DIAGNOSTICS

Chronic Kidney Disease Learning Guide series ACKNOWLEDGEMENTS

EDITOR: Anthony A. Killeen, M.D., Ph.D., the editor of this entry in the Abbott Learning Guide series, is Professor and Vice-Chair for Clinical Affairs in the Department of Laboratory Medicine and Pathology at the University of Minnesota. His research interests include quality performance in clinical laboratories, and clinical trials related to the epidemiology of cardiovascular disease.

LEARNING GUIDE: CHRONIC KIDNEY DISEASE (CKD) 2 TO THE TABLE OF CONTENTS ABBOTT DIAGNOSTICS RENAL EDUCATIONAL SERIES

INTENDED AUDIENCE This Learning Guide is meant to serve the basic educational needs of healthcare professionals who are involved in the laboratory or manage patients who have or are at risk for chronic kidney disease. The Renal Educational Series comprises three modules: • Learning Guide: Kidneys • Learning Guide: Chronic Kidney Disease (CKD) • Renal Disease: Shedding Light on Renal Disease

The first module focuses on the structure and function of the kidney. The second and third expand on this foundation, covering the epidemiology, pathophysiology, diagnosis and management of Chronic Kidney Disease (CKD).

HOW TO USE THIS LEARNING GUIDE To offer you the most benefit from this Learning Guide, each section begins with a set of learning objectives. These will help you focus on the key concepts presented in each section. There is a short quiz at the end of each section designed to help reinforce key concepts covered in that section. A glossary is included at the end of this Learning Guide for quick reference.

LEARNING GUIDE: CHRONICDIABETES KIDNEY DISEASE (CKD) 3 BACK TO TOTHE THE TABLE TABLE OF OFCONTENTS CONTENTS CONTENTS

INTRODUCTION CHRONIC KIDNEY DISEASE (CKD) LEARNING GUIDE ...... 5

SECTION 1 OVERVIEW OF CKD ...... 6

SECTION 2 COMPLICATIONS OF CKD ...... 18

SECTION 3 DIAGNOSIS AND MONITORING OF CKD ...... 26

SECTION 4 MANAGEMENT OF CKD ...... 40

APPENDIX APPENDIX A: GLOSSARY OF TERMS ...... 49

APPENDIX B: REFERENCES ...... 52

APPENDIX C: CORRECT RESPONSES ...... 55

LEARNING GUIDE: CHRONIC KIDNEY DISEASE (CKD) 4 INTRODUCTION CHRONIC KIDNEY DISEASE (CKD) LEARNING GUIDE

The kidneys play a vital role in elimination of wastes, regulation of blood composition, blood volume and blood pressure, as well as mineral homeostasis.

They are essential for keeping the rest of the body in balance.

Chronic kidney disease (CKD), one form of kidney dysfunction, is increasingly recognized as a major public health concern.1 The continuum of CKD ranges from mild kidney damage to end­-stage renal disease (ESRD). At this stage, kidney function is no longer sufficient to sustain life; therefore, dialysis or kidney transplantation is required.2

Complications that arise as CKD advances include anemia, hypertension, systemic disorders of mineral and bone metabolism, cardiovascular disease and widespread effects on other body systems.3 Early detection and appropriate management can help delay progression to kidney failure and the development of complications.

LEARNING GUIDE: CHRONIC KIDNEY DISEASE (CKD) 5 BACK TO THE TABLE OF CONTENTS SECTION 1 OVERVIEW OF CKD

LEARNING OBJECTIVES After completing this section, you will be able to:

• Define CKD and its stages.

• Discuss the epidemiology, causes and risk factors associated with CKD.

• Understand how CKD is classified.

LEARNING GUIDE: OVERVIEW OF CKD 6 BACK TO THE TABLE OF CONTENTS DEFINITION AND STAGES OF CKD The kidneys are involved in fluid and electrolyte balance, waste removal and hormone production. Some conditions that can impact kidney function include infections, kidney stones, acute kidney injury (AKI) and chronic kidney disease (CKD). When the kidneys are damaged or diseased, they can abruptly or progressively lose their ability to perform these vital functions. This results in waste and fluid buildup and abnormal hormonal regulation of blood pressure and mineral homeostasis.

DEFINITION OF CKD The 2012 Practice Guideline from the Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group define CKD as: 1-1 • Kidney damage for >3 months, as characterized by structural or functional abnormalities of the kidney, with or without decreased glomerular filtration rate (GFR), manifested by either: — Pathological abnormalities. — Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests. • GFR <60 mL/min/1.73 m2 for ≥3 months, with or without kidney damage. GFR is typically used to assess the level of kidney function and to monitor disease progression and treatment response.1-2 One of the major abnormalities seen in CKD is proteinuria, an excess of protein in the urine. KDOQI recommends monitoring levels of the protein albumin in the urine as part of the diagnosis of CKD.1-1

FAST FACT GFR is a measure of the overall filtration rate of all nephrons.1-2 It is considered the best index of overall kidney function in both the healthy and diseased kidney.1 Estimated GFR (eGFR) is calculated with two commonly used equations incorporating the measured serum creatinine concentration, age, sex and ethnic origin.1-1

LEARNING GUIDE: OVERVIEW OF CKD 7 BACK TO THE TABLE OF CONTENTS STAGES OF CKD KDOQI has identified five stages of CKD, defined according to estimated GFR.1-3

STAGE DESCRIPTION GFR RATE (ML/MIN/1.73 M2)

G1 Kidney damage with normal or increased GFR ≥ 90

G2 Kidney damage with mild decrease in GFR 60–89

G3a Mild to moderately decreased GFR 45–59

G3b Moderately to severely decreased GFR 30–44

G4 Severe decrease in GFR 15–29

G5 Kidney failure < 15 (or dialysis)

Table 1-1: Stages of Chronic Kidney Disease 1-3.

A modification of this initial classification system was proposed at the 2004 KDOQI conference. Suffixes can be added: “T” for kidney transplant recipient at all levels of GFR and “D” for people with stage G5 CKD treated with dialysis. A second modification was made in 2012 to divide category 3 into G3a (mild to moderate decrease in GFR) and G3b (moderate to severely decreased GFR). 1-3

CKD is associated with a progressive decline in GFR and increased complications over time. Figure 1-1 illustrates the KDOQI conceptual model for the development, progression and complications of CKD.1

COMPLICATIONS

Normal Increased Damage GFR Kidney Death risk decline failure

Figure 1-1: Conceptual model of CKD continuum: development, progression and complications . “Complications” refers to all complications of CKD and its treatment, including complications of decreased glomerular filtration rate (GFR) and cardiovascular disease 1.

LEARNING GUIDE: OVERVIEW OF CKD 8 BACK TO THE TABLE OF CONTENTS Stage 1 3.20%

Stage 2 4.10%

EPIDEMIOLOGY Stage 3 CKD is a major public health problem worldwide.1 7.80%

PREVALENCE OF CKD Based on U.S. National Health and Nutrition Examination Survey (NHANES) data, the CDC reports Stages 4–5 0.50% that the percentage of adults with CKD Stage G1–G4 remained relatively unchanged from 1999–2016 at about 14% of the U.S adult population. The prevalence of CKD is increasing in the U.S., partially due to the growing number of CKD risk factors, including advanced age, diabetes mellitus, hypertension and obesity.1-5

Figure 1-2 shows the prevalence of CKD among U.S. adults by CKD stage, based on 1999–2016 NHANES data, determined using creatinine-based GFR estimates.1-4

16%

14% CKD Stage G1

CKD Stage G2 12% CKD Stages G3a/G3b

10% CKD Stage G4

CKD Stages G1–G4 8%

6%

Percentage/Incidence of CKD 4%

2%

1999–2000 2001–2002 2003–2004 2005–2006 2007–2008 2009–2010 2011 –2012 2013–2014 2015–2016 Year Figure 1-2: Incidence of CKD in U .S . NHANES adult population (1999–2016) . The percentage of adults affected by CKD is given according to disease stage 1-4.

Population studies from Australia and Japan have shown similar incidences of CKD. The results of these studies are summarized in Table 1-2.

AUSTRALIA1-5 JAPAN1-6

Modification of Diet in Renal Disease eGFR calculation Cockcroft-Gault equation (MDRD) study equation

Percentage of population with 11 4%. 19% eGFR <60 mL/min/1 73. m2

Percentage of population with 0 .3% 0 .2% eGFR <30 mL/min/1 73. m2

Table 1-2: Prevalance of CKD in Australia and Japan .

LEARNING GUIDE: OVERVIEW OF CKD 9 BACK TO THE TABLE OF CONTENTS INCIDENCE AND PREVALENCE OF ESRD The incidence of end-stage renal disease (ESRD), which is defined by the event of initiating renal replacement therapy rather than by GFR, varies widely among countries. In 2019, the rate of new ESRD cases in the U.S. was approximately 370.2 per million population (pmp) per year. The prevalence of ESRD was approximately 2,203 pmp. 1-7 Across 36 European countries, in 2016, an overall incidence of ESRD was 121 cases pmp (ranging from 29 to 251 pmp, depending on region, per year, shown in Figure 1-3. The overall prevalence was 823 pmp per year. 1-8

≤100 pmp

100-149 pmp

150-199 pmp Iceland ≥200 pmp

no data available

Finland

Norway Sweden Estonia Russia

Latvia

Denmark Lithuania

Ireland Belarus United Kingdom Netherlands Poland

Belgium Germany Ukraine Czech Luxembourg Republic Slovakia Moldova Georgia Austria Hungary Switzerland France Slovenia Romania Croatia

Bosnia and Serbia Herzegovina Italy Bulgaria Kosovo Montenegro Portugal Andorra Macedonia Albania Spain Turkey Greece

Syria Cyprus Lebanon

Malta Israel Morocco Algeria Tunisia

Figure 1-3: Incidence of RRT pmp on 31 December 2016 by country/region, European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) Registry 1-8.

LEARNING GUIDE: OVERVIEW OF CKD 10 BACK TO THE TABLE OF CONTENTS CAUSES OF CKD AND ESRD Diabetes (diabetic nephropathy) and hypertension are the two most common causes of CKD. Other causes include glomerulonephritis and polycystic kidney disease. The causes of ESRD are summarized in Figure 1-4.1-7

Primary Diagnosis in ESRD Patients

Other/ Cystic kidney disease 3% Unknown 14% Glomerulonephritis 7% Diabetes 47%

Hypertension 29%

Figure 1-4: Causes of ESRD in the U .S . (2019) . Diabetes accounts for almost half of the cases of kidney failure and more than one- quarter of cases can be attributed to hypertension 1-7.

MORBIDITY AND MORTALITY CKD is associated with high rates of morbidity and decreased quality of life.1 The incidence of hospitalizations among people with CKD is higher than among those without CKD. Some common causes for hospitalization seen in CKD patients include cardiovascular disease (CVD), infections such as pneumonia and bacteremia/septicemia.1-4 Factors that increase the rate of hospitalization in CKD patients include: 1-4 • Older age. • Comorbidities, such as diabetes and congestive heart failure. • Progression of CKD. • Dialysis, which increases the risk of infections at the site of catheter placement and mortality.

CKD is also linked to premature mortality. The risk of death is almost doubled by CKD, and more than tripled when people have CKD plus cardiovascular disease (CVD) and diabetes.1-4

FAST FACT Age is one factor affecting kidney function. Normal GFR in individuals aged 30 years or younger is about 125 mL/min/1.73 m2. After the age of 30 years, GFR decreases by 1 mL/min/1.73 m2 per year.1-2

LEARNING GUIDE: OVERVIEW OF CKD 11 BACK TO THE TABLE OF CONTENTS HEALTHCARE COSTS Across healthcare systems, treating CKD has significant costs. For example, in 2017, the United States spent: 1-7 • $84 billion of Medicare was spent on CKD for people over 65 years old. • An additional $36 billion was spent on ESRD. • $12 billion was spent on CKD for people under 65 years old. Expenditures increase dramatically during the transition from CKD to ESRD. Most of these high costs are related to dialysis and hospitalizations for arteriovenous fistula placement, vascular access failure, declotting procedures and infectious complications.1-9,1-10

FAST FACT Detecting CKD early, and preventing its progression to end-stage renal disease, could potentially improve patient quality of life and help save healthcare dollars.1-11

RISK FACTORS Several risk factors for the development or progression of CKD have been identified and are presented in Figure 1-5. Risk factors are generally classified as:1-1 • Susceptibility factors — increase susceptibility to kidney damage. • Initiating factors — directly initiate kidney damage. • Progression factors — exacerbate kidney damage or accelerate GFR decline.

In general, people at high risk for CKD include those with diabetes, hypertension and CVD, or those with a family history of these conditions or CKD.1-11 Certain risk factors, including diabetes and hypertension, are considered modifiable risk factors because they may be controlled through treatment or lifestyle changes to help reduce the risk of a patient developing CKD. Other factors, however, such as family history, age, race and ethnicity, are not modifiable.1-1

LEARNING GUIDE: OVERVIEW OF CKD 12 BACK TO THE TABLE OF CONTENTS INITIATING FACTORS: SUSCEPTIBILITY FACTORS: - Older age - Older age - Certain ethnic populations (Black, Hispanic, Asian, - Family history of CKD Pacific Islander or Native American Indian) - Diabetes mellitus - Hypertension - Autoimmune diseases - Systemic infections KIDNEY CKD - Urinary tract infections FAILURE - Urinary stones - Lower urinary tract obstruction - Neoplasia - Family history of CKD PROGRESSION FACTORS: - Recovery from acute kidney injury - Reduction in kidney mass - Higher level of proteinuria - Exposure to certain drugs, chemicals or - Hypertension environmental conditions - Poor glycemic control in diabetes - Low birth weight - Smoking

Figure 1-5: Risk factors for the development and progression of CKD 1-1.

COMORBIDITIES CKD is linked to numerous comorbidities, including diabetes, hypertension and CVD. Prevalence of these conditions tends to rise with increasing stage of disease.1-4

A number of comorbid conditions accompany CKD. These are summarized in Table 1-3.1-1 CVD is considered separately due to its complex relationship with CKD, which incidentally is an independent risk factor for CVD.1 Dyslipidemia, a primary risk factor for CVD, also contributes to CKD development and progression.1-2,1-12

TYPE OF COMORBID EXAMPLES MANAGEMENT GOALS CONDITION

Diseases causing CKD • Diabetes • Improve CKD • Hypertension • Improve functioning and well-being • Urinary tract obstruction • Integration of care with • Acute kidney injury management of CKD

Diseases unrelated to CKD • Chronic obstructive pulmonary • Improve functioning and well-being • Do not affect course of CKD, disease (COPD) • Integration of care with management but may impair functioning and • Degenerative joint disease of CKD patient well-being • Alzheimer’s disease • Malignancies

Cardiovascular disease (CVD) • Atherosclerotic CVD • Evaluation and management of • Leading, yet potentially preventable, • Heart failure CVD risk factors cause of morbidity and mortality in • Left ventricular hypertrophy • Possibly improve CKD people with CKD • Improve functioning and well-being • Integration of care with management of CKD

Table 1-3: Classification and management of comorbid conditions in CKD 1-1.

LEARNING GUIDE: OVERVIEW OF CKD 13 BACK TO THE TABLE OF CONTENTS CLASSIFICATION AND CLINICAL FEATURES OF CKD Kidney diseases may be divided into three broad categories based on their etiology and pathology: (1) diabetic, (2) nondiabetic and (3) diseases in the kidney transplant (Table 1-4). Diabetic kidney disease is classified separately because it is the single largest cause of kidney failure.1-1 Regardless of cause, one of the hallmarks of CKD is persistently increased excretion of albumin or other proteins in the urine.1-1 As GFR declines, the final common pathway of CKD leads to complications such as hypertension, CVD and uremia.1-1, 1-13

DISEASE MAJOR CAUSES

Diabetic kidney • Type 1 diabetes disease • Type 2 diabetes

Nondiabetic kidney • Glomerular diseases (affecting the glomeruli), e .g ., autoimmune diseases (lupus), diseases systemic infections (hepatitis, human immunodeficiency virus [HIV]), drugs, neoplasia • Vascular diseases (affecting the renal vasculature), e .g ., large vessel disease, hypertension, small vessel disease (microangiopathy) • Tubulointerstitial diseases (affecting the renal tubules and interstitium), e .g ., urinary tract infection, stones, obstruction, drug toxicity • Cystic diseases, e .g ., polycystic kidney disease • Acute kidney injury

Diseases in the • Chronic rejection kidney transplant • Drug toxicity • Recurrent disease, e .g ., glomerular diseases • Transplant glomerulopathy

Table 1-4: Classification of CKD 1-1.

FAST FACT Polycystic kidney disease is one of the most common genetic disorders with the autosomal dominant type, affecting one in 500–1000 live births.1-14 It is characterized by the development of cysts (fluid-filled sacs) in the kidney tubules. This leads to progressive kidney dysfunction, which eventually evolves into ESRD.1-15

LEARNING GUIDE: OVERVIEW OF CKD 14 BACK TO THE TABLE OF CONTENTS MARKERS OF POTENTIAL KIDNEY DAMAGE CKD is typically a silent condition until its late stages.1-16 Most patients have no symptoms, or may present with nonspecific complaints such as fatigue, malaise or anorexia.1-17

CLINICAL CONNECTION The fact that the early stages of CKD are asymptomatic reduces opportunities for preventing adverse outcomes.1-16

SIGNS AND SYMPTOMS Kidney dysfunction leads to the accumulation of waste products and excess fluid.1-15 As CKD progresses, signs and symptoms greatly increase, such that the majority of people with CKD are usually detected shortly before symptomatic kidney failure develops. Potential signs and symptoms are: 1-17

Urinary symptoms • Dysuria: Difficult or painful urination 1-18 • Nocturia: Excessive urination at night 1-18 • Dark-colored urine

Nonurinary symptoms • Edema • Hypertension • Arthralgia (joint pain) 1-18 • Fatigue • Fever • Skin rash • Weight loss

Asymptomatic urinalysis abnormalities • Hematuria: Blood or red blood cells in the urine 1-19 • Pyuria: White blood cell casts, kidney tubular cells and coarse granular casts in urine • Non-nephrotic proteinuria: <3,500 mg protein in urine/day

Asymptomatic radiographic abnormalities1-1 • Hydronephrosis • Asymmetry of kidney size or function • Obstructing stones, tumors, cysts or scarring

LEARNING GUIDE: OVERVIEW OF CKD 15 BACK TO THE TABLE OF CONTENTS Related syndromes • Nephritic syndrome (acute glomerulonephritis, inflammation of glomeruli): Hypertension, edema, hematuria, red blood cell casts1-1 • Nephrotic syndrome: Massive proteinuria (>3,500 mg/day), hyperlipidemia, hypoalbuminemia and edema1-1,1-15 • Tubular syndromes: Diverse disorders related to abnormal handling of water or solutes by renal tubules1-1 • Sustained hypertension1-1

ESRD AND UREMIA As kidney function deteriorates, urea and nitrogenous wastes accumulate in the blood because the kidneys can no longer remove wastes from the body.2 Symptoms of uremia include anorexia, nausea, vomiting, malaise, muscle weakness, platelet dysfunction, pericarditis, mental status changes, seizures and possibly coma.1-2 Kidney failure is defined as either : 1-1 • Stage G5 CKD, corresponding to GFR <15 mL/min/1.73 m2, usually accompanied by signs and symptoms of uremia. • A need to initiate kidney replacement therapy (dialysis or transplantation).

Permanent kidney failure, in which a patient requires dialysis or transplantation to survive, is referred to as end-stage renal disease (ESRD).2

LEARNING GUIDE: OVERVIEW OF CKD 16 BACK TO THE TABLE OF CONTENTS REVIEW QUESTIONS: SECTION 1 Answers are provided at the end of this Learning Guide. 1. What is considered to be the leading cause of kidney failure among CKD patients?

A Chronic obstructive pulmonary disease

B Diabetes

C Proteinuria

D Hypertension

2. Match the clinical signs of CKD with the correct clinical terms. Write your answers in the spaces provided.

CLINICAL TERM MEDICAL DESCRIPTION

Excretion of small abnormal amounts of albumin

Presence of blood in urine

Toxic levels of urea in blood

Possible answers: hematuria, microalbuminuria, uremia

3. What is the GFR corresponding to stage G3a CKD?

2 A 60–89 mL/min/1.73 m 2 B 45–59 mL/min/1.73 m 2 C 15–29 mL/min/1.73 m D <15 mL/min/1.73 m2

4. Polycystic kidney disease is a subset of which CKD classification?

A Diabetic CKD

B ESRD

C Nondiabetic CKD

D CKD in transplant

LEARNING GUIDE: OVERVIEW OF CKD 17 BACK TO THE TABLE OF CONTENTS SECTION 2 COMPLICATIONS OF CKD

LEARNING OBJECTIVES After completing this section, you will be able to:

• List the main complications associated with CKD and how they contribute to disease progression.

• Identify the components of CKD–mineral and bone disorder (CKD–MBD) and its clinical consequences.

• Describe the effects of CKD on other body systems.

LEARNING GUIDE: COMPLICATIONS OF CKD 18 BACK TO THE TABLE OF CONTENTS OVERVIEW The kidneys regulate many of the body’s functions and control numerous processes that maintain homeostasis. As wastes and fluids accumulate due to impaired kidney function, multiple body systems are affected.Figure 2-1 shows complications that arise and manifest as CKD advances.2-1 The prevalence of complications is largely based on the level of GFR.1-1

Integumentary Cardiovascular

Bruises, pruritus, dry skin, High blood pressure, increased heart rate, skin color changes, dry brittle hair dysrhythmias, electrocardiographic changes, and nails abnormal heart sounds, retinopathy, fluid retention with peripheral edema and/or pulmonary edema

Respiratory Musculoskeletal Increased respiratory rate, crackles, decreased blood oxygen Renal osteodystrophy, decreased calcium, CLINICAL vitamin D impairment, hyperparathyroidism, MANIFESTATIONS pathological fractures OF CHRONIC Renal KIDNEY DISEASE Immune Decreased urine output, increased nitrogen, protein in Increased risk of infection urine, uric acid in urine

Gastrointestinal Hematological Neurological

Anorexia, nausea, vomiting, Anemia, weakness, fatigue, pallor, Peripheral neuropathy, restless legs, change halitosis, metallic taste in mouth, lethargy, bleeding due to impaired in level of consciousness, lethargy, confusion, bleeding in GI tract platelet aggregation encephalopathy, altered motor function

Figure 2-1: Clinical manifestations of CKD . Note how CKD impacts almost every body system .2-1

ANEMIA Anemia manifests early in the course of CKD and worsens as kidney function declines.2-2 Anemia is categorized by a lessened capacity of the blood to carry enough oxygen, most commonly due to a lower than normal amount of hemoglobin (Hb). 2-3 Erythropoietin (EPO) is a hormone produced by cells in the kidney. It stimulates erythropoiesis, the formation of red blood cells in bone marrow. Decreased EPO production by the failing kidneys is considered the primary cause of anemia in CKD patients.2-2

FAST FACT Anemia is a recognized independent risk factor for CKD and an important predictive factor for progression to ESRD. The anemia of CKD also amplifies the risk for CVD, which may lead to further kidney dysfunction and culminate in a vicious cycle, termed the cardiorenal anemia syndrome.2-2

LEARNING GUIDE: COMPLICATIONS OF CKD 19 BACK TO THE TABLE OF CONTENTS HYPERTENSION Hypertension (high blood pressure) is both a cause and an early complication of CKD.1-1 High blood pressure can directly damage the small blood vessels within nephrons — the functional units of the kidneys. The kidneys then lose their ability to autoregulate GFR and blood pressure, with consequent albuminuria and proteinuria. The proximal tubules then reabsorb excess protein and secrete vasoactive substances that further damage the nephrons. Nephron damage activates the renin-angiotensin-aldosterone system. Increased fluid retention exacerbates the progression of hypertension and nephron loss.1-2 Overall, the fluid retention associated with hypertension contributes to the development of respiratory and cardiovascular complications.2-1 Left untreated, hypertension can accelerate CKD progression.1

EDEMA Edema (accumulation of excess fluid in tissues) is an important marker of kidney damage. Edema develops as the kidneys lose their ability to excrete water due to impaired nephron function and resultant decrease in GFR. Other contributing factors include proteinuria and increased renin secretion.2-1 Edema associated with kidney disease usually occurs around the eyes, ankles, feet and abdomen.1-17

CKD–MINERAL AND BONE DISORDER As CKD advances, it is accompanied by progressive deterioration in mineral and bone metabolism, with disturbances in calcium, phosphorus, vitamin D and parathyroid hormone (PTH) homeostasis.1-3 CKD–mineral and bone disorder (CKD–MBD) is a clinical syndrome encompassing mineral, bone and calcific cardiovascular abnormalities that develop as a complication of CKD (summarized in Figure 2-2): 1-3, 2-4

REDUCED KIDNEY FUNCTION

CKD-MBD - Calcium and phosphorus abnormalities - Secondary hyperparathyroidism - Vitamin D deficiency - Vascular calcification - Bone abnormalities

Cardiovascular Decreased Mortality Fractures disease quality of life

Figure 2-2: Complications caused by disturbances in mineral metabolism in CKD .2-5

LEARNING GUIDE: COMPLICATIONS OF CKD 20 BACK TO THE TABLE OF CONTENTS The components of CKD–MBD (biochemical abnormalities, bone abnormalities and extraskeletal calcification) are closely interrelated, and together, contribute to the high morbidity and mortality observed in people with CKD.3

BIOCHEMICAL DISTURBANCES Calcium and phosphorus homeostasis relies on a complex, tightly regulated system involving parathyroid hormone (PTH), vitamin D and other factors. Abnormalities in mineral metabolism usually originate from failure to maintain this critical regulatory system.2-6

Table 2-1 summarizes the changes in mineral metabolism that occur with advancing CKD.

GFR RATE CHANGE IN SERUM LEVELS STAGE 2 (mL/min/1.73 M ) 1,25D Phosphate Calcium Pth

G2 60–89 $ 1 1 ­#

G3a 45–59 $$ ­# 1 ­#2-fold

G3b 30–44 $$ ­# 1 ­#2-fold

G4 15–29 $$$ ##­­  ­ #­ 4-fold

G5 < 15 $$$$ ###­­­  ­#8-fold

Table 2-1: Changes in mineral metabolism with progressing CKD .2-7

Abbreviations: 1,25D = 1,25-dihydroxyvitamin D; $ = decrease; ­# = increase; 1 = no change

SECONDARY HYPERPARATHYROIDISM (SHPT) PTH is the most important regulator of calcium metabolism. It is secreted in response to hypocalcemia and hyperphosphatemia.2-6 Regulation of the vitamin D–PTH axis is disrupted in early CKD.2-7 The net effect is a continuous stimulation of the parathyroid glands and persistent, excessive secretion of PTH. This leads to: 2-8 • Increased calcium release from bone, potentially causing bone disease. • Reduced activation of vitamin D in the kidneys. • Decreased calcium absorption from the GI tract.

Secondary hyperparathyroidism (SHPT) begins as early as stage G3a CKD. Most, if not all, untreated people with CKD will develop SHPT, which is associated with increased fracture risk and cardiovascular complications.2-8

LEARNING GUIDE: COMPLICATIONS OF CKD 21 BACK TO THE TABLE OF CONTENTS BONE DISEASE Bone disease may occur early in the course of CKD and worsen with progressive kidney dysfunction. By CKD stage G5, bone disease is common, with nearly all patients affected upon dialysis initiation.2-9 • People with CKD stages G1–G3a often have low bone mineral density (BMD), which is diagnosed as osteopenia or osteoporosis, depending on degree. • People with more advanced CKD (stages G3b–G5) who display biochemical abnormalities of mineral metabolism are designated as having renal osteodystrophy — a spectrum of bone defects characterized by abnormalities in bone turnover (remodeling), mineralization and volume.1-3, 2-4 • Both osteoporosis and renal osteodystrophy can increase bone fragility and fractures despite their different pathophysiological backgrounds.1-3

VASCULAR CALCIFICATION The prevalence of extraosseous tissue calcification (at sites other than bone and teeth) increases with deteriorating kidney function. In CKD, poorly controlled metabolic disease contributes to calcification of the inner and middle layers of arterial walls, and is associated with atherosclerosis (plaque formation) and stiffening of the arteries. Accelerated atherosclerosis in CKD, and especially ESRD, is linked to cardiovascular events and death.1-3, 2-10

CARDIOVASCULAR DISEASE Cardiovascular disease (CVD) is a well-known complication of CKD. In CKD patients, increased CVD risk is associated with:2-11 • Traditional risk factors, such as hypertension, hyperlipidemia and diabetes. • Nontraditional risk factors, such as anemia, abnormal PTH levels, hyperphosphatemia, inflammation, proteinuria and vascular calcification. Cardiovascular diseases encountered in CKD include:2-8 • Left ventricular hypertrophy (LVH) — thickening of the muscle of the lower left chamber of the heart. • Congestive heart failure (CHF) — inability of the heart to maintain adequate blood circulation causing congestion and edema in body tissues.1-18 • Peripheral artery disease (PAD) — occlusion of the blood vessels serving the lower extremities leading to pain during activities, resting pain or numbness.

LEARNING GUIDE: COMPLICATIONS OF CKD 22 BACK TO THE TABLE OF CONTENTS CARDIORENAL SYNDROME CKD, CVD and CHF share a number of causes (e.g., hypertension, dyslipidemia, diabetes) and risk factors (e.g., older age, obesity). These conditions coexist in a large number of patients.2-2 Recall that kidney dysfunction can negatively impact the heart and circulation, while heart disease can impair kidney function. Consequently, acute or chronic dysfunction of one organ may result in secondary dysfunction of the other. This phenomenon, a simplified version of which is shown in Figure 2-3, is sometimes referred to as the cardiorenal syndrome.2-12

- Smoking CKD - Obesity STAGE G1G2 - Hypertension Glomerular/interstitial - Dyslipidemia damage

- Genetic risk factors - Acquired risk factors - Primary nephropathy - Diabetes mellitus CKD STAGE G3aG4 - Anemia, uremic toxins Sclerosis-Fibrosis - Ca and Phos abnormalities - Nutritional status + - Na + H2O overload

- Anemia and malnutrition - Cardiac remodeling CKD - Ca2+ and Phos abnormalities - Coronary and tissue STAGE G5 - Soft tissue calcification calcification + Dialysis - Na + H2O overload - EPO resistance - Uremic toxins

- Artificial surfaces - Chronic inflammation - Contaminated dialysis fluids

- Inflammatory response

Monocyte stimulation

- Vascular - Bone - Eƒects on calcification remodeling other organs - Atherosclerosis

Figure 2-3: Cardiorenal syndrome . Pathophysiological interactions between the heart and kidney in CKD, CVD and heart failure .2-12

LEARNING GUIDE: COMPLICATIONS OF CKD 23 BACK TO THE TABLE OF CONTENTS EFFECTS ON OTHER BODY SYSTEMS Many of the effects of CKD on other body systems are related to the buildup of uremic toxins as the kidneys fail.

SYSTEM COMPLICATION OF CKD

Endocrine system2-13 • Decreased production of kidney-derived hormones (e .g ., EPO, 1,25-dihydroxyvitamin D)­ • Impaired production, clearance or response to hormones as a result of uremia

Gastrointestinal (GI) • Elevated levels of urea, metabolic acids, ammonia, metabolic waste products cause system2-1, 2-13 GI complaints • Manifestations include halitosis (bad breath), mouth ulcers, metallic taste, anorexia, weight loss, nausea, vomiting, hiccups, GI bleeding

Nervous system1-1, • Central nervous system: uremic encephalopathy presents with fatigue, confusion or impaired 2-1, 2-14 concentration; may develop to seizures and coma • Peripheral nervous system: peripheral neuropathy results from nerve damage due to uremia; characterized by restless leg syndrome, leg pain and sensations of tightness, changes in gait and fine motor movement

Immune system2-1, 2-11 • Impaired immune and inflammatory responses and overall immune dysfunction • Increased risk of infection • Elevated inflammatory markers linked to CVD susceptibility

Integumentary • Uremic pruritus: dry skin, color changes, bruises, mechanical skin damage due to continuous system2-1, 2-15 scratching, brittle nails and hair • Calcific uremic arteriolopathy: potentially life-threatening vascular disorder of skin and subcutaneous tissue; lesions on the abdomen, buttocks and thigh evolve into painful, necrotic ulcers covered by dry scabs • Nephrogenic systemic fibrosis: occurs in people with CKD, acute kidney injury (AKI) and kidney transplants; characterized by painful, progressive fibrosis and thickening of the skin

Table 2-2: Additional complications of CKD .

LEARNING GUIDE: COMPLICATIONS OF CKD 24 BACK TO THE TABLE OF CONTENTS REVIEW QUESTIONS: SECTION 2 Answers are provided at the end of this Learning Guide.

1. Which condition is linked to decreased production of erythropoietin?

A Anemia

B Hypertension

C Neuropathy

D Susceptibility to infection

2. Which biochemical changes are typically associated with CKD progression?

A Hyperphosphatemia

B Parathyroid hormone elevation

C Vitamin D deficiency

D All of the above

3. What changes in mineral metabolism occur with progression of CKD?

A Elevated parathyroid hormone levels

B Hyperphosphatemia

C Hypocalcemia

D All of the above

4. Name at least two cardiovascular complications associated with CKD.

LEARNING GUIDE: COMPLICATIONS OF CKD 25 BACK TO THE TABLE OF CONTENTS SECTION 3 DIAGNOSIS AND MONITORING OF CKD

LEARNING OBJECTIVES After completing this section, you will be able to:

• Understand the importance of medical history and physical examination.

• Explain the tests of blood and urine used to diagnose and monitor CKD.

• Understand how glomerular filtration rate is estimated.

• Understand how imaging studies are used in the evaluation of CKD.

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 26 BACK TO THE TABLE OF CONTENTS MEDICAL HISTORY Most people with CKD have no symptoms, or have only nonspecific complaints, such as fatigue, loss of appetite or general malaise. For this reason, people may not be diagnosed until CKD is already advanced. Therefore, a complete medical history is very important. It will entail questions about: 1-17 • Risk factors for CKD, such as hypertension or diabetes. • Recurrent urinary tract infections or kidney stones. • Family history of kidney disease. • Any joint pain, skin rashes, fever or unexplained weight loss. • Use of prescription and over-the-counter medications, illicit drugs or herbal preparations. Additionally, a patient’s old medical records should be reviewed, if possible, to determine their previous level of renal functioning.1-17

PHYSICAL EXAMINATION A physical examination must be conducted to identify signs of systemic kidney disease and rule out an alternate diagnosis. Specific symptoms include: 1-17 • Urinary symptoms (nocturia, hematuria, dark urine). • Hypertension. • Edema. Blood pressure is classified on the basis of systolic and diastolic blood pressures. In 2017, the American College of Cardiology published the below guidelines (Table 3-1):3-1, 3-2

SYSTOLIC BLOOD DIASTOLIC BLOOD CATEGORY PRESSURE (mmHg) PRESSURE (mmHg)

Normal < 120 and < 80

Elevated 120–129 or < 80

Hypertension Stage 1 130–139 or 80–89

Hypertention Stage 2 ≥ 140 or ≥ 99

Table 3-1: 2017 Guideline for High Blood Pressure in Adults .3-1, 3-2

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 27 BACK TO THE TABLE OF CONTENTS ROUTINE BLOOD TESTS Biochemical abnormalities are the primary indicators by which CKD and its complications are diagnosed and managed. Common blood tests used to monitor kidney function and complications of CKD are summarized in Table 3-2.

CHEMISTRY NORMAL RANGE CKD FINDINGS AND IMPLICATIONS

Serum creatinine 1-17 0 6–1. 1. mg/dL Increased in CKD (53–98 μmol/L) for females Can be used to estimate GFR 0 8–1. .3 mg/dL (71–116μmol/L) for males

Blood urea nitrogen 7–20 mg/dL Increased in CKD 1-17, 3-3 (BUN) (2 5–7. 1. mmol/L) Used in conjunction with serum creatinine BUN to creatinine ratio 10:1

Calcium 1-1, 3-3 8 7–10. .2 mg/dL Decreased in CKD (2 .2–2 6. mmol/L) Not evident until GFR <30 mL/min/1 73. m2

Phosphorus1-1, 3-3 2 5–4. .3 mg/dL Increased in CKD (0 81–1. 4. mmol/L) Not evident until GFR <60 mL/min/1 73. m2

1,25-dihydroxyvitamin D 3-3, Summer: 15–80 ng/mL Decreased in CKD 3-4 (37 4–200. nmol/L) Not evident until GFR <30 mL/min/1 73. m2 Winter: 14–42 ng/mL (34 9–105. nmol/L)

Hemoglobin (Hb)1-1, 3-3 12–15 8. g/dL for females Decreased in CKD 13 .3–16 .2 g/dL for males Low levels warrant further testing

Parathyroid hormone 8–51 pg/mL Increased in CKD 1-1, 3-3 (PTH) High levels cause bone disease

Table 3-2: Blood tests used to assess kidney function and complications of CKD .

CREATININE Creatinine, a product of muscle breakdown, is produced at a constant daily rate. It is eliminated mostly by glomerular filtration. Creatinine provides an approximate measure of GFR. Creatinine levels: 1-17 • Increase as a marker of kidney damage. • May be falsely elevated by certain medications that interfere with excretion.

FAST FACT The serum creatinine level in men is higher than in women because men have greater muscle mass. Creatinine is also higher in younger rather than older individuals, and higher in blacks than in whites.1-1

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 28 BACK TO THE TABLE OF CONTENTS BLOOD UREA NITROGEN (BUN) Blood urea nitrogen (BUN), a major end product derived from protein, reflects dietary protein intake as well as the rate of protein breakdown. BUN is excreted by glomerular filtration, but a substantial amount is reabsorbed along the renal tubules. BUN is often used with serum creatinine to measure renal function. BUN levels: 1-17 • Vary with respect to blood volume. • May be increased by high-protein diet, certain medications or urinary tract obstruction. • May be decreased by a low-protein diet or liver disease.

SERUM PHOSPHORUS When kidney function declines, excretion of phosphorus is diminished and serum phosphorous levels rise. Phosphorous abnormalities may not become evident until CKD stage G3 (GFR <60 mL/ min/1.73 m2).1-1

SERUM CALCIUM When elevated phosphorous levels suppress calcitriol (bioactive vitamin D [1,25-dihydroxyvitamin D]) production, calcium absorption from the GI tract decreases. Calcium abnormalities may not become evident until CKD stage G4 (GFR <30 mL/min/1.73 m2).1-1

SERUM VITAMIN D Humans with intact kidney and liver function can make vitamin D3 from exposure to sunlight and consume vitamin D2 or D3 from the diet or dietary supplements. Collectively, vitamins D2 and D3 are referred to as vitamin D. Vitamin D is metabolized in the liver to 25-hydroxyvitamin D and then in the kidneys to its active form, 1,25-dihydroxyvitamin D (calcitriol). In people without significant renal disease, vitamin D status is determined by measuring serum levels of 25-hydroxyvitamin D, the primary circulating form of vitamin D.3-4 Levels of vitamin D are inversely related to parathyroid hormone (PTH) levels. Vitamin D deficiency may develop in CKD stages G4 or G5 (GFR <30 mL/min/1.73 m2).3-4

HEMOGLOBIN It is well established that anemia develops during the course of CKD. People with CKD and GFR <60 mL/min/1.73m2 should be evaluated for anemia, which consists of: 1-1 • Measurement of hemoglobin levels. • A complete blood count. • Physical examination for any signs of gastrointestinal bleeding.

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 29 BACK TO THE TABLE OF CONTENTS ESTIMATES OF GLOMERULAR FILTRATION RATE (EGFR) Estimates of GFR (eGFR) measure the filtering capacity of the kidneys and are the best overall indication of the level of kidney function. The eGFR is reported in terms of mL/min/1.73 m2 (an average body surface area).1-1

CLINICAL CONNECTION Persistently low or declining GFR indicates CKD. GFR can also be a strong predictor of the time to kidney failure as well as the risk of complications due to CKD.1-1

CREATININE CLEARANCE Serum creatinine alone is not an accurate index of GFR. The rate of creatinine clearance in the urine is one way to obtain a rough estimate of GFR.1-1 Urinary clearance of creatinine is computed from a timed urine collection (e.g., a 24-hour urine collection) and blood sampling during the collection period. However, timed urinary collections are cumbersome and susceptible to error, and thus are not routinely used.2-4 The amount of creatinine excreted in the urine corresponds to the creatinine filtered by the nephrons (i.e., glomerular filtration) plus the creatinine secreted by the proximal tubules. Because creatinine clearance includes tubular secretion, it overestimates the GFR by 10–40%.1-1 Creatinine clearance can be derived as follows: 1-17

CREATININE CLEARANCE (mL/min) = Urinary creatinine (mg/dL) x Volume of urine (mL/min)* / Plasma creatinine (mg/dL)

*If the volume of urine corresponds to a 24-hour collection, the volume is divided by 1,440 (60 min/hour x 24 hours/day) .

The normal range for creatinine clearance is 95–105 mL/min/1.73 m2.

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 30 BACK TO THE TABLE OF CONTENTS FAST FACT Creatinine excretion varies from day to day; thus, creatinine clearance estimates of GFR are imprecise, even from a 24-hour urine collection. Furthermore, urinary excretion of creatinine is lower in CKD, leading to an overestimation of GFR using creatinine clearance.1-1

EQUATIONS TO ESTIMATE GFR Equations to estimate GFR have been developed to overcome some of the limitations of using creatinine alone. These equations adjust serum creatinine measurements for factors such as age, sex, race and body size.3-5

MODIFICATION OF DIET IN RENAL DISEASE (MDRD) LONG FORMULA The Modification of Diet in Renal Disease (MDRD) study equation was developed using data from a large sample of people with CKD.3-5 It can be used to estimate GFR up to approximately 90 mL/min/1.73 m2.1-1 The original MDRD equation included six parameters: creatinine, albumin, age, sex, race and BUN.3-6

ESTIMATED GFR (mL/min/1.73 m2) = 170 x (Serum creatinine)-0.999 x (Age)-0.176 x (BUN)-0.170 x (Albumin)0.318

Note: For women, the final value is multiplied by 0 762. . For blacks, the final value is multiplied by 1 180. .

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 31 BACK TO THE TABLE OF CONTENTS MDRD 4-PARAMETER FORMULA The MDRD equation was later simplified into a 4-parameter formula.3-7 The 4-parameter MDRD equation requires only serum creatinine value, age, sex and race.1-1

ESTIMATED GFR (mL/min/1.73 m2) = 175 x (Serum creatinine)-1.154 x (Age)-0.203 Notes: • For women, the final value is multiplied by 0 742. . For blacks, the final value is multiplied by 1 .212 . • When serum creatinine levels are measured in μmol/L, the value is multiplied by different factors 3-5. • Creatinine should be measured with an assay for which calibration is traceable to an isotope-dilution mass spectrometry (IDMS) method .

CKD-EPI EQUATION Other equations are also used to estimate GFR. A new equation was recently developed and named the Chronic Kidney Disease Epidemiology Collaboration (CKD–EPI) equation. This equation is used for large studies because it provides better accuracy and reduced variability.3-7

ESTIMATED GFR (mL/min/1.73 m2) = α -1.209 Age 141 x min (Scr /κ, 1) x max (Scr /κ, 1) x 0.993 x 1.018 [if female] x 1.159 [if black] Where: • Scr is serum creatinine in mg/dL • min indicates the minimum of Scr /κ or 1 • κ is 0 7. for females and 0 9. for males • max indicates the maximum of Scr /κ or 1 • α is -0 .329 for females and -0 411. for males

Both the 4-parameter MDRD equation and the CKD-EPI equation are widely used to estimate eGFR in clinical settings.

CYSTATIN C Cystatin C is a low molecular weight protein that is freely filtered across the glomerular membrane. It is then reabsorbed and broken down in the renal tubules. Cystatin C is not normally excreted in urine, unless there is kidney damage. However, it can be accurately measured in blood serum: 3-5, 3-8 • An increase in serum cystatin C is a marker of declining kidney function • Urinary excretion is predictive of kidney failure and need for dialysis • Urine cystatin C is elevated in CKD and acute kidney injury

Unlike serum creatinine, cystatin C levels are not significantly affected by age, sex, race or muscle mass. Thus, cystatin C provides a more accurate estimate of GFR in people with CKD. 3-8 Moreover, cystatin C is more sensitive for detecting small decreases in GFR in people with mild renal dysfunction. 3-9

Cystatin C has been standardized and a eGFR equation is available for standardized assays. 3-7

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 32 BACK TO THE TABLE OF CONTENTS URINE TESTS Routine assessment of kidney function involves the evaluation of both quantity and quality of urine.1-15

SEDIMENTATION Analysis of urinary sediment is recommended for people with CKD or who are at increased risk of developing CKD.1-1 Microscopic examination of the urine sample may reveal cells, casts, crystals and microorganisms.1-17 Urinary casts form when a high molecular weight protein derived from epithelial cells of the nephron precipitates within the renal tubules. The protein forms a gel that can trap cell debris, cells, crystals, fat and filtered proteins. Cast production increases when urine is highly concentrated or acidic.1-1 Formed elements in the urinary sediment may indicate glomerular, tubular or vascular kidney disease. Significant numbers of red blood cells, white blood cells or casts suggest acute or chronic kidney disease that requires further analysis.1-1

OSMOLARITY The osmolarity of urine is determined by the regulation of the loss of water and solutes in the urine by the kidneys and is maintained at a relatively constant level. If disease alters kidney function, then substances normally not present in urine may appear and increase its osmolarity.1-15

URINARY PROTEIN Individuals with normal kidney function usually excrete little or no protein in the urine. A persistently high level of protein in the urine is usually a marker of kidney damage. The specific type of protein that is excreted in the urine varies, depending on the type of disease: 1-1 • Urinary albumin is a marker for CKD, diabetes, hypertension and glomerular disease • Low molecular weight globins are indicative of certain tubulointerstitial diseases

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 33 BACK TO THE TABLE OF CONTENTS Proteinuria can be considered within the normal physiological range when levels are low and within defined limits. When levels exceed the physiologic range, the terminology used changes in relation to protein levels (see Table 3-3): 3-10

ALBUMINURIA PROTEINURIA

Physiologic range proteinuria <20 mg/day <150 mg/day Increased urinary excretion of proteins in general (15 mcg/min) (e .g ., albumin, other specific proteins, total protein)

Microalbuminuria 30–300 mg/day — Albumin excretion above normal range, but below (20–200 mcg/min) level of detection of tests for total protein

Macroalbuminuria >300 mg/day — Albumin excretion above normal range, detectable (>200 mcg/min) on tests for total protein

Nephrotic range proteinuria — >3 5. g/day Massive excretion of protein

Table 3-3: Terminology Used to Describe Proteinuria 1-1,. 3-10

Proteinuria is a key prognostic finding in CKD, and severity of disease often correlates with the level and persistence of proteinuria over time. Therefore, regular screening for proteinuria is recommended.1-1 Under most circumstances, a random (or “spot”) urine dipstick test is used to detect and monitor proteinuria. A positive dipstick test for protein should be followed with a quantitative measurement of protein-to-creatinine ratio or albumin-to-creatinine ratio within three months.1-1

FAST FACT Microalbuminuria is the earliest manifestation of diabetic kidney disease. It is typically followed by proteinuria, hypertension and progressively declining GFR, depending on the stage of CKD.1-1

URINARY ALBUMIN-TO-CREATININE RATIO (UACR) Urinary protein-to-creatinine ratio and the more common and preferred urinary albumin-to-creatinine ratio (UACR) provide accurate estimates of the urinary protein and albumin excretion rate, regardless of hydration status. Urinary proteins and creatinine dissolve easily in water. Therefore, their dilution in urine should be similar and their ratio should be constant. Because the rate of creatinine excretion is relatively steady throughout the day, the UACR in a random urine sample reflects the excretion of protein.1-1

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 34 BACK TO THE TABLE OF CONTENTS PTH IMMUNOASSAYS Elevated serum parathyroid hormone (PTH) may be the earliest marker of abnormal bone mineral metabolism, detectable before changes in phosphorus and calcium. The following interpretive guidelines for PTH have been proposed: 1-1 • <65 pg/mL is predictive of normal bone (normal range 8–51 pg/mL3-2) in people with normal kidney function • >450 pg/mL reflects a high turnover rate

PTH relates directly to bone turnover, with the caveat that it is not reliably correlated with turnover rate in severe CKD requiring dialysis.1-1 The Kidney Disease: Improving Global Outcomes (KDIGO) and KDOQI guidelines recommend periodic monitoring of serum levels of calcium, phosphorus and PTH in all people with CKD stage G3a or higher, according to the schedule in Table 3-4.1-3, 3-11

CKD GFR RANGE MEASUREMENT OF MEASUREMENT OF PTH STAGE (mL/min/1.73 M2) CALCIUM/PHOSPHORUS

According to baseline PTH level G3a 45–59 Every 6–12 months and CKD progression

According to baseline PTH level G3b 30–44 Every 6–12 months and CKD progression

G4 15–29 Every 6–12 months Every 3–6 months

G5 < 15 or dialysis Every 3–6 months Every 1–3 months

Table 3-4: Frequency of serum PTH and calcium/phosphorus monitoring .3-11 Based on KDIGO 2017 recommendations 1-3.

PTH levels are measured by immunoassay. Current assays detect biologically active intact PTH (iPTH), rather than fragments of PTH that may be inactive. They are detected as: 3-12 • Immunoradiometric (IRMA), meaning that antibodies bound to PTH are detected with a radioactive tag. • Immunochemiluminescent (ICMA), meaning that antibodies bound to PTH are detected using a tag that emits light when a chemical reagent is added.

FAST FACT Approximately 50% of circulating PTH in people with kidney failure consists of large fragments of PTH, and not the intact form. Older PTH assays detected fragments of PTH. Newer assays are specific for the full-length molecule, designated as “whole,” “bioactive” or “intact” PTH.3-12

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 35 BACK TO THE TABLE OF CONTENTS KIDNEY IMAGING STUDIES Imaging studies are recommended for people with CKD and for people who are at an increased risk of developing CKD due to urinary tract stones, infection or obstruction.1-1 Imaging studies used to evaluate kidney damage include: • Ultrasound — Uses high-frequency sound waves that bounce off structures and are converted to images. 3-13 • Intravenous pyelography (IVP) — The entire urinary system is visualized through a series of x-ray images, taken sequentially before and after injection of radioactive contrast medium. 3-13 • Computed tomography (CT) — Cross-sectional imaging technique uses computerized reconstruction to generate an image “slice”. 3-13 • Magnetic resonance imaging (MRI) — Cross-sectional images are obtained by a complex interaction between atoms in the cells and radiofrequency waves in a strong magnetic field. 3-13 Each of these imaging techniques is useful for identifying urinary tract obstructions such as kidney stones, cysts and tumors. In ultrasonography, CKD is generally indicated by small kidneys that produce a strong echo.1-1

KIDNEY BIOPSY A kidney biopsy provides tissue that can be used to help confirm diagnosis and to assess the chronicity and severity of the injury. Renal biopsy is indicated only when the cause of kidney disease cannot be determined by less invasive diagnostic procedures. 3-14

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 36 BACK TO THE TABLE OF CONTENTS EVALUATION OF BONE In addition to the laboratory parameters discussed earlier, there are a number of evaluations specific to bone. These include markers of bone turnover, bone density and evaluation of bone histology.

CKD

Abnormal levels and bioactivity of laboratory parameters:

Laboratory PTH Calcium Phosphorus 25(OH)D 1,25(OH)2D surrogate High Normal High Normal Normal outcomes Normal Low Normal Low Low

Bone disease: Bone Bone turnover abnormal surrogate Bone mineralization/density structure or outcomes Bone biopsy function

Fractures, pain, decreases in mobility, strength or growth Clinical outcomes

Disability, decreased QOL, hospitalizations, death

Figure 3-1: Evaluation of bone disease in people with CKD 1-3. QOL: quality of life .

MARKERS OF BONE TURNOVER Bone turnover (remodeling) is a coupled process in which resorption of old bone by osteoclasts is followed by formation of new bone by osteoblasts. The process is regulated by PTH, vitamin D metabolites and various other factors.3-15 Biochemical markers that reflect the remodeling process can be measured in blood and/or urine. They include: 3-15 • Enzymes or proteins secreted by cells involved in remodeling. • By-products generated during the resorption or formation of bone.

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 37 BACK TO THE TABLE OF CONTENTS CLINICAL CONNECTION In CKD, changes in bone remodeling may be dramatic (such as in renal osteodystrophy); however, most are rather subtle (such as in osteoporosis).3-15 Definitive diagnosis of the type of bone disease requires bone biopsy.1-1

BONE MINERAL DENSITY (BMD) MEASUREMENT

Bone mineral density (BMD) can be measured using noninvasive X-ray techniques.1-3 A low or decreasing BMD value is indicative of abnormal bones: 1-3 • In CKD stages G1–G3b, BMD is an important predictor of fracture risk 1-3 • In CKD stages G3b–G5, once CKD–MBD begins to develop, BMD does not predict fractures very well, and routine testing is not recommended 1-3 • Following kidney transplant, there is a rapid loss of bone mass and increased fracture risk; regular BMD monitoring is recommended2-9

CLINICAL CONNECTION As part of the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994, a correlation was noted between BMD and Cockcroft-Gault eGFR in 13,831 adults older than 20 years old. Low BMD was more prevalent among those with CKD than with normal kidney function.1-3

RADIOGRAPHY The bone disease component of CKD–MBD may result in fractures, including asymptomatic vertebral fractures. Fractures can be identified on standard radiographs (X-rays).1-3

BONE BIOPSY Bone biopsy is the gold standard for the diagnosis of renal osteodystrophy. Unfortunately, the procedure is invasive and cannot be readily performed in all patients.1-3 Bone biopsies help to assess bone quality and the underlying pathophysiology of bone disease. In people with CKD stages G3a–G5, bone biopsy may be warranted if there are unexplained fractures, persistent bone pain, unexplained hypercalcemia or hypophosphatemia or possible aluminum toxicity, and before initiating certain treatments.1-3

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 38 BACK TO THE TABLE OF CONTENTS REVIEW QUESTIONS: SECTION 3 Answers are provided at the end of this Learning Guide.

1. Which measure would you expect to decrease as CKD progresses?

A 1,25-dihydroxyvitamin D

B Parathyroid hormone

C Serum phosphorus

D Urinary albumin

2. Which method can be used to estimate glomerular filtration rate (GFR)?

A Serum creatinine measurement

B Parathyroid hormone (PTH) assay

C Serum calcium x phosphorous product

D Urinary albumin to creatine ratio

3. Serum creatinine levels vary according to which of the following criteria?

A Age

B Race

C Sex

D All of the above

4. How often should serum parathyroid hormone (PTH) levels be measured in people with stage G3a CKD?

A Every 1–3 months

B Every 3–6 months

C Every 6–12 months

D Every 12–24 months

LEARNING GUIDE: DIAGNOSIS AND MONITORING OF CKD 39 BACK TO THE TABLE OF CONTENTS SECTION 4 MANAGEMENT OF CKD

LEARNING OBJECTIVES After completing this section, you will be able to:

• Identify key guidelines for long-term management of people with CKD.

• Recognize treatments that may slow progression of CKD.

• Describe the conditions associated with CKD, and how to manage them.

• Understand renal replacement therapy and renal transplantation.

LEARNING GUIDE: MANAGEMENT OF CKD 40 BACK TO THE TABLE OF CONTENTS MANAGEMENT OVERVIEW Clinical practice guidelines help healthcare providers consistently manage long-term treatment of CKD. Two key organizations publish guidelines for CKD diagnosis, evaluation, classification and treatment: • The U.S. National Kidney Foundation – Kidney Disease Outcome Quality Initiative (NKF–KDOQI)1-1 • The International Society of Nephrology: Kidney Disease: Improving Global Outcomes (KDIGO)1-3

According to the NKF–KDOQI, a clinical action plan should be developed for each patient, based on the stage of disease as defined inTable 4-1.1-1

GFR STAGE DESCRIPTION ACTION (mL/min/1.73 M2)

At increased risk ≥ 90 Screening, (with CKD risk factors) CKD risk reduction

G1 Kidney damage with ≥ 90 Diagnosis and treatment normal or # GFR Treatment of comorbid conditions Slowing progression Reduction of cardiovascular risks

G2 Kidney damage with 60–89 Estimating progression mild  GFR

G3a Moderate  GFR 45–59 Evaluating and treating complications

G3b Moderate  GFR 30–44 Evaluating and treating complications

G4 Severe  GFR 15–29 Preparation for renal replacement therapy (dialysis or transplant)

G5 Kidney failure < 15 (or dialysis) Renal replacement therapy, if uremia is present

Table 4-1: Chronic kidney disease: a clinical action plan 1-1.

LEARNING GUIDE: MANAGEMENT OF CKD 41 BACK TO THE TABLE OF CONTENTS SLOWING PROGRESSION OF CKD The major outcomes of CKD are the progressive loss of kidney function leading to kidney failure and complications such as cardiovascular disease (CVD) and bone disease. Therefore, the goal of medical management of CKD is to slow the progressive loss of kidney function. The rate of GFR decline should be assessed to predict the onset of kidney disease and possible interventions evaluated to slow GFR decline.1-1 In people with CKD, serum creatinine should be measured:1-1 • At least yearly, in order to monitor GFR. • More frequently than once a year if GFR <60 mL/min/1.73 m2 or if there are risk factors for fast progression.

Early interventions to slow the progression of CKD include dietary restrictions, tight control of blood sugar and maintaining blood pressure and blood lipids within a reasonable range, as summarized in Table 4-21-1. The dyslipidemia of CKD primarily is comprised of high triglyceride levels and low HDL cholesterol levels. 4-1 Although the NKF-KDIGO recommends following ACC goals, the patients with CKD are known to be challenging to treat and this is particularly true regarding triglyceride management. It is usually recommended that targeted management be made for CKD patients whose triglycerides reach levels of 500 mg/dL. Specific treatment recommendations are not provided in the guide.

GOALS APPROACHES

Protein intake1-1 Reduce accumulation of toxic urea and creatinine • Dietary protein restriction in CKD stages G4–G5 (if not on dialysis)

Energy intake1-1 Improve nitrogen utilization • Increased caloric intake in CKD Prevent malnutrition and weight loss stages G4–G5 (if not on dialysis)

Blood glucose1-1 Control blood glucose in diabetics • Diet, exercise, weight loss Reduce retinopathy, microalbuminuria, kidney disease, • Oral antidiabetic medications cardiovascular risk and/or insulin

Blood pressure1-1, Reduce hypertension, glomerular capillary pressure, • Diet (reduce salt, fluids), exercise 4-2 protein filtration • Antihypertensive medications: Blood pressure targets: angiotensin-converting enzyme inhibitors, angiotensin receptor • CKD stages G1–G4 with proteinuria (<1 g/day) or diabetic blockers, diuretics, beta blockers, kidney disease: <125/75 mmHg calcium channel blockers • CKD stages G1–G4 without proteinuria: <130/80 mmHg • In CKD stage G5: Guidelines are not well defined

Blood lipids1-1, Control dyslipidemias and reduce risk of atherosclerosis • Diet, exercise, weight loss 4-3, 4-4 (rather than slow CKD progression) • Lipid-lowering medications: statins, Lipid targets: fibrates, niacin, bile sequestrants • Triglycerides <150 mg/dL 4-5 • Low-density lipoprotein cholesterol <100 mg/dL • High-density lipoprotein cholesterol between 30mg/dL and 60mg/dL

Table 4-2: Approaches to slowing CKD progression .

LEARNING GUIDE: MANAGEMENT OF CKD 42 BACK TO THE TABLE OF CONTENTS MANAGING CONDITIONS ASSOCIATED WITH CKD Decreased GFR is associated with complications in virtually all organ systems. These complications manifest first by high blood pressure and abnormal blood tests, then by symptoms and abnormalities on physical examination. As GFR declines, complications generally worsen. Some important complications to be managed in CKD are malnutrition, anemia, neuropathy, hyperphosphatemia, secondary hyperparathyroidism (SHPT) and bone disease. Management goals and approaches for each are summarized in Table 4-3.1-1

GOALS APPROACHES

Anemia1-1, 2-3 Correct iron deficiency • Iron supplements Stimulate red blood cell production and raise • Erythropoiesis-stimulating agents hemoglobin levels (ESAs): epoetin alfa, epoetin beta, darbepoeitin

Malnutrition1-1 Evaluate nutritional status • Counseling, education Address protein energy malnutrition • Dietary modification

Hyperphosphatemia1-3, 2-9 Reduce blood phosphate levels • Phosphate-restricted diets Phosphate targets: • Oral phosphate binders to reduce phosphate absorption: aluminum • CKD stages G3 and G4: 2 7–4. 6 mg/dL. hydroxide, calcium salts, (0 87–1. 49. mmol/L) non-calcium-based phosphate binders • CKD stage G5 and dialysis patients: (sevelamer and lanthanum salts) 3 5–5. 5. mg/dL (1 13–1. 78 mmol/L).

Secondary Correct hypocalcemia and vitamin D • Oral calcium salts, increased calcium hyperparathyroidism deficiency, reduce PTH levels dialysate concentration (SHPT)1-3 PTH targets (iPTH assay) • Vitamin D, vitamin D analogs • CKD stages G3a–G5: maintain below • Calcimimetics upper normal limit of assay • Parathyroidectomy (surgical removal • CKD stage G5 on dialysis: maintain within of parathyroid glands) 2–9x upper normal limit of assay

Osteoporosis1-3, 2-9 Increase BMD, reduce fracture risk in • Bone resorption inhibitors: CKD stages G1–G3b without biochemical bisphosphonates, raloxifene abnormalities of CKD–MBD or SHPT • Bone anabolic: teriparatide (1–34 PTH)

Uremic neuropathy4-6 Halt progression of neuropathy • Renal transplant or dialysis

Table 4-3: Managing CKD complications .

LEARNING GUIDE: MANAGEMENT OF CKD 43 BACK TO THE TABLE OF CONTENTS RENAL REPLACEMENT THERAPY (RRT) People with kidney failure ultimately require dialysis or kidney transplantation to sustain life. Some experts advocate “early initiation of dialysis” or “preemptive” kidney transplantation prior to the onset of kidney failure.1-1 Recall that kidney failure is defined as one of two conditions: • GFR <15 mL/min/1.73 m2, usually accompanied by signs of uremia • Need to initiate kidney replacement therapy such as dialysis or transplantation for treatment of complications of decreased GFR, which would otherwise increase the risk of mortality and morbidity Note: Some patients may require dialysis or transplantation at GFR ≥15 mL/min/1.73 m2 because of symptoms of uremia.1-1 If kidney function is inadequate, then blood must be cleansed artificially by dialysis. This process separates large solutes from smaller ones by diffusion through a selectively permeable membrane.1-15 Dialysis cannot replace the endocrine function of the kidney — secretion of erythropoietin (involved in red blood cell production) and calcitriol (involved in bone formation). Therefore, dialyzed people need to be supplemented to control for anemia and bone disorder.4-7

HEMODIALYSIS Hemodialysis directly filters the blood through a membrane and returns it to the body. Dialysate fluid surrounds the membrane and maintains a concentration gradient, so substances diffuse between dialysate and blood:1-15 • Wastes, excess electrolytes and fluid flow from the blood into the dialysate • The blood is replenished with needed substances from the dialysate

Following filtration, the cleansed blood passes through a mechanism to remove any air, and an agent is added to prevent the blood from clotting. Most people require hemodialysis for 6–12 hours per week, divided into two sessions.1-15 Hemodialysis requires a vascular access site, either in the form of a temporary catheter, or a permanent access that is surgically created: • Arteriovenous (AV) fistulas connect an artery directly to a vein, usually in the forearm; the vein then thickens, allowing repeated needle insertions 1-19 • Grafts in hemodialysis connect an artery to a vein using a synthetic tube 1-19

LEARNING GUIDE: MANAGEMENT OF CKD 44 BACK TO THE TABLE OF CONTENTS Figure 4-1: Hemodialysis: Blood is filtered through a selectively permeable membrane and then returned to the body .

PERITONEAL DIALYSIS Peritoneal dialysis uses the peritoneum (lining of the abdominal cavity) as a filter because it has a large surface area and numerous blood vessels. Dialysate is drained from a bag through a catheter inserted in the abdomen. Wastes, excess electrolytes and fluid diffuse into the dialysate, and the solution is then drained, discarded and replaced. Each cycle is called an exchange.1-15 • Continuous ambulatory peritoneal dialysis (CAPD) needs no machine — it can be performed at home with the dialysate drained and replenished four times a day and once at night during sleep. 1-19 • Continuous cycler-assisted peritoneal dialysis (CCAPD) uses a portable cycler to automatically fill and drain the dialysis solution from the abdomen; a typical schedule involves 3–5 exchanges during the night while the person sleeps, and one exchange during the day. 1-19, 4-8

LEARNING GUIDE: MANAGEMENT OF CKD 45 BACK TO THE TABLE OF CONTENTS RENAL TRANSPLANTATION A kidney transplant is the treatment of choice for people with CKD stage G5:1-1, 4-9 • Kidney transplant recipients have a higher mean GFR (usually 30–60 mL/min/1.73 m2) and a better average outcome than dialysis patients • Risk of death among transplant recipients is less than half of that among people on dialysis

REJECTION RISK Acute rejection may occur when the recipient mounts an immune response against the kidney. It is accompanied by a decline in kidney function and histological changes in the new kidney. Precautions must be taken to reduce the risk of the new kidney being rejected: 4-9 • Before transplantation, induction treatment with an immunosuppressive agent is initiated to deplete immune cells or modulate immune responses • Following transplantation, long-term immunosuppressive therapy is required to prevent rejection and deterioration of kidney function — higher doses are given in the first three months, when risk of rejection is greatest

POSTTRANSPLANT BONE DISEASE Rapid loss of bone mass within the first six months after a kidney transplant leads to osteopenia, which may worsen to the point of osteoporosis. This is accompanied by increased risk of fractures, particularly for the first two years after transplant. Corticosteroids and immunosuppressive therapies contribute to this rapid bone loss.2-9 Bone mineral density (BMD) in transplant recipients should be regularly monitored using dual-energy X-ray absorptiometry (DXA). If osteoporosis develops, then appropriate therapy should be initiated.2-9

LEARNING GUIDE: MANAGEMENT OF CKD 46 BACK TO THE TABLE OF CONTENTS REVIEW QUESTIONS: SECTION 4 Answers are provided at the end of this Learning Guide.

1. Which modality may require surgical creation of an arteriovenous fistula?

A Continuous ambulatory peritoneal dialysis

B Continuous cycling peritoneal dialysis

C Hemodialysis

D Renal transplant

2. A calcimimetic could be used to treat which complication of CKD?

A Anemia

B Hypertension

C Osteoporosis

D SHPT

3. Which measures may help slow CKD progression?

A Blood pressure control

B Glycemic control

C Protein restriction

D All of the above

4. At which stage of CKD should preparation for dialysis or transplant begin?

A Stage G2

B Stage G3a

C Stage G4

D Stage G5

LEARNING GUIDE: MANAGEMENT OF CKD 47 BACK TO THE TABLE OF CONTENTS APPENDIX

APPENDIX A: GLOSSARY OF TERMS APPENDIX B: REFERENCES APPENDIX C: CORRECT RESPONSES

LEARNING GUIDE: APPENDIX 48 BACK TO THE TABLE OF CONTENTS APPENDIX A: GLOSSARY OF TERMS

Albumin: The major plasma protein, approximately 60% of the total, and is responsible for much of the osmotic pressure of the plasma. It acts as a transport protein for fatty acids, drugs and hormones, among others. It is synthesized in the liver and its concentration is decreased in the context of renal disease.A-1

Anemia: Condition categorized by a lessened capacity of the blood to carry enough oxygen, most commonly due to a lower-than-normal amount of red blood cells or hemoglobin.2-3

Arteriovenous (AV) fistula: Surgical connection of an artery directly to a vein, usually in the forearm; causes vein to thicken, allowing repeated needle insertions for hemodialysis. 1-19

Atherosclerosis: Disease characterized by irregularly distributed lipid deposits in the intima of large and medium arteries. Such deposits provoke fibrosis and calcification. Deposits hinder or eventually shut off blood flow.1-18

Comorbidity: Medical condition other than the primary disease.1-1

Creatinine: A waste product from meat protein in the diet and from the muscles of the body.1-19

Cystatin C: A low-molecular weight protein produced at a constant rate by all nucleated cells and freely filtered by the glomerulus, which is then reabsorbed and degraded by the tubules. Serves as a novel serum marker of GFR.A-2

Diabetes mellitus: A condition characterized by high blood glucose (sugar); encompasses type 1 and type 2 diabetes.1-19

Dialysate (dialysis solution): A cleansing liquid used in the two major forms of dialysis — hemodialysis and peritoneal dialysis. This solution contains dextrose (a sugar) and other chemicals similar to those in the body. Dextrose draws wastes and extra fluid from the body into the dialysis solution.1-19

Diastolic blood pressure: The force exerted by blood on arterial walls during relaxation of the heart muscle; the lowest blood pressure measured in the large arteries.A-3

Dyslipidemia: Abnormal lipid metabolism. A-4

Edema: An abnormally high accumulation of tissue fluid.A-3

Encephalopathy: Any disorder of the brain.1-18

Erythropoiesis: The production of red blood cells.A-5

Erythropoiesis-stimulating agent (ESA): Any agent that augments erythropoiesis through direct or indirect action on the erythropoietin receptor. ESAs include epoetin alfa, epoetin beta, and darbepoetin alfa.2-3

Erythropoietin (EPO): A hormone made by the kidneys to help form red blood cells. Lack of this hormone may lead to anemia.1-19

Glomerular filtration rate (GFR): The amount of filtrate formed in all the renal corpuscles of both kidneys each minute (mL/min).1-15

Hemodialysis (HD): Use of a machine to remove wastes and extra fluid from the blood after kidney failure; cleaned blood flows through a set of tubes back into the body.1-19

Hemoglobin (Hb): A protein in red blood cells consisting of the protein globin and the iron-containing red pigment heme, which transports most of the oxygen and some carbon dioxide in blood.A-3

Homeostasis: The condition in which the body’s internal environment remains relatively constant and within physiological limits.A-3

Hypercalcemia: An abnormally high concentration of calcium in blood.1-18

LEARNING GUIDE: APPENDIX 49 BACK TO THE TABLE OF CONTENTS GLOSSARY OF TERMS, CONTINUED

Hyperlipidemia: An elevated level of lipids (cholesterol, triglycerides, fatty acids) in the blood.1-18

Hyperphosphatemia: Elevation of phosphorus concentration in blood.1-18

Hypoalbuminemia: Low blood albumin level due to loss of albumin in urine.1-15

Hypophosphatemia: Deficiency of phosphorus in blood.1-18

Insulin: A hormone produced by the pancreas that decreases blood glucose levels.A-3

Kidney Disease: Improving Global Outcomes (KDIGO): Independent, international, nonprofit foundation with a mission to improve the care and outcomes of kidney disease patients worldwide through developing and implementing clinical practice guidelines.1-3

Kidney Disease Outcome Quality Initiative (KDOQI): Workgroup of the National Kidney Foundation; provides recommendations on optimal clinical practices for dialysis, vascular access and anemia in CKD.1-4

Modification of Diet in Renal Disease (MDRD): The MDRD study equation was developed using data from 1,628 people with CKD. It is used to estimate GFR adjusted for body surface area.3-5

National Health and Nutrition Examination Survey (NHANES): Survey conducted by the National Center for Health Statistics (NCHS) at the Centers for Disease Control and Prevention; uses home interviews and health tests to collect information on health and diet in the U.S.1-6

Nephrotic proteinuria: Persistent massive proteinuria in excess of 3,500 mg/day.1-1

Neuropathy: Any disorder affecting the nervous system.1-18

Osmolarity: The measure of the total number of dissolved particles per liter of solution.1-15

Osteoblast: Cell that makes bone by producing a matrix that then becomes mineralized.A-3

Osteoclast: A large, multinucleated cell that resorbs (breaks down) bone matrix.A-3

Osteopenia: Decrease in bone mass below normal.A-1

Osteoporosis: Decreased bone mass which can result in low-trauma or fragility fractures, especially vertebral, hip, wrist, and thoracic and lumbar spine.A-1

Parathyroid hormone (PTH): A hormone secreted by the principal cells of the parathyroid glands that increases blood calcium level and decreases blood phosphate level.A-3

Parenchyma: The functional part of the kidney. Contains approximately one million nephrons — the filtration units of the kidney.1-15

Pericarditis: Inflammation of the pericardium (the fibrous membrane surrounding the heart).1-18

Peritoneal dialysis (PD): Cleaning the blood by using the lining of the abdominal cavity as a filter. Cleansing liquid, called dialysis solution, is drained from a bag into the abdomen; the solution is then drained from the abdomen, removing extra fluids and wastes.1-19

Peritoneum: The largest serous membrane of the body that lines the abdominal cavity and covers the viscera.A-3

LEARNING GUIDE: APPENDIX 50 BACK TO THE TABLE OF CONTENTS GLOSSARY OF TERMS, CONTINUED

Proteinuria: A condition in which the urine contains a large amount of protein; a sign that the kidneys are not functioning properly.1-19

Pruritus: Itching.1-18

Renal osteodystrophy (ROD): Alteration of bone morphology in people with CKD; one measure of the skeletal component of the systemic disorder of CKD–MBD that is quantifiable by histomorphometry of bone biopsy; common problem for people on dialysis who have hyperphosphatemia or insufficient vitamin D supplementation.1-3, 1-19

Renin: Enzyme released by the kidneys in response to low blood pressure; first step of the renin-angiotensin-aldosterone pathway that regulates aldosterone secretion.A-6

Renin-angiotensin-aldosterone system (RAAS): Pathway that regulates secretion of aldosterone to help control blood volume, blood pressure and levels of Na+, K+ and H+ in the blood.A-6

Risk factor: An attribute associated with increased risk of an outcome. Relationship between risk factor and outcome may be either causal or noncausal.1-1

Secondary hyperparathyroidism (SHPT): A disease associated with CKD that is characterized by increased phosphorous levels and increased PTH, leading to bone disease and other complications.2-6

Systolic blood pressure: The force exerted by blood on arterial walls during contraction of the heart muscle; the highest pressure measured in the large arteries.A-3

Tubulointerstitial diseases: Group of diseases that primarily affect the renal tubules and interstitium.1-17

Type 1 diabetes: Condition in which the body does not produce enough insulin.1-19

Type 2 diabetes: Condition in which the body responds poorly to insulin.1-19

Uremia: Accumulation of toxic levels of urea and other nitrogenous waste products in the blood, usually due to severe kidney malfunction.A-3

Urinary cast: Cylindrical sediment formed when protein precipitates within the renal tubules; may entrap various cells and debris.1-19

Vascular access: In dialysis, the point on the body where a needle or catheter is inserted.1-19

LEARNING GUIDE: APPENDIX 51 BACK TO THE TABLE OF CONTENTS APPENDIX B: REFERENCES

1. Levey AS, Stevens LA, Coresh J. Conceptual model of CKD: applications and implications. Am J Kidney Dis. 2009;53 (3 Suppl 3):S4-16. 2. Guyton AC, Hall JE. Micturition, diuretics, and kidney diseases. In: Textbook of Medical Physiology. 9th ed. Philadelphia, PA: W.B. Saunders Company; 1996:405-421. 3. Moe SM, Drueke T, Lameire N, et al. Chronic kidney disease-mineral-bone disorder: a new paradigm. Adv Chronic Kidney Dis. 2007;14(1):3-12. 1-1. Levin A, Stevens PE, Bilous RW, et al. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements. 2013;3:1-150. 1-2. Snively CS, Gutierrez C. Chronic kidney disease: prevention and treatment of common complications. Am Fam Physician. 2004;70(10):1921-1928. 1-3. Kidney Disease: Improving Global Outcomes. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Kidney International Supple. 2017 Vol7.1 1-4. Centers for Disease Control and Prevention. Chronic Kidney Disease Surveillance System—United States. http:// www.cdc.gov/ckd 1-5. Chadban SJ, Briganti EM, Kerr PG, et al. Prevalence of kidney damage in Australian adults: The AusDiab Kidney Study. J Am Soc Nephrol. 2003;14(90002):S131-S138. 1-6. Imai E, Horio M, Iseki K, et al. Prevalence of chronic kidney disease (CKD) in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient. Clinical and Experimental Nephrology. 2007;11(2):156-163. 1-7. United States Renal Data System 2019 annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2019. 1-8. Kramer A, Pippias M, Noordzij M, Stel V, et al. The European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2016: A summary. Clinical Kidney Journal. 2016, 1-19 1-9. USRDS. Volume 1 CKD: Cost of chronic kidney disease. In: USRDS. 2009 Annual Data Report. Volume 1: Atlas of Chronic Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009:131-138. 1-10. USRDS. Volume 2 ESRD: Costs of ESRD. In: USRDS. 2009 Annual Data Report. Volume 2: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009:335-342. 1-11. St Peter WL. Chronic kidney disease: a burgeoning health epidemic. J Manag Care Pharm. 2007;13(9 Suppl D): S13-S18. 1-12. Eckardt KU, Berns JS, Rocco MV, et al. Definition and classification of CKD: the debate should be about patient prognosis – a position statement from KDOQI and KDIGO. Am J Kidney Dis. 2009;53(6):915-920. 1-13. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49(2 Suppl 2):S12-154. 1-14. Polycystic kidney disease: National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2020 Jan 7. polycystic kidney disease; [reviewed 2014 May; cited 2020 Jan 10]; [about 6 screens]. Available from: https://ghr.nlm.nih.gov/condition/polycystic-kidney-disease# 1-15. Tortora GJ, Derrickson B. The urinary system. In: Principles of Anatomy and Physiology. 11th ed. Hoboken, NJ: John Wiley & Sons Inc; 2006:992-1035. 1-16. Zhang QL, Rothenbacher D. Prevalence of chronic kidney disease in population-based studies: systematic review. BMC Public Health. 2008;8:117. 1-17. Andreoli TE, Carpenter CCJ, Griggs RC, et al. Approach to the patient with renal disease. In: CECIL Essentials of Medicine. 6th ed. Philadelphia, PA: Saunders; 2004:237-242.

LEARNING GUIDE: APPENDIX 52 BACK TO THE TABLE OF CONTENTS REFERENCES, CONTINUED

1-18. Stedman's Medical Dictionary for the Health Professions and Nursing. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2008. 1-19. National Institute of Diabetes and Digestive and Kidney Diseases. Kidney failure glossary. U.S. Department of Health and Human Services. 2003; NIH Publication No. 03–4894:1-14. 2-1. Broscious SK, Castagnola J. Chronic kidney disease: acute manifestations and role of critical care nurses. Crit Care Nurse. 2006;26(4):17-27. 2-2. Kazory A, Ross EA. Anemia: the point of convergence or divergence for kidney disease and heart failure? J Am Coll Cardiol. 2009;53(8):639-647. 2-3. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(5 Suppl 3):S11-145. 2-4. Gal-Moscovici A, Sprague SM. Bone health in chronic kidney disease-mineral and bone disease. Adv Chronic Kidney Dis. 2007;14(1):27-36. 2-5. Komaba H, Tanaka M, Fukagawa M. Treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Intern Med. 2008;47(11):989-994. 2-6. Saliba W, El-Haddad B. Secondary hyperparathyroidism: pathophysiology and treatment. J Am Board Fam Med. 2009;22(5):574-581. 2-7. Andress DL. Vitamin D treatment in chronic kidney disease. Semin Dial. 2005;18(4):315-321. 2-8. Joy MS, Karagiannis PC, Peyerl FW. Outcomes of secondary hyperparathyroidism in chronic kidney disease and the direct costs of treatment. J Manag Care Pharm. 2007;13(5):397-411. 2-9. Eknoyan G, Levin A, Levin NW. Bone metabolism and disease in chronic kidney disease; K/DOQI Clinical Practice Guidelines. Am J Kidney Dis. 2003;42(suppl 3):1-201. 2-10. Bover J, Farre N, Andres E, et al. Update on the treatment of chronic kidney disease-mineral and bone disorder. J Ren Care. 2009;35 Suppl 1:19-27. 2-11. Thomas R, Kanso A, Sedor JR. Chronic kidney disease and its complications. Prim Care. 2008;35(2):329-344. 2-12. Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52(19):1527-1539. 2-13. Schaefer F. Endocrine and growth disorders in chronic kidney disease. Springer-Verlag Berlin Heidelberg. 2009:1713-1753. 2-14. Chikotas N, Gunderman A, Oman T. Uremic syndrome and end-stage renal disease: physical manifestations and beyond. J Am Acad Nurse Pract. 2006;18(5):195-202. 2-15. Kuypers DR. Skin problems in chronic kidney disease. Nat Clin Pract Nephrol. 2009;5(3):157-170. 3-1. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/AphA/ASH/ASPC/NMA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e127-e248. 3-2. Tara I. Chang, Mark J. Sarnak. Intensive Blood Pressure Targets and Kidney Disease. Clin J Am Soc Nephrol 13: 1575-1577, 2018 doi: https://doi.org/10.2215/CJN.02010218 3-3. Kratz A, Pesce MA, Fink DJ. Appendix: Laboratory values of clinical importance. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Medical; 2008:A-1 – A-16. 3-4. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281. 3-5. Stevens LA, Coresh J, Greene T, et al. Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med. 2006;354(23):2473-2483. 3-6. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-470.

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3-7. Soares AA, Eyff TF, Campani RB, et al. Glomerular filtration rate measurement and prediction equations. Clin Chem Lab Med. 2009;47(9):1023-1032. 3-8. Parikh CR, Devarajan P. New biomarkers of acute kidney injury. Crit Care Med. 2008;36(4 Suppl):S159-S165. 3-9. Roos JF, Doust J, Tett SE, et al. Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children – a meta-analysis. Clin Biochem. 2007;40(5-6):383-391. 3-10. Naderi ASA, Reilly RF. Primary care approach to proteinuria. J Am Board Fam Med. 2008;21(6):569-574. 3-11. Ketteler M, Block GA, Evenepoel P, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease-Minearl and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. Kidney International (2017) 92, 26-36, http://dx.doi.org/10.1016/j.kint.2017.04.006. 3-12. Shoback D, Sellmeyer D, Bikle DD. Metabolic bone disease. In: Gardner DG, Shoback D, eds. Greenspan's Basic and Clinical Endocrinology. 8th ed. New York, NY: McGraw-Hill; 2007:281-345. 3-13. Rous SN. Imaging of the urinary tract. In: Rous SN, ed. Urology: A Core Textbook. 1st ed. Cambridge, MA: Blackwell Science; 1996:53-91. 3-14. Jennette JC, Falk RJ. Glomerular clinicopathologic syndromes. In: Greenberg A, ed. Primer on Kidney Diseases. 4th ed. Philadelphia, PA: Elsevier Saunders; 2005:150-164. 3-15. Watts NB. Clinical utility of biochemical markers of bone remodeling. Clin Chem. 1999;45(8 Pt 2):1359-1368. 4-1. Tannock L. Dyslipidemia in Chronic Kidney Disease. [Updated 2018 Jan 22]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www. ncbi.nlm.nih.gov/books/NBK305899/ 4-2. Chang AR, Loser M, Malhotra R, Appel, L. Blood Pressure Goals in patients with CKD: A Review of Evidence and Guidelines. Clin J Am Soc Nephrol 14: 161-169, 2019. doi: https://doi.org/10.2215/CJN.07440618 4-3. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Am J Kidney Disease. 2003;41(4(suppl 3)):S1-S91. 4-4. Kronenberg, Florian. HDL in CKD – The Devil is in the Detail. J am Soc Nephrol 29: 1356-1371, 2018. doi: https:// doi.org/10.1681/ASN.2017070798 4-5. Mikolasevic, L; Zutelija, M; Mavrinac, V; Orlic, L. Dyslipidemia in patients with chronic kidney disease: etiology and management. International journal of Nephrology and Renovascular Disease. 7 Feb. 2017. 4-6. Krishnan AV, Kiernan MC. Neurological complications of chronic kidney disease. Nat Rev Neurol. 2009;5(10):542-551. 4-7. Renal replacement therapy. In: Beers MH, Porter RS, Jones TV, et al, eds. The Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:1989-1996. 4-8. Blake PG. Cycling forward. Perit Dial Int. 2006;26(3):306-308. 4-9. Kidney Disease: Improving Global Outcomes (KDIGO) Workgroup. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3(9):S1-155. A-1. Dorland WAN. Dorland's Illustrated Medical Dictionary. 30th ed. Philadelphia, PA: Saunders; 2003. A-2. Zahran A, El-Husseini A, Shoker A. Can cystatin C replace creatinine to estimate glomerular filtration rate? A literature review. Am J Nephrol. 2007;27(2):197-205. A-3. Tortora GJ, Derrickson B. Glossary. In: Principles of Anatomy and Physiology. 11th ed. Hoboken, NJ: John Wiley & Sons Inc; 2006:G2-G37. A-4. Taal MW, Brenner BM. Predicting initiation and progression of chronic kidney disease: developing renal risk scores. Kidney Int. 2006;70(10):1694-1705. A-5. Tortora GJ, Derrickson B. The cardiovascular system: the blood. In: Principles of Anatomy and Physiology. 11th ed. Hoboken, NJ: John Wiley & Sons Inc; 2006:666-694. A-6. Tortora GJ, Derrickson B. The endocrine system. In: Principles of Anatomy and Physiology. 11th ed. Hoboken, NJ: John Wiley & Sons Inc; 2006:616-665.

LEARNING GUIDE: APPENDIX 54 BACK TO THE TABLE OF CONTENTS APPENDIX C: CORRECT RESPONSES

SECTION 1 1. B 2. CLINICAL TERM MEDICAL DESCRIPTION Microalbuminuria Excretion of small abnormal amounts of albumin Hematuria Presence of blood in urine Uremia Toxic levels of urea in blood

3. B 4. C

SECTION 2 1. A 2. D 3. D 4. Hypertension, atherosclerosis, left ventricular hypertrophy, congestive heart failure, peripheral vascular disease

SECTION 3 1. A 2. A 3. D 4. C

SECTION 4 1. C 2. D 3. D 4. C

LEARNING GUIDE: APPENDIX 55 BACK TO THE TABLE OF CONTENTS CORELABORATORY.ABBOTT

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