Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus
- David K McCulloch, MD
David K McCulloch, MD
- Washington Permanente Medical Group
- George L Bakris, MD
George L Bakris, MD
- Editor-in-Chief — Nephrology
- Section Editor — Hypertension
- Professor of Medicine
- The University of Chicago
- Section Editors
- Richard J Glassock, MD, MACP
Richard J Glassock, MD, MACP
- Editor-in-Chief — Nephrology
- Section Editor — Glomerular Diseases
- Emeritus Professor
- The David Geffen School of Medicine at UCLA
- David M Nathan, MD
David M Nathan, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Diabetes Mellitus
- Professor of Medicine
- Harvard Medical School
INTRODUCTION AND DEFINITIONS
Increased urinary protein excretion may be an early clinical manifestation of diabetic nephropathy [1-6]. However, when assessing protein excretion, the urine dipstick is a relatively insensitive marker for initial increases in protein excretion, not becoming positive until protein excretion exceeds 300 to 500 mg/day (upper limit of normal less than 150 mg/day, with most individuals excreting less than 100 mg/day).
Using a specific assay for albumin is a more sensitive technique. The normal rate of albumin excretion is less than 30 mg/day (20 mcg/min); persistent albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min) is called moderately increased albuminuria (the new terminology for what was formerly called "microalbuminuria") . Albumin excretion above 300 mg/day (200 mcg/min) is considered to represent severely increased albuminuria (the new terminology for what was formerly called "macroalbuminuria" , and which is also called overt proteinuria, clinical renal disease, or dipstick positive proteinuria) .
Although these cut-offs defining moderately increased albuminuria and severely increased albuminuria facilitate determining the risk for progression of nephropathy, the risk of developing overt diabetic nephropathy is probably directly related to albumin excretion rates at all levels.
The clinical significance, screening, and management of moderately increased albuminuria in patients with type 2 diabetes will be reviewed here. In addition to being a marker of cardiovascular risk, moderately increased albuminuria that is increasing when factors such as blood pressure and blood glucose are controlled is also associated with development of nephropathy in both diabetic and nondiabetic patients. As will be described below, moderately increased albuminuria is often present at diagnosis in patients with type 2 diabetes and reflects underlying cardiovascular disease .
The significance of moderately increased albuminuria in patients with type 1 diabetes, the mechanisms of moderately increased albuminuria, the association of moderately increased albuminuria with cardiovascular risk, and the treatment of overt diabetic nephropathy are discussed separately. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease" and "Treatment of diabetic nephropathy".)
- Sacks DB, Arnold M, Bakris GL, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care 2011; 34:e61.
- Chapter 1: Definition and classification of CKD. Kidney Int Suppl (2011) 2013; 3:19.
- Gross JL, de Azevedo MJ, Silveiro SP, et al. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 2005; 28:164.
- Ruggenenti P, Remuzzi G. Nephropathy of type-2 diabetes mellitus. J Am Soc Nephrol 1998; 9:2157.
- Ismail N, Becker B, Strzelczyk P, Ritz E. Renal disease and hypertension in non-insulin-dependent diabetes mellitus. Kidney Int 1999; 55:1.
- Mogensen CE. Prediction of clinical diabetic nephropathy in IDDM patients. Alternatives to microalbuminuria? Diabetes 1990; 39:761.
- Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK). Am J Kidney Dis 2003; 42:617.
- Bakris GL, Molitch M. Microalbuminuria as a risk predictor in diabetes: the continuing saga. Diabetes Care 2014; 37:867.
- Mogensen CE, Vestbo E, Poulsen PL, et al. Microalbuminuria and potential confounders. A review and some observations on variability of urinary albumin excretion. Diabetes Care 1995; 18:572.
- K/DOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis 2007; 49(2 Suppl 2):S12.
- Consensus development conference on the diagnosis and management of nephropathy in patients with diabetes mellitus. American Diabetes Association and the National Kidney Foundation. Diabetes Care 1994; 17:1357.
- Zelmanovitz T, Gross JL, Oliveira JR, et al. The receiver operating characteristics curve in the evaluation of a random urine specimen as a screening test for diabetic nephropathy. Diabetes Care 1997; 20:516.
- Schwab SJ, Dunn FL, Feinglos MN. Screening for microalbuminuria. A comparison of single sample methods of collection and techniques of albumin analysis. Diabetes Care 1992; 15:1581.
- Nathan DM, Rosenbaum C, Protasowicki VD. Single-void urine samples can be used to estimate quantitative microalbuminuria. Diabetes Care 1987; 10:414.
- Lambers Heerspink HJ, Gansevoort RT, Brenner BM, et al. Comparison of different measures of urinary protein excretion for prediction of renal events. J Am Soc Nephrol 2010; 21:1355.
- Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983; 309:1543.
- Witte EC, Lambers Heerspink HJ, de Zeeuw D, et al. First morning voids are more reliable than spot urine samples to assess microalbuminuria. J Am Soc Nephrol 2009; 20:436.
- Jefferson IG, Greene SA, Smith MA, et al. Urine albumin to creatinine ratio-response to exercise in diabetes. Arch Dis Child 1985; 60:305.
- Younes N, Cleary PA, Steffes MW, et al. Comparison of urinary albumin-creatinine ratio and albumin excretion rate in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Clin J Am Soc Nephrol 2010; 5:1235.
- Mattix HJ, Hsu CY, Shaykevich S, Curhan G. Use of the albumin/creatinine ratio to detect microalbuminuria: implications of sex and race. J Am Soc Nephrol 2002; 13:1034.
- Newman DJ, Mattock MB, Dawnay AB, et al. Systematic review on urine albumin testing for early detection of diabetic complications. Health Technol Assess 2005; 9:iii.
- ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358:2560.
- Adler AI, Stevens RJ, Manley SE, et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003; 63:225.
- Young BA, Katon WJ, Von Korff M, et al. Racial and ethnic differences in microalbuminuria prevalence in a diabetes population: the pathways study. J Am Soc Nephrol 2005; 16:219.
- Parving HH, Lewis JB, Ravid M, et al. Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int 2006; 69:2057.
- Hypertension in Diabetes Study (HDS): I. Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertens 1993; 11:309.
- Mykkänen L, Haffner SM, Kuusisto J, et al. Microalbuminuria precedes the development of NIDDM. Diabetes 1994; 43:552.
- Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984; 310:356.
- Klein R, Klein BE, Moss SE, Cruickshanks KJ. Ten-year incidence of gross proteinuria in people with diabetes. Diabetes 1995; 44:916.
- Rossing K, Christensen PK, Hovind P, et al. Progression of nephropathy in type 2 diabetic patients. Kidney Int 2004; 66:1596.
- Nelson RG, Bennett PH, Beck GJ, et al. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med 1996; 335:1636.
- Ravid M, Savin H, Jutrin I, et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993; 118:577.
- Araki S, Haneda M, Sugimoto T, et al. Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetes. Diabetes 2005; 54:2983.
- Araki S, Haneda M, Koya D, et al. Reduction in microalbuminuria as an integrated indicator for renal and cardiovascular risk reduction in patients with type 2 diabetes. Diabetes 2007; 56:1727.
- Gaede P, Tarnow L, Vedel P, et al. Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria. Nephrol Dial Transplant 2004; 19:2784.
- Mavrakanas TA, Gariani K, Martin PY. Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: an emerging paradigm in diabetic nephropathy: a systematic review. Eur J Intern Med 2014; 25:173.
- Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int 2004; 65:1991.
- Parving HH, Lehnert H, Bröchner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345:870.
- Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000; 321:1440.
- Patel A, ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370:829.
- Lebovitz HE, Wiegmann TB, Cnaan A, et al. Renal protective effects of enalapril in hypertensive NIDDM: role of baseline albuminuria. Kidney Int Suppl 1994; 45:S150.
- Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med 1996; 156:286.
- Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004; 351:1952.
- Viberti G, Wheeldon NM, MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002; 106:672.
- Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 1999; 353:617.
- Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348:383.
- Bennett PH, Haffner S, Kasiske BL, et al. Screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis 1995; 25:107.
- Qaseem A, Hopkins RH Jr, Sweet DE, et al. Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2013; 159:835.
- Parving HH, Gall MA, Skøtt P, et al. Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int 1992; 41:758.
- Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28:103.
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837.
- Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 2010; 376:419.
- Strippoli GF, Craig M, Schena FP, Craig JC. Antihypertensive agents for primary prevention of diabetic nephropathy. J Am Soc Nephrol 2005; 16:3081.
- Ravid M, Brosh D, Levi Z, et al. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998; 128:982.
- Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002; 61:1086.
- Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998; 317:713.
- Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004; 351:1941.
- Ruggenenti P, Perna A, Ganeva M, et al. Impact of blood pressure control and angiotensin-converting enzyme inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: a post hoc analysis of the BENEDICT trial. J Am Soc Nephrol 2006; 17:3472.
- Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359:1004.
- Bilous R, Chaturvedi N, Sjølie AK, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med 2009; 151:11.
- Parfrey PS. Angiotensin-receptor blockers in the prevention or treatment of microalbuminuria. Ann Intern Med 2009; 151:63.
- Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 2009; 361:40.
- Weil EJ, Fufaa G, Jones LI, et al. Effect of losartan on prevention and progression of early diabetic nephropathy in American Indians with type 2 diabetes. Diabetes 2013; 62:3224.
- Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011; 364:907.
- Ingelfinger JR. Preemptive olmesartan for the delay or prevention of microalbuminuria in diabetes. N Engl J Med 2011; 364:970.
- INTRODUCTION AND DEFINITIONS
- Approach to detection
- Urine albumin concentration
- Urine albumin-to-creatinine ratio
- - Predictive value
- - Limitations
- NATURAL HISTORY
- Progression to severely increased albuminuria
- Regression to normal albuminuria
- ACE inhibitors pt ARBs
- Calcium channel blockers
- Glucose control
- Intensive combined risk factor modification therapy
- PRIMARY PREVENTION
- Glycemic control
- ACE inhibitors or ARBs
- - Normotensive patients
- - Hypertensive patients
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS