Background Markers of kidney dysfunction such as proteinuria or albuminuria have been reported to be associated with coronary heart disease, but the consistency and strength of any such relationship has not been clearly defined. This lack of clarity has led to great uncertainty as to how proteinuria should be treated in the assessment and management of cardiovascular risk. We therefore undertook a systematic review of published cohort studies aiming to provide a reliable estimate of the strength of association between proteinuria and coronary heart disease. Methods and Findings A meta-analysis of cohort studies was conducted to obtain a summary estimate of the association between measures of proteinuria and coronary risk. MEDLINE and EMBASE were searched for studies reporting an age- or multivariate-adjusted estimate and standard error of the association between proteinuria and coronary heart disease. Studies were excluded if the majority of the study population had known glomerular disease or were the recipients of renal transplants. Two independent researchers extracted the estimates of association between proteinuria (total urinary protein >300 mg/d), microalbuminuria (urinary albumin 30–300 mg/d), macroalbuminuria (urinary albumin >300 mg/d), and risk of coronary disease from individual studies. These estimates were combined using a random-effects model. Sensitivity analyses were conducted to examine possible sources of heterogeneity in effect size. A total of 26 cohort studies were identified involving 169,949 individuals and 7,117 coronary events (27% fatal). The presence of proteinuria was associated with an approximate 50% increase in coronary risk (risk ratio 1.47, 95% confidence interval [CI] 1.23–1.74) after adjustment for known risk factors. For albuminuria, there was evidence of a dose–response relationship: individuals with microalbuminuria were at 50% greater risk of coronary heart disease (risk ratio 1.47, 95% CI 1.30–1.66) than those without; in those with macroalbuminuria the risk was more than doubled (risk ratio 2.17, 1.87–2.52). Sensitivity analysis indicated no important differences in prespecified subgroups. Conclusion These data confirm a strong and continuous association between proteinuria and subsequent risk of coronary heart disease, and suggest that proteinuria should be incorporated into the assessment of an individual's cardiovascular risk.
References
[1]
Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, et al. (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364: 937–952.
[2]
Zhang X, Patel A, Horibe H, Wu Z, Barzi F, et al. (2003) Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J Epidemiol 32: 563–572.
[3]
Woodward M, Zhang X, Barzi F, Pan W, Ueshima H, et al. (2003) The effects of diabetes on the risks of major cardiovascular diseases and death in the Asia-Pacific region. Diabetes Care 26: 360–366.
[4]
Woodward M, Lam TH, Barzi F, Patel A, Gu D, et al. (2005) Smoking, quitting, and the risk of cardiovascular disease among women and men in the Asia-Pacific region. Int J Epidemiol 34: 1036–1045.
[5]
Ni Mhurchu C, Rodgers A, Pan WH, Gu DF, Woodward M (2004) Body mass index and cardiovascular disease in the Asia-Pacific Region: an overview of 33 cohorts involving 310 000 participants. Int J Epidemiol 33: 751–758.
[6]
Kengne AP, Patel A, Barzi F, Jamrozik K, Lam TH, et al. (2007) Systolic blood pressure, diabetes and the risk of cardiovascular diseases in the Asia-Pacific region. J Hypertens 25: 1205–1213.
[7]
Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, et al. (2004) C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 350: 1387–1397.
[8]
Danesh J, Whincup P, Walker M, Lennon L, Thomson A, et al. (2001) Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis. Circulation 103: 2323–2327.
[9]
Danesh J, Lewington S, Thompson SG, Lowe GD, Collins R, et al. (2005) Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 294: 1799–1809.
[10]
Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, et al. (2003) Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108: 2154–2169.
[11]
Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS (2003) Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41: 1–12.
[12]
Chadban SJ, Briganti EM, Kerr PG, Dunstan DW, Welborn TA, et al. (2003) Prevalence of kidney damage in Australian adults: The AusDiab kidney study. J Am Soc Nephrol 14: S131–138.
[13]
White SL, Cass A, Atkins RC, Chadban SJ (2005) Chronic kidney disease in the general population. Adv Chronic Kidney Dis 12: 5–13.
[14]
Lindner A, Charra B, Sherrard D, Scribner B (1974) Accelerated atherosclerosis in prolonged maintenance haemodialysis. New Engl J Med 290: 69–701.
[15]
de Zeeuw D, Parving HH, Henning RH (2006) Microalbuminuria as an early marker for cardiovascular disease. J Am Soc Nephrol 17: 2100–2105.
[16]
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, et al. (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283: 2008–2012.
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21: 1539–1558.
[19]
Duval S, Tweedie R (2000) Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56: 455–463.
[20]
Beilin J, Stanton KG, McCann VJ, Knuiman MW, Divitini ML (1996) Microalbuminuria in type 2 diabetes: An independent predictor of cardiovascular mortality. Aust N Z J Med 26: 519–525.
[21]
Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS (1999) Urinary albumin excretion: An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol 19: 1992–1997.
[22]
Culleton BF, Larson MG, Parfrey PS, Kannel WB, Levy D (2000) Proteinuria as a risk factor for cardiovascular disease and mortality in older people: A prospective study. Am J Med 109: 1–8.
[23]
Florkowski CM, Scott RS, Coope PA, Moir CL (2001) Predictors of mortality from type 2 diabetes mellitus in Canterbury, New Zealand; a ten-year cohort study. Diabetes Res Clin Pract 53: 113–120.
[24]
Fuller JH, Stevens LK, Wang SL, Lee ET, Keen H, et al. (2001) Risk factors for cardiovascular mortality and morbidity: The WHO multinational study of vascular disease in diabetes. Diabetologia 44: S54–S64.
[25]
Hu D, Jablonski KA, Sparling YH, Robbins DC, Lee ET, et al. (2002) Accuracy of lipoprotein lipids and apoproteins in predicting coronary heart disease in diabetic American Indians: the Strong Heart Study. Ann Epidemiol 12: 79–85.
[26]
Irie F, Iso H, Sairenchi T, Fukasawa N, Yamagishi K, et al. (2006) The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population. Kidney Int 69: 1264–1271.
[27]
Jensen JS, Feldt-Rasmussen B, Strandgaard S, Schroll M, Borch-Johnsen K (2000) Arterial hypertension, microalbuminuria, and risk of ischemic heart disease. Hypertension 35: 898–903.
[28]
Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen G, Clausen P, et al. (2004) Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation 110: 32–35.
[29]
Lee YT, Fujita T, Shimamoto K, Wu Z, Zhu J, et al. (2006) Other health matters to be considered for the Asian population: Hypertensive patients at high risk. Int J Clin Pract 60: 17–19.
[30]
Leelawattana R, Rattarasarn C, Lim A, Soonthornpun S, Setasuban W (2003) Causes of death, incidence and risk factors of cardiovascular diseases in Thai type 2 diabetic patients: A 5-year follow-up study. Diabetes Res Clin Pract 60: 183–189.
Madison JR, Spies C, Schatz IJ, Masaki K, Chen R, et al. (2006) Proteinuria and risk for stroke and coronary heart disease during 27 years of follow-up: The Honolulu Heart Program. Arch Intern Med 166: 884–889.
[33]
Mattock MB, Barnes DJ, Viberti G, Keen H, Burt D, et al. (1998) Microalbuminuria and coronary heart disease in NIDDM: an incidence study. Diabetes 47: 1786–1792.
[34]
Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, et al. (1996) Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke 27: 2033–2039.
[35]
Muntner P, He J, Hamm L, Loria C, Whelton PK (2002) Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 13: 745–753.
[36]
Sasaki A, Horiuchi N, Hasegawa K, Uehara M (1995) Mortality from coronary heart disease and cerebrovascular disease and associated risk factors in diabetic patients in Osaka District, Japan. Diabetes Res Clin Pract 27: 77–83.
[37]
Shimozato M, Nakayama T, Yokoyama T, Yoshi-ike N, Yamaguchi M, et al. (1996) A 15.5-year cohort study on risk factors for possible myocardial infarction and sudden death within 24 hours in a rural Japanese community. J Epidemiol 6: 15–22.
[38]
Soedamah-Muthu SS, Chaturvedi N, Toeller M, Ferriss B, Reboldi P, et al. (2004) Risk factors for coronary heart disease in type 1 diabetic patients in Europe: The EURODIAB Prospective Complications Study. Diabetes Care 27: 530–537.
[39]
Tillin T, Forouhi N, McKeigue P, Chaturvedi N (2005) Microalbuminuria and coronary heart disease risk in an ethnically diverse UK population: a prospective cohort study. Journal of the American Society of Nephrology: JASN 16: 3702–3710.
[40]
Torffvit O, Lovestam-Adrian M, Agardh E, Agardh CD (2005) Nephropathy, but not retinopathy, is associated with the development of heart disease in Type 1 diabetes: A 12-year observation study of 462 patients. Diabet Med 22: 723–729.
[41]
Valmadrid CT, Klein R, Moss SE, Klein BEK (2000) The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Archives Intern Med 160: 1093–1100.
[42]
Wagener DK, Harris T, Madans JH (1994) Proteinuria as a biomarker: Risk of subsequent morbidity and mortality. Environ Res 66: 160–172.
[43]
Wang Z, Hoy WE (2005) Albuminuria and incident coronary heart disease in Australian Aboriginal people. Kidney Int 68: 1289–1293.
[44]
Yuyun MF, Khaw KT, Luben R, Welch A, Bingham S, et al. (2004) A prospective study of microalbuminuria and incident coronary heart disease and its prognostic significance in a British population: The EPIC-Norfolk Study. Am J Epidemiol 159: 284–293.
[45]
Corona AJ, Martinez DR, Avila MH, Haffner S, Williams K, et al. (2005) Microalbuminuria as a predictor of myocardial infarction in a Mexican population: the Mexico City Diabetes Study. Kidney Int Suppl. pp. S34–39.
[46]
Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, et al. (2007) Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 115: 1481–1501.
[47]
Gansevoort RT, Brinkman J, Bakker SJ, De Jong PE, de Zeeuw D (2006) Evaluation of measures of urinary albumin excretion. Am J Epidemiol 164: 725–727.
[48]
Hallan S, Astor B, Romundstad S, Aasarod K, Kvenild K, et al. (2007) Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: The HUNT II Study. Arch Intern Med 167: 2490–2496.
[49]
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, et al. (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–860.
[50]
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, et al. (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869.
[51]
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, et al. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342: 145–153.
[52]
de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, et al. (2004) Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 65: 2309–2320.
[53]
Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, et al. (2005) Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension 45: 198–202.
