﬂ uence on the mitogenic-induced effect of the peritoneal efﬂ uent in CAPD patients. In: Adv Peritoneal Dial, Vol 7, Khanna, R, Nolph, KD, Prowant, B, et 230 al (Eds), University of Toronto Press, 1991, pp. 161-164. 12. Tzamaloukas, AH, Oreopoulos, DG. Subcutaneous versus intraperitoneal insulin in the management of diabetics on CAPD: A review. In: Adv Peritoneal Dial, Vol 7, Khanna, R, Nolph, KD, Prowant, B, et al (Eds), University of Toronto Press, 1991, pp 81-85. Diabetes Treatment and CKD

231

Diet for Patients with Diabetes and CKD

233 The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To know the importance of maintaining a good nutritional status as part of diabetes treatment in renal disease • To know the proper distribution of macro and micronutrients in the different therapies and stages of CKD and during kidney or kidney-pancreas transplantation

INTRODUCTION Nutritional care in diabetic nephropathy is of great importance; nutritional assessment requires special attention and will help minimise many of the diabetic patient’s problems. Outlined in this chapter are the nutritional requirements at every stage of renal disease in diabetic nephropathy.1, 2, 3, 4 Nutritional aims in diabetes according to the recommendations of the American Diabetes Association (ADA) are: • Maintenance of serum glucose concentrations by regulating the supply, use of insulin and/or oral hypoglycaemic agents. • Standard serum lipid concentrations. • Adequate energy intake to maintain weight. • Prevention and treatment of risk factors and 234 complications of diabetes.1

1.-PRE-DIALYSIS: There must be an adequate caloric intake to maintain weight within normal parameters. In type 1 diabetes mellitus caloric Diet for Patients with Diabetes and CKD intake should be adjusted so that the patient achieves their optimal weight (many patients with type 1 diabetes mellitus are below their optimal weight, whereas in type 2 patients are overweight or obese). Recommended carbohydrate intake should cover 50-60% of total Kcal diet, they should be high in fi ber and low on the glycaemic index, as well as a lipid intake of 30% (less than 10% of saturated fatty acids). Protein intake should be restricted to avoid the progression of renal failure; it should be between10-20% of total Kcal. At the fi rst sign of Nephrotic Syndrome and consequent urinary protein loss, measures must be taken to replace the loss. As nephropathy progresses the patient may become anorexic and lose weight. If we add the gastrointestinal disorders such as diabetic gastroparesis, these patients are placed at a higher risk of malnutrition, so their protein intake must be monitored closely. Once the glomerular fi ltration rate decreases, protein restriction should be 0.6-0.8 g/Kg of body weight per day. Foods with high biological value protein (HBV) should be chosen and the risk of malnutrition closely monitored. Control of hypertension, reducing sodium intake and if necessary taking antihypertensive treatment, lower weight, physical exercise, food protein restriction and glucose control are vital to reduce and delay the development progression of Chronic Kidney Disease (CKD).1, 5

2.-HAEMODIALYSIS: Diabetic patients on haemodialysis need to increase their protein intake due to the loss of amino acids 235 through the dialysis procedure. The recommended minimum protein intake is 1.2 g/Kg of body weight per day, representing 20% total Kcal (over 60% of HBV proteins). Caloric intake should be at least 35 Kcal/Kg of body weight per day to prevent further protein catabolism. The Diabetic Patient and Chronic Kidney Disease

The recommended intake of carbohydrates is 50-60% of total Kcal, they must be rich in fi ber and contain the carbohydrates lowest on the glycaemic index. It is important to achieve and maintain good blood sugar control, not only for adequate nutritional status, but also to avoid excessive interdialytic weight gain. Lipid intake should comprise 30% of total Kcal (with less than 10% of saturated fatty acids). A moderate amount of sodium is recommended, and hypertensive patients should consume less than 2000mg per day of foods high in sodium, including salt. Potassium intake restriction in the diet must be strict and very controlled in diabetic patients and should not exceed 2000mg/day. Foods rich in potassium are strongly discouraged. Cooking techniques, by soaking and cooking foods, such as vegetables and legumes to remove some potassium should be done. Patients should avoid fasting, and have 5 or 6 meals a day, balanced in quantity and time, maintain good control and stability of blood glucose. Calcium and phosphorus in the diet is recommended to prevent or regulate the metabolic imbalance. To cover calcium needs patients should have at least two servings of dairy food per day. To maintain regular phosphorous levels during treatment the use of binders to reduce absorption is recommended. Due to the loss of vitamins through dialysis fl uid and the diffi culty of supplementing the diet, vitamin supplements are often necessary.

236 Water and ﬂ uids should be monitored. It is recommended to drink a volume similar to residual diuresis over 500mL, including liquid food; in hot weather or increased sweating due to physical exercise the intake increases to 750mL. Interdialytic weight gain should not be more than 2-2.5Kg. 1, 6, 7, 8 Diet for Patients with Diabetes and CKD

3.-PERITONEAL DIALYSIS Peritoneal Dialysis is the dialysis therapy of choice for the diabetic population mainly due to increased haemodynamic stability; however, it poses the great challenge of glycaemic control and weight gain. Protein intake should be at least 1.2-1.5 g/Kg of body weight per day, due to protein and amino acid loss through dialysis ﬂ uid, these losses being greater in episodes of peritonitis. The absorption of glucose from peritoneal dialysate, apart from increased caloric intake, interferes with blood sugar control, so it is vital that the patient self-monitor. The glucose absorbed should be 20-30% of daily caloric intake. Oral intake of carbohydrates should only cover 35% of total caloric intake and sources must be low on glycaemic index and be rich in ﬁ ber. Lipids should comprise the remaining 35% of caloric intake and contain a higher percentage of mono and polyunsaturated fatty acids. A moderate amount of sodium is recommended and hypertensive patients should consume less than 2000mg per day of foods high in sodium, including salt. Depending on the level of potassium in the blood foods rich in potassium should be restricted. Patients should monitor their caloric intake to prevent excessive weight gain or loss, because patients with gastroparesis may not meet nutritional aims. 1, 8, 9, 10

4.-KIDNEY TRANSPLANTATION: 237 The nutritional care for transplant patients is divided into two phases. • Immediate post-transplant period: Covers the period from 4 to 6 weeks after Tx where what matters is the The Diabetic Patient and Chronic Kidney Disease

combination of the stress of the surgery with the use of high doses of immunosuppressive therapy. Due to the high protein catabolism the need for protein intake is >1.2 g/Kg of body weight/day, with adequate caloric intake, at least 35 Kcal/Kg of body weight/day to prevent further protein catabolism, healing problems and increased susceptibility to infection. Due to steroid induced insulin resistance, which enhanced in type 2 DM, patients should limit consumption of carbohydrates to 50% of total caloric intake. Carbohydrate should be split into several meals and be low on the glycaemic index, with close monitoring of blood glucose and the convenient administration of insulin according to the guidelines. Fat intake should comprise 30% of total Kcal (with less than 10% of saturated fatty acids and low in cholesterol). The diet is restrictive in potassium until the normalization of renal function. Liquids shall conform to the diuresis, keeping at ﬁ rst a slightly positive balance so the kidney does not suffer restrictions.

• Late post-transplant period : During this period patients often have a variety of nutritional problems as a result of the side effects of immunosuppression such as obesity, dyslipidaemia, glucose intolerance, hypertension and osteoporosis among others. The nutritional pattern in this period is intended to alleviate the adverse consequences of these alterations. The need for protein intake is normalized to a quantity of 0.8-1.2 g/Kg of body weight/day, with adequate caloric intake to age, physical activity and presence of obes- 238 ity, between 30-35 Kcal/weight. The carbohydrates should cover 50-60% of total caloric intake, split into several meals and they must be low on the glycaemic index. Fat intake should comprise less than 30% of total Kcal, with less than 10% of saturated fatty acids and low in cholesterol and consist mainly of mono and Diet for Patients with Diabetes and CKD

polyunsaturated fatty acids; hyperlipidaemia is one of the main factors of mortality A moderate amount of sodium is recommended and in the case of hypertensive patients should consume less than 2000mg per day of foods high in sodium, including salt. To cover calcium needs patients should consume at least three servings of lacteous food a day, unless indicated otherwise. The diet at this stage is ﬂ exible but is part of the transplant treatment. 1, 3, 4, 11

5.-KIDNEY-PANCREAS TRANSPLANTATION Kidney-Pancreas transplantation with normal function will restore the glucose levels regulated by endogenous insulin secretion, correct the progression of complications of diabetes, protect the transplanted kidney from hyperglycaemia and improve the quality of life of diabetic patients. The diet will not differ from that after renal transplantation. At ﬁ rst there will be strict controls of blood glucose and amylase levels, and the convenient administration of insulin. The glycaemic control will reduce complications and diet will be an integral part of treatment.1, 11, 12

239 The Diabetic Patient and Chronic Kidney Disease

Proteins (% Kcal/day) extra protein to replace urine loss HBV If high catabolism replace the lost 10-15% (0.8-1.2g/Kg) > 60% HBV 20% (>1.2g/Kg) >60% HBV 10-15% (0.8-1.2g/Kg) > 60% HBV Lipids (% Kcal/day) 30%, <10% saturated fat 10-20%, (1-1.5g/Kg), 30%, <10% saturated fat 10% (0.6-0.8g/Kg) >60% cholesterol <300mg/day 30%, <10% saturated fat 20% (1.2-1.5g/Kg) 35%, <10% saturated fat g/Kg) 20% (11.2-1.5 30%, <10% saturated fat, cholesterol <300mg/day <30%,> mono and polyunsaturated fats, cholesterol <300mg/day , low ber 30%, <10% saturated fat, ber, low ber, ber low ber, fi fi fi fi ber, low ber, fi ber, low ber, fi uid glycaemic index glycaemic index (% Kcal/day) glycaemic index 50-60%, high fl 50% high glycaemic index 50-60%, high glycaemic index 50-60%, high 50-60%, high

240 Nephrotic S. Progressive Nephropathy 60%, high Haemodialysis Stage of disease Carbohydrates Peritoneal dialysis Kidney Transplantation -Immediate posttransplant 35% diet + 20-30% dialysis period -Late pottransplant period Kidney-pancreas transplantation Diet for Patients with Diabetes and CKD

Key Points • When diabetic nephropathy is diagnosed, the goal is to retain kidney function for as long as possible.

• Monitoring of clinical and nutritional status of diabetic nephropathy is of great importance.

• Therapeutic measures and the nutritional guidelines for these patients, strict control of blood glucose and blood pressure, dietary protein restriction and correction of hyperlipidaemia, are essential to prevent progression of complications.

• Nutritional regimen is conditioned by the CKD stage and treatment modality.

241 The Diabetic Patient and Chronic Kidney Disease

References:

1. Mara da Silva M, Martins C, Riella MC. Nutrición y Nefropatía Diabética. En: Riella MC, Martins C. Nutrición y Riñón. Ed. Médica Panamericana. Buenos Aires 2006. Sección III-16:182-192. 2. Martin de Francisco AL, Aljama P. Nefropatía diabética. En: Aljama P, Arias M, Valderrábano F. Insufi ciencia Renal Progresiva. Ed. Grupo E. Entheos. Madrid 2000. 199-222. 3. Andreu L, Force E. 500 Cuestiones que plantea el cuidado del enfermo renal. 2ª Edición. Ed. Masson. Barcelona 2001. 4. Martin JL, Guerrero MA. La dieta en la Nefropatía diabética. Revista Sociedad Española de Enfermería Nefrológica 2001; 6:37-43. 5. Riella MC, Martins C. Nutrición en la progresión de la insufi ciencia renal crónica. En: Riella MC, Martins C. Nutrición y Riñón. Ed. Médica Panamericana. Buenos Aires 2006. Sección III-16:182-192. 6. Martins C, Riella MC. Nutrición y Hemodiálisis. En: Riella MC, Martins C. Nutrición y Riñón. Ed. Médica Panamericana. Buenos Aires 2006. Sección III-10:97-109. 7. Fernández S, Conde N, Caverni A, Ochando A. La alimentación en la Enfermedad Renal. Primera Edición. Fundación Renal ALCER 2009. 8. Lorenzo V, Rufi no M, Banis E. Nutrición en Diálisis. En: Lorenzo V, Torres A, Hernández D, Ayus JC. Manual de Nefrología Clínica. Diálisis y trasplante Renal. Madrid: Harcount Brace 1997. 551- 569. 9. Martins C, Pecoits FS, Riella MC. Nutrición y Dialisis Peritoneal. Ed. Médica Panamericana. Buenos Aires 2006. Sección III-13:143- 161. 10. Guerrero A. Nutrición y diálisis adecuada en diálisis peritoneal. Revista SEDEN 1999; 1(2) 6-17. 11. Martins C, Furukawa LL. Nutrición y Trasplante Renal. En: Riella MC, Martins C. Nutrición y Riñón. Ed. Médica Panamericana. Buenos Aires 2006. Sección III-14:162-175. 12. Robertson RP. Seminars in medicine of the Beth Israel Hospital, 242 Boston: Pancreatic and islet transplantation for diabetes--cures or curiosities. N Engl J Med 1992; 327(26):1861-8. Diet for Patients with Diabetes and CKD

243

Health Education in Diabetic and CKD Patients

245 The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To know the different types of education for Diabetes Mellitus • To know the various stages of the education process

INTRODUCTION Diabetes education is a learning process directed to the acquisition of a series of theoretical-practical knowledge, techniques and skills that allow the patient to adopt certain attitudes and habits that will improve their quality of life and the evolution of the illness.1, 2, 3 Diabetes education tries to provide people with diabetes and their families with knowledge that could be used in making daily decisions. This includes: • Understanding what diabetes is and its treatment. • Undertaking technical monitoring of blood glucose and insulin. • Providing knowledge in preventing and knowing how to react to acute complications: hyperglycaemia and hypoglycemia. • Adapting the food plan to the patient’s schedule and work activities. • Providing knowledge about preventing vascular risk factors: smoking cessation, hypertension, cholesterol, sedentary lifestyle, etc. 246 • Providing knowledge about preventing foot injuries. • Increasing an awareness of the importance of going to regular medical review.1, 2, 4 Health Education in Diabetic and CKD Patients

There are many implications of the disease such as its epidemiology, its chronic state, its specifi c complications and the complexity of treatment required.1, 2 Diabetes is a chronic disease that requires active participation from the patient to achieve adequate control. Diet, exercise and medication cannot be introduced without fi rst informing and motivating the patient on how to be in control of their disease. The successful management of the disease depends largely on the patient’s involvement in the management of it.3, 4 The health educator’s main purpose is to help individuals make voluntary changes in habits and lifestyles to improve their health. Education takes place at an early stage after individual diagnosis and in the second phase. People with diabetes will benefi t from group education due to contributions from other experienced colleagues. There are three stages in the educational process: 1. Immediate phase: Diagnosis of the disease and recently diagnosed patients who have not yet accepted their condition. 2. Expansion Phase: Patients who have already accepted the disease and are motivated to change and improve their self-care. 3. Deepening phase: Patients with extensive knowledge of their disease, who are motivated and want to enhance their independence in health.

There are some essential features to be taken into account by the educator: • Education should not always focus on diagnosis. • It should be timely and must be continuous. • It requires persistence and patience. 247 • Do not start a new topic without having consolidated the previous. The Diabetic Patient and Chronic Kidney Disease

• Do not be disciplinary. Have a caring attitude; it is not easy to change habits overnight. • Never try to motivate through fear, always use positive reinforcement. • We must adapt the goals to the diabetic and not vice versa.1, 3, 4, 5

If diabetic education begins early in the disease, the long-term quality of life of patients will likely improve and associated health care costs may be reduced.

1.- INDIVIDUAL HEALTH EDUCATION The individual approach is always preferred at the beginning of the disease through personal interviews. Individual education and skills are based on the characteristics of the patient. This method facilitates communication, participation and feedback, allowing more privacy and interaction with staff. It is the method of choice until the patient completes the ﬁ rst phase of health education and has gained certain self-care abilities. The goal of education is to help individual patients obtain the necessary tools to accept the disease, handle situations that require their intervention and know when to ask for help. Educational content is organized into two distinct phases: 1.- Basic or survival level: The patient is told that they have diabetes and are given the immediate management tool, but not the time for comprehensive information regarding the emphasis of active participation in managing the disease. a. For type 1 diabetics information may include: • What is type 1 diabetes? 248 • Types of Insulin • Blood glucose self-monitoring • Appropriate Food Health Education in Diabetic and CKD Patients

• Management of Hypoglycaemia • Understanding of Ketosis • Understanding of objectives they can control: weight, blood pressure, cholesterol, triglycerides, glucose levels, glycated haemoglobin, smoking...

b. For type2 diabetics information may include: • What is type 2 diabetes? • Appropriate Food • Encouragement of Exercise • Management of Hypoglycaemia • Oral antidiabetic agent treatment • Blood glucose self-monitoring

2.- Advanced level: After the initial phase the patient, at 4-6 weeks, is much more emotionally stable and is more ready to learn. This is the advanced or consolidation phase. This is when the educator can choose either group education, deeper individual education or both. At this stage all the points raised are reviewed and new information is presented in a way that further deepens knowledge. These issues include:

• Self-modifying treatment • Managing diabetes when unwell, eating out, during travel, during shift work and special events, ... • How to prevent long term complications • Managing the diabetic foot • Linking with support Associations for Diabetics, where patients can ﬁ nd out more information

An individualized education programme must have a rating or 249 evaluation system that tells us if the patient has acquired the knowledge.6 The Diabetic Patient and Chronic Kidney Disease

2 .- GROUP HEALTH EDUCATION The health education group is deﬁ ned as a set of activities aimed at a group of patients with the aim of improving their ability to address health problems. During the education process, it is intended that the patient will develop abilities that allow them to make informed decisions and be independent with their health. Any educational programme must involve a number of programming phases: a. Analysis of the situation: Before you start working with a group the current situation must be known, the right members must be chosen, the group should be as homogeneous as possible, socio-cultural level, degree of motivation. That is, after an initial diagnosis we provide the basis for planning the work with a particular group. b. Objectives and Content: Objectives should be outlined, and with the implementation of a programme can be modiﬁ ed depending on the outcome of each session. The educator applies the content and has to respond to the needs, problems, interests and motivations of the group. c. Methodology: Each issue may contain one or more educational techniques according to each learning objective, time and resource. d. Evaluation: Provides information regarding the degree of achievement of the objectives and the effectiveness of the process.

Group educational techniques: 250 To achieve the required results, techniques should be adapted to the objectives and tailored to the circumstances of the process. There are several types of instructional techniques: Health Education in Diabetic and CKD Patients

• Research techniques in the classroom: Tools for sharing knowledge, skills and feelings: brainstorming, quizzes, whispering, picture-word. • Technical exhibition: Used to transmit information and reorganization of knowledge: round-table discussions, debates, videos and discussion. • Technical analysis: These serve to address cognitive and emotional areas helping to explore attitudes and misconceptions and includes discussions on various topics, and searching for alternatives. • Technical skills: These are used for training in speciﬁ c skills and searching the patient’s abilities: role-playing, practical exercises, workouts, games, videos.

In addition to these techniques other activities can be performed in and outside the classroom depending on the different types of resources available. Group education is complemented by individual teaching, improving knowledge and monitoring of patients; and is considered the most efﬁ cient by the use of the resources. It aims to provide not only knowledge but also improved skills and behavioral change.6, 7, 8, 9

251 The Diabetic Patient and Chronic Kidney Disease

Key Points • Health education will allow us to instruct the patient on three basic pillars for the management of diabetes mellitus: dietary therapy, physical activity and drug therapy.

• Individual education is always the ﬁ rst step; the learning process starts in the initial phase of diabetes. Individual education can be divided into periods where the content continuously evolves.

• Content can be as wide as the patient’s demand for information.

• The goal of individual education is to help the patient to obtain the necessary tools to accept the disease, to handle the situations that require their intervention, and to identify those they cannot control.

• Professional caregivers must identify new needs throughout the course of the disease.

• Individual education does not eliminate the possibility of being part of an educational group.

• An individualized educational programme must have a rating system that tells us if the patient has acquired the knowledge set as the goal.

• Group education is complemented by individual 252 education. Health Education in Diabetic and CKD Patients

• Group education can be more efﬁ cient due to the fact that it takes better advantage of the educational resources.

• Health education groups should be homogeneous in composition, both in level of knowledge, abilities and socio-cultural level.

• Group health education aims to not only provide knowledge but also to provide improved skills and effect behavioral change.

• The most appropriate group/technique must be chosen based on the aim.

253 The Diabetic Patient and Chronic Kidney Disease

References

1. Arias M, Alonso R, Menezo R, Escallada R. Educación del paciente en Insufi ciencia Renal Progresiva. En: Aljama P, Arias M, Valderrábano F. Insufi ciencia Renal Progresiva. Ed. Grupo E. Entheos. Madrid 2000 . 285-297. 2. Andreu L, Force E. 500 Cuestiones que plantea el cuidado del enfermo renal. 2ª Edición. Ed. Masson. Barcelona 2001. 3. Richard S, Weinger K et cols. Education in Diabetes Treatment. Joslin´s Diabetes Mellitus. 14ª ed. Editorial Wolters Kluwer. 2007. 35: 597-610. 4. Davies MJ, Heller S et cols. Educación y autocontrol de pacientes diabeticos. Benefi cios adicionales sobre las conductas del paciente. BMJ 2008. 336; 491-495. 5. Pérez Jarauta MJ, Echauri Ozcoidi. Instituto de Salud Publica. Navarra. 6. Metodología de la Educación para la salud individual y grupal. www.cfnavarra.es/isp/actividades/PROMOMETODO.HTM 7. Escalona EM, Fernandez C, Pérez E, Romero M, Serrano P. Educación grupal a pacientes con diabetes mellitus tipo 2. Enfermería Clinica 2000. 10(3): 125-129. 8. Normas para el desarrollo de programas de educación sobre la diabetes en América. Comité de educación. DOTA. Revista Panam salud pública/Pan Am J public Health 10(5), 2001: 349-353. 9. Gonzalez MB, Ballesteros A M, Otero MC, Sanchez MB, Duarte G. Educación para la salud grupal o individual en diabetes mellitus. Revisión sistemática. Consejería de Sanidad de la Junta de Castilla y León. Servicio de Salud de Castilla y León.

254 Health Education in Diabetic and CKD Patients

255

De Novo Diabetes Mellitus in Post-transplant Patients

257 The Diabetic Patient and Chronic Kidney Disease

Learning outcomes • To review the indications of kidney transplantation in diabetic patients • To understand the fundamental post-transplant care that can improve graft and recipient survival • To know the beneﬁ ts of kidney transplantation

INTRODUCTION Post Transplant Diabetes Mellitus (PTDM) is deﬁ ned as the appearance of diabetes after a transplant in patients that did not have the illness beforehand. It is similar to type 2 diabetes as it is characterised by the co-existence of peripheral insulin resistance and a relative deﬁ cit of its secretion. The development of PTDM is a frequent complication that compromises the survival of the graft and the patient.1 The appearance of PTDM is many times preceded by an altered basal glycaemia and an intolerance to oral glucose overload, just as with type 2 diabetes in the general population. This situation can go on for 2 years before the patients shows symptoms of PTDM. It is necessary to detect these pre- diabetic states immediately post-transplant, with the purpose of taking preventative measures and implementing treatment as soon as possible. Studies based on large groups have shown that the risk of PTDM increases with time. Up to 24% of patients develop this 258 illness three years after transplantation.2 De Novo Diabetes Mellitus in Post-transplant Patients

The relative mortality risk is 1.9 times higher in patients with PTDM than those without it. Risk of ischemic heart disease and cerebrovascular disease is signiﬁ cantly increased in patients with PTDM. After a 12 year follow-up, the survival rate of transplant patients with PTDM was 48% compared to 70% of those without PTDM. The cause of this lower survival rate is unknown, but the development of diabetic nephropathy or vascular alterations due to this illness might be contributing factors.3,4

Risk Factors Associated with PTDM Identifying the risk factors associated with the development of PTDM is necessary, not only to strategise prevention and/or treatment in the event that the disease appears after transplantation, but also to improve the survival of the graft and patient. Factors that predispose a patient to developing PTDM are: age, family history of DM type 2, race, obesity, the presence of hepatitis C and immunosuppressants; which can have added affects.5,6

Factors Associated with a High PTDM Risk

Risk Factors Uncontrollable Controllable Associated with Risk Factors Risk Factors Immunosuppressant Treatment

• Body Mass Index • Positive serology • Tacrolimus • Recipient’s Age for hepatitis C • Steroids • African Ethnicity • High number of incompatibilities • Cyclosporine between the donor and recipient 259 The Diabetic Patient and Chronic Kidney Disease

Immunosuppressant treatment associated with a lower PTDM risk

• Mychofenolate Mofetile • Azathioprine

Uncontrollable Factors:

• The development of Diabetes is more common in older patients. • Among patients of African ethnicity, there is a higher risk of acute rejection and chronic nephropathy of the transplant, also the incidence of PTDM is greater, possibly due to the use of higher doses of tacrolimus and corticosteroids. Although these factors are not controllable, they do serve to take appropriate preventative measures at the moment of transplantation.

Controllable Factors:

• Avoiding obesity and a sedentary life, controlling hepatitis C virus receptors and the histocompatability between the donor and the receptor should be the greatest in order to avoid a higher incidence of PTDM, and infection or cytomegalovirus.

Factors Associated with Immunosuppressants:

• Immunosuppressants taken by the transplant patient intervene in such a clear way with the physiopathology of PTDM that is why the choice and maintenance of immunosuppressant treatment should be taken into account at the moment of preventing and treating 260 PTDM. De Novo Diabetes Mellitus in Post-transplant Patients

• Steroids generate resistance to insulin due to the dose-dependent effect. • Cyclosporine and tacrolimus are also associated with the development of PTDM. • The risk is greater with tacrolimus (with plasma levels of >15ng/mlL) during the ﬁ rst year after transplantation. This medication is more often given to patients of African ethnicity or in carriers of the hepatitis C virus. The level of tacrolimus should be maintained between 5-15ng/mL during the ﬁ rst months after the transplant and a reduction of steroids help to prevent this substantial complication.7,8 • Using mycophenolate mofetile or azathioprine has a protective effect over PTDM and even over the appearance of diabetic nephropathy of the graft in those patients that have already developed PTDM.9

Prevention of PTDM The prevention of PTDM should begin before transplantation. When a patient is going to be included on the transplant waiting list, all of the antecedents should be noted: possible gestational diabetes, family history, cardiovascular proﬁ le (smoker), hypertension, history of stroke in a family member and/or in the patient. Regarding analysis, the basal glucose should be evaluated repeatedly in order to determine all the parameters related to cardiovascular risk. It is recommended that the patient not gain weight. It must be explained to them that after the transplantation their appetite will increase and as will the propensity to gain weight, due to the use of corticoid steroids especially during the ﬁ rst days when the doses are higher. 261 The Diabetic Patient and Chronic Kidney Disease

Treatment and Recommendations for PTDM

Immunosuppresant Treatment in the presence of PTDM ↓

Withdrawal or Minimization of Steroids ↓

Reduction of Tacromilus dose ↓

Conversion to Cyclosporine

Before modifying the immunosuppressive therapy the patient’s immune risk should always be evaluated. • Frequent determination of glucose as well as the glycated haemoglobin (HbA1C) • Careful use of oral antidiabetics • Insulin, if uncontrolled metabolism persists, to avoid complications of diabetes. • Hygienic and dietary measures to prevent obesity, regular exercise, no smoking, control blood pressure, etc...

The Nurse’s Role in PTDM Prevention and individualised treatment like education are key in caring for a transplant patient with a new incidence of diabetes; not only due to this complication but also because of what can happen after transplantation. The care plan should be focused on early detection and control of the changes in PTDM in an interdisciplinary way with a 262 nephrologist and include information, learning and assessment De Novo Diabetes Mellitus in Post-transplant Patients so the patient will be able to care for them self and control their therapeutic regimen to better their quality of life. PTDMis as an independent risk factor for patient survival and the graft.10 It should be dealt with in the preventative facet as well as after the patient undergoes transplant surgery. Transplant patients should avoid obesity, a sedentary lifestyle, and have a plan for an immunosuppressant therapy that is balanced with the immunological risk and the development of PTDM.

Key Points • The appearance of diabetes after transplantation in those patients that did not have the illness prior is a situation like diabetes type II.

• Consequences of PTDM • increased risk of loss of the graft • increased risk of late onset hypertension • increased risk of chronic rejection • increase of hepatic steatosis

• Treatment of PTDM immediately post-transplant includes insulin, decrease in steroids, diet and physical exercise.

263 The Diabetic Patient and Chronic Kidney Disease

References

1. Ibrahim HN, Kukla A, Cordner G, et al. Diabetes after kidney donation. Am J Transplant 2010; 10: 331-337.

2. Kasiske BL, Snyder JJ, Gilbertson D, et al. Diabetes Mellitus after kidney transplantation in the United States. Am J Transplantation 2003; 3: 178-185.

3. Cosio FG, Hickson LJ, Grifﬁ n MD, et al. Patient survival and cardiovascular risk after kidney transplantation: The challenge of diabetes. Am J Transplantation 2008; 8: 593-599.

4. Parekh J, Bostrom A, Feng S. Diabetes Mellitus: A risk factor for delayed graft function after deceased donor kidney transplantation. Am J Transplantation 2010; 10: 298-303.

5. Abbott KC, Lentine KL, Bucci JR, et al. Impact of diabetes and hepatitis after kidney transplantation on patients who are affected by hepatitis C virus. J Am Soc Nephrol 2004; 15: 3166-3174.

6. Araki M, Flechner SM, Ismail HR, et al. Posttransplant diabetes mellitus in kidney transplant recipients receiving calcineurin or mTOR inhibitor drugs. Transplantation 2006; 81: 335-341.

7. Matas AJ, Kandaswamy R, Gillingham KJ, et al. Prednisone-free maintenance immunosuppression-a 5-year experience. Am J Transplantation 2005; 5: 2473-2478.

8. Teutonico A, Schena PF, Di Paolo S, et al. Glucose metabolism in renal transplant recipients: Effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 2005; 16: 3128- 3135.

9. Mendez R, Gonwa T, Yang HC, et al. A prospective, randomized trial of tacrolimus in combination with sirolimus or micophenolate mofetil in kidney transplantation: Results at 1 year. Transplantation 2005; 80: 303-309.

10. Cosio FG, Pesavento TE, Kim S, et al. Patient survival after kidney transplantation: IV. Impact of post-transplant diabetes. Kidney Int 264 2002; 62: 1440-1446. De Novo Diabetes Mellitus in Post-transplant Patients

265