The Relationship between Proteinuria and Coronary Risk: A Systematic Review and Meta-Analysis
Vlado Perkovic1,2*, Christine Verdon2, Toshiharu Ninomiya1, Federica Barzi1,2, Alan Cass1,2, Anushka Patel1,2, Meg Jardine1, Martin Gallagher1,2, Fiona Turnbull1,2, John Chalmers1,2, Jonathan Craig2, Rachel Huxley1,2 1 The George Institute for International Health, Sydney, New South Wales, Australia, 2 University of Sydney, Sydney, New South Wales, Australia
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.
Funding: This project did not have any specific funding, but the work was supported in part by a Program Grant from the National Health and Medical Research Council of Australia. VP holds an Heart Foundation of Australia Astra Zeneca fellowship and the Royal Australasian College of Physicians Pfizer Cardiovascular Research fellowship. TN holds a Banyu Life Science Foundation Fellowship and International Society of Hypertension Visiting Postdoctoral Award from the Foundation for High Blood Pressure Research in Australia. Alan Cass holds a Senior Research Fellowship from the NHMRC of Australia. AP holds a Career Development Award from the National Heart Foundation of Australia. These funding sources had no input into any aspect of this work.
Competing Interests: The authors had full access to the data. JC has received research grants from Servier, administered through the University of Sydney, as co-principal investigator for PROGRESS and ADVANCE. VP, AP, and JC have received honoraria from Servier for speaking about these studies at scientific meetings.
Academic Editor: Giuseppe Remuzzi, Instituto Mario Negri, Italy
Citation: Perkovic V, Verdon C, Ninomiya T, Barzi F, Cass A, et al. (2008) The Relationship between Proteinuria and Coronary Risk: A Systematic Review and Meta-Analysis. PLoS Med 5(10): e207 doi:10.1371/journal.pmed.0050207
Received: April 2, 2008; Accepted: September 9, 2008; Published: October 21, 2008
Copyright: © 2008 Perkovic et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abbreviations: CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; RR, relative risk
