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Pitfalls of Using Microalbuminuria As a Screening Tool to Identify Subjects with Increased Risk for Kidney and Cardiovascular Disease

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Pitfalls of Using Microalbuminuria As a Screening Tool to Identify Subjects with Increased Risk for Kidney and Cardiovascular Disease Pitfalls of using microalbuminuria as a screening tool to identify subjects with increased risk for kidney and cardiovascular disease Results of the Unreferred Renal Insufficiency (URI) study and the Early Renal Impairment and Cardiovascular Assessment in Belgium study (ERICABEL). Arjan van der Tol Promotor: Prof. dr. Wim Van Biesen Co-promotor: Prof. dr. Raymond Vanholder Thesis submitted in fulfillment of the requirements for the degree of ‘Doctor in Health Sciences’ 2014 Contents TABLE OF CONTENTS LIST OF ABBREVIATIONS ....................................................................................................... 5 CHAPTER 1: INTRODUCTION ................................................................................................ 7 1.1 Preface ................................................................................................................................... 9 1.2. Normal renal handling of albuminuria ................................................................................. 11 1.3. Mechanisms of tubular and glomerular albuminuria ........................................................... 13 1.4. Albuminuria as a manifestation of chronic kidney disease ................................................. 18 1.5. Albuminuria as a manifestation of cardiovascular disease .................................................. 21 1.6. The prevalence of albuminuria ............................................................................................ 25 1.7. How to measure albuminuria ............................................................................................... 27 1.8. Outline and aims of the thesis .............................................................................................. 30 1.9. Participants and methods ..................................................................................................... 31 1.10. References ............................................................................................................................ 33 CHAPTER 2: RESULTS ............................................................................................................ 43 2.1. Screening for cardiovascular and renal markers in unselected subjects: results from URI trial ...................................................................................................................... 43 2.1.1. Towards a rational screening strategy for albuminuria ............................................. 45 2.1.2. Microalbuminuria is more consistent in presence of risk factors ............................... 65 2.1.3. Should screening of renal markers be recommended in a working population ......... 78 2.2. Screening for kidney disease in selected hypertensive subjects: results from the ERICABEL study ................................................................................................................ 96 2.2.1 Statin use and the presence of microalbuminuria ....................................................... 97 CHAPTER 3: GENERAL DISCUSSION AND CONCLUSIONS ....................................... 115 3.1. The prevalence of microalbuminuria and macroalbuminuria, and the associations with traditional cardiovascular risk factors in a general population .................................. 118 3.2. Should we use microalbuminuria as a screening tool to identify subjects with unrecognized cardiovascular risk factors in a presumably healthy population ........................................ 120 Contents 3.3. Conditions which could lead to false positive test results of microalbuminuria ............... 121 3.4. Can we prevent ESRD by screening for microalbuminuria in a general population ......... 123 3.4.1. The disease should be an obvious burden for the individual and the community in terms of death, poor quality of life and socio-economic factors including health care costs ........................................................................................................ 124 3.4.2. The natural course of disease should be well-known and the disease should go through an initial latent stage or be determined by risk factors, which can be detected by appropriate tests .................................................................................... 125 3.4.3. A suitable test is highly sensitive and specific for the disease as well as being acceptable to the person screened ............................................................................ 126 3.4.4. Screening followed by diagnosis and interventions in an early stage of the disease should provide a better prognosis than intervention after spontaneously sought treatment ................................................................................................................... 127 3.4.5. Adequate treatment or other intervention possibilities are indispensable. Adequacy is determined both by proven medical effect and ethical and legal acceptability .............................................................................................................. 128 3.4.6. The cost of case-finding should be economically balanced in relation to possible expenditure on medical care as a whole ................................................................... 129 3.4.7. Case-finding should be a continuing process and the interval of testing should be known ....................................................................................................................... 130 3.5 Conclusions ........................................................................................................................ 132 3.6 References .......................................................................................................................... 135 3.7 Conclusies .......................................................................................................................... 143 3.8 References .......................................................................................................................... 146 Dankwoord .................................................................................................................................. 149 Curriculum Vitae ......................................................................................................................... 151 List of abbreviations LIST OF ABBREVIATIONS ACR urinary albumin creatinine ratio (mg/g) ACE-I angiotensin concerting enzyme inhibitor ADA American Diabetes Association ADVANCE Preterax and Diamicron Modified Released Control Education study AER albumin excretion rate (mg/24 h) AKI acute kidney injury ARB angiotensin receptor blocker Aus Diab Kidney study Australian Diabetes, Obesity and Lifestyle Study BMI body mass index BP blood pressure CGA CKD classification: Cause, Glomerular filtration rate, Albuminuria CVD cardiovascular disease CKD chronic kidney disease CKD-EPI Chronic Kidney Disease Epidemiology Collaboration DALY disability adjusted life year DM diabetes mellitus EPIC-Norfolk European Prospective Investigation into Cancer in Norfolk ERA-EDTA European Renal Association-European Dialysis Transplantation Association ERICABEL Early Renal Impairment and Cardiovascular Assessment in Belgium study ESRD end stage renal disease GDP gross domestic product GFR glomerular filtration rate HMG-CoA reductase 3-hydroxy-3-methylglutaryl-CoA reductase HOPE Heart Outcomes and Prevention Evaluation Study HPLC high performance liquid chromatography HUNT Nord-Trøndelag Health Study HT hypertension IDMS isotope dilution mass spectrometry IFCC International Federation of Clinical Chemistry IGT impaired glucose tolerance IMAU intermittent microalbuminuria List of abbreviations K/DOQI Kidney Disease Outcomes Quality Initiative KDIGO Kidney Disease Improving Global Outcomes KEAPS Kidney Evaluation and Awareness Program in Sheffield NCEP National Cholesterol Education Program NHANES National Health and Nutrition Examination Survey NKF National Kidney Foundation NPHS1/2 congenital nephrotic syndrome of Finnish type MAU microalbuminuria MDRD Modification of Diet in Renal Disease OCRL-1 oculocerebrorenal locus 1 ONTARGET Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial PCER physicochemical exposure risk PCR protein creatinine ratio PMAU persistent microalbuminuria PolNef Early detection of chronic kidney disease in Poland PREVEND Prevention of Renal and Vascular End Stage Disease Study Group QALY Quality Adjusted Life Year RAAS renin angiotensin aldosterone system RCT randomized control trial RENAAL Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan ROADMAP Randomized Olmesartan and Diabetes Microalbuminuria Prevention RRT renal replacement therapy SGLT-2 sodium glucose co-transporter 2 SNP single nucleotide polymorphism TRPC transient receptor potential canonical UAC urinary albumin concentration (mg/l) USRDS United States Renal Data System URIS Unreferred Renal Insufficiency Study WHO World Health Organization Zo-1 Zona Occludens 1 CHAPTER 1: INTRODUCTION CHAPTER 1: Introduction 1.1 Preface Around 20-25% of the Belgian population has hypertension and 5% has diabetes mellitus (1, 2). Patients with diabetes mellitus and/or hypertension have an increased risk for chronic kidney disease (CKD), yet only a small proportion of these patients progresses to end stage renal disease (ESRD) to a degree that renal replacement therapy (RRT) in the form of dialysis or kidney transplantation is required (3, 4). The prevalence of RRT was 1200 per million
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