Moderately increased albuminuria (microalbuminuria) and cardiovascular disease
- George L Bakris, MD
George L Bakris, MD
- Editor-in-Chief — Nephrology
- Section Editor — Hypertension
- Professor of Medicine
- The University of Chicago
INTRODUCTION, TERMINOLOGY, AND DEFINITIONS
The urine dipstick is a relatively insensitive marker for albuminuria, not becoming positive until albumin excretion exceeds 300 to 500 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 (formerly called "microalbuminuria") [1,2]. Albumin excretion above 300 mg/day (200 mcg/min) is considered to represent overt or dipstick positive proteinuria (also called severely increased albuminuria [formerly called "macroalbuminuria"]). (See "Definition and staging of chronic kidney disease in adults".)
The distinction between the terms "albuminuria" and "proteinuria" is discussed elsewhere in detail. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Definitions'.)
Initial studies demonstrated that moderately increased albuminuria may be the earliest clinical manifestation of diabetic nephropathy in patients with type 1 diabetes, and first begins to appear five years after diagnosis. This is no longer thought to be the case, as albuminuria levels are quite variable early in the course of disease [3-5]. By comparison, moderately increased albuminuria is often present at diagnosis in patients with type 2 diabetes and may reflect underlying cardiovascular disease rather than diabetic nephropathy. Yearly screening for moderately increased albuminuria is recommended in patients with both type 1 diabetes (starting five years after disease onset) and type 2 diabetes (starting at disease onset). (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus".)
In addition to being associated with diabetic nephropathy, moderately increased albuminuria has also been associated with cardiovascular disease in both nondiabetic and diabetic patients. These studies will be reviewed here.
Establishing the diagnosis of moderately increased albuminuria (formerly called "microalbuminuria") requires the demonstration of a persistent elevation in albumin excretion. Transient elevations in the excretion of albumin can be seen in the following settings  (see "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults"):
Subscribers log in hereLiterature review current through: Nov 2017. | This topic last updated: Jul 26, 2016.References
- Chapter 1: Definition and classification of CKD. Kidney Int Suppl (2011) 2013; 3:19.
- Stevens PE, Levin A, Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 2013; 158:825.
- Steinke JM, Sinaiko AR, Kramer MS, et al. The early natural history of nephropathy in Type 1 Diabetes: III. Predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients. Diabetes 2005; 54:2164.
- 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.
- Glassock RJ. Debate: CON position. Should microalbuminuria ever be considered as a renal endpoint in any clinical trial? Am J Nephrol 2010; 31:462.
- 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.
- 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.
- Sacks DB, Arnold M, Bakris GL, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem 2011; 57:e1.
- 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.
- 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.
- 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.
- Nathan DM, Rosenbaum C, Protasowicki VD. Single-void urine samples can be used to estimate quantitative microalbuminuria. Diabetes Care 1987; 10:414.
- 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.
- Jefferson IG, Greene SA, Smith MA, et al. Urine albumin to creatinine ratio-response to exercise in diabetes. Arch Dis Child 1985; 60:305.
- 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.
- 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.
- 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.
- Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001; 286:421.
- Wachtell K, Ibsen H, Olsen MH, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med 2003; 139:901.
- Hillege HL, Fidler V, Diercks GF, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002; 106:1777.
- Roest M, Banga JD, Janssen WM, et al. Excessive urinary albumin levels are associated with future cardiovascular mortality in postmenopausal women. Circulation 2001; 103:3057.
- Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation 2004; 110:32.
- Wang TJ, Evans JC, Meigs JB, et al. Low-grade albuminuria and the risks of hypertension and blood pressure progression. Circulation 2005; 111:1370.
- Diercks GF, Hillege HL, van Boven AJ, et al. Microalbuminuria modifies the mortality risk associated with electrocardiographic ST-T segment changes. J Am Coll Cardiol 2002; 40:1401.
- Mattock MB, Morrish NJ, Viberti G, et al. Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 1992; 41:736.
- Stehouwer CD, Nauta JJ, Zeldenrust GC, et al. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 1992; 340:319.
- UK Prospective Diabetes Study (UKPDS). X. Urinary albumin excretion over 3 years in diet-treated type 2, (non-insulin-dependent) diabetic patients, and association with hypertension, hyperglycaemia and hypertriglyceridaemia. Diabetologia 1993; 36:1021.
- Feldt-Rasmussen B, Mathiesen ER, Deckert T. Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes. Lancet 1986; 2:1300.
- Valmadrid CT, Klein R, Moss SE, Klein BE. The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med 2000; 160:1093.
- Bianchi S, Bigazzi R, Campese VM. Microalbuminuria in essential hypertension: significance, pathophysiology, and therapeutic implications. Am J Kidney Dis 1999; 34:973.
- Calviño J, Calvo C, Romero R, et al. Atherosclerosis profile and microalbuminuria in essential hypertension. Am J Kidney Dis 1999; 34:996.
- Wachtell K, Olsen MH, Dahlöf B, et al. Microalbuminuria in hypertensive patients with electrocardiographic left ventricular hypertrophy: the LIFE study. J Hypertens 2002; 20:405.
- Hoehner CM, Greenlund KJ, Rith-Najarian S, et al. Association of the insulin resistance syndrome and microalbuminuria among nondiabetic native Americans. The Inter-Tribal Heart Project. J Am Soc Nephrol 2002; 13:1626.
- De Leeuw PW, Thijs L, Birkenhäger WH, et al. Prognostic significance of renal function in elderly patients with isolated systolic hypertension: results from the Syst-Eur trial. J Am Soc Nephrol 2002; 13:2213.
- Muntner P, He J, Hamm L, et al. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 2002; 13:745.
- Romundstad S, Holmen J, Kvenild K, et al. Microalbuminuria and all-cause mortality in 2,089 apparently healthy individuals: a 4.4-year follow-up study. The Nord-Trøndelag Health Study (HUNT), Norway. Am J Kidney Dis 2003; 42:466.
- Kuusisto J, Mykkänen L, Pyörälä K, Laakso M. Hyperinsulinemic microalbuminuria. A new risk indicator for coronary heart disease. Circulation 1995; 91:831.
- Ibsen H, Olsen MH, Wachtell K, et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension 2005; 45:198.
- McCullough PA, Jurkovitz CT, Pergola PE, et al. Independent components of chronic kidney disease as a cardiovascular risk state: results from the Kidney Early Evaluation Program (KEEP). Arch Intern Med 2007; 167:1122.
- Arnlöv J, Evans JC, Meigs JB, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation 2005; 112:969.
- Kistorp C, Raymond I, Pedersen F, et al. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA 2005; 293:1609.
- Klausen KP, Scharling H, Jensen G, Jensen JS. New definition of microalbuminuria in hypertensive subjects: association with incident coronary heart disease and death. Hypertension 2005; 46:33.
- McQueen MJ, Gerstein HC, Pogue J, et al. Reevaluation by high-performance liquid chromatography: clinical significance of microalbuminuria in individuals at high risk of cardiovascular disease in the Heart Outcomes Prevention Evaluation (HOPE) Study. Am J Kidney Dis 2006; 48:889.
- Clausen P, Jensen JS, Jensen G, et al. Elevated urinary albumin excretion is associated with impaired arterial dilatory capacity in clinically healthy subjects. Circulation 2001; 103:1869.
- Pedrinelli R, Giampietro O, Carmassi F, et al. Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet 1994; 344:14.
- Cosson E, Pham I, Valensi P, et al. Impaired coronary endothelium-dependent vasodilation is associated with microalbuminuria in patients with type 2 diabetes and angiographically normal coronary arteries. Diabetes Care 2006; 29:107.
- Barzilay JI, Peterson D, Cushman M, et al. The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study. Am J Kidney Dis 2004; 44:25.
- Knight EL, Kramer HM, Curhan GC. High-normal blood pressure and microalbuminuria. Am J Kidney Dis 2003; 41:588.
- Sibley SD, Hokanson JE, Steffes MW, et al. Increased small dense LDL and intermediate-density lipoprotein with albuminuria in type 1 diabetes. Diabetes Care 1999; 22:1165.
- Freedman BI, Langefeld CD, Lohman KK, et al. Relationship between albuminuria and cardiovascular disease in Type 2 diabetes. J Am Soc Nephrol 2005; 16:2156.
- Mann JF, Gerstein HC, Yi QL, et al. Development of renal disease in people at high cardiovascular risk: results of the HOPE randomized study. J Am Soc Nephrol 2003; 14:641.
- Boulware LE, Jaar BG, Tarver-Carr ME, et al. Screening for proteinuria in US adults: a cost-effectiveness analysis. JAMA 2003; 290:3101.
- Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004; 110:2809.
- Ibsen H, Wachtell K, Olsen MH, et al. Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A LIFE substudy. J Hypertens 2004; 22:1805.
- Bakris GL, Ruilope L, Locatelli F, et al. Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the IMPROVE trial. Kidney Int 2007; 72:879.
- Tuttle KR. Albuminuria reduction: the holy grail for kidney protection. Kidney Int 2007; 72:785.
- INTRODUCTION, TERMINOLOGY, AND DEFINITIONS
- Urine albumin concentration
- Albumin-to-creatinine ratio
- - Limitations
- CORRELATION OF MODERATELY INCREASED ALBUMINURIA (MICROALBUMINURIA) WITH CARDIOVASCULAR DISEASE
- Clinical trials
- Population-based studies
- High-normal albuminuria
- ST and T wave changes
- Possible mechanisms
- CORRELATION OF CARDIOVASCULAR DISEASE WITH MODERATELY INCREASED ALBUMINURIA (MICROALBUMINURIA)
- Antihypertensive drugs
- Statin therapy
- SUMMARY AND RECOMMENDATIONS