Original Investigation
Pathogenesis and Treatment of Kidney Disease
Proteinuria and Stroke: A Meta-analysis of Cohort Studies

https://doi.org/10.1053/j.ajkd.2008.08.032Get rights and content

Background

The associations between decreased kidney function and cardiovascular disease recently have been established. However, there is uncertainty about the consistency between the independent associations of proteinuria as a risk factor across all cardiovascular end points. We undertook a meta-analysis of published cohort studies to provide a reliable estimate of the strength of association between proteinuria and risk of stroke.

Study Design

Meta-analysis of observational cohort studies.

Setting & Population

General population of participants with diabetes. Studies were excluded if participants had known glomerular disease or had undergone dialysis or transplantation.

Selection Criteria for Studies

MEDLINE, EMBASE, and CINAHL databases were searched for studies that reported age- or multivariate-adjusted risk ratio with some estimate of the variance of the association between proteinuria and risk of stroke, without language restriction.

Factor

Proteinuria or albuminuria.

Outcomes

Fatal or nonfatal stroke.

Results

Data from 10 published studies involving 140,231 participants and 3,266 strokes were eligible for inclusion. Participants with proteinuria had a 71% greater risk of stroke compared with those without proteinuria (95% confidence interval, 1.39 to 2.10). There was evidence of significant quantitative heterogeneity in the magnitude of the association across studies (I2 = 60%; P for heterogeneity = 0.008), which was partially explained by differences in methods for measuring proteinuria. The risk of stroke remained significant after adjustment for other vascular risk factors.

Limitations

Because individual patient data were unavailable, we were unable to fully examine the impact of adjustment for known cardiovascular risk factors on the strength of the association between proteinuria and stroke risk. It is possible that the pooled estimate was affected by regression dilution bias.

Conclusions

These findings support the independent relationship between proteinuria and stroke. Additional studies are warranted to determine whether interventions to reduce proteinuria are effective at reducing rates of stroke.

Section snippets

Search Strategy and Selection Criteria

The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for the conduct of meta-analyses of observational cohort studies14 were followed. Relevant studies published between 1966 and November 2006 were identified from MEDLINE, EMBASE, and CINAHL by using relevant text words and medical subject headings that included all spellings of “proteinuria,” “albuminuria,” “microalbuminuria,” and “macroalbuminuria” and combined these with all spellings of “stroke,” “apoplexy,”

Literature Search

The literature search yielded 3,028 articles, of which 220 were reviewed in full. Ten published studies5, 6, 7, 8, 9, 10, 11, 16, 19, 20 including information for 140,231 participants and 3,266 stroke events (37.0% fatal) were eligible for inclusion in the analysis. A flow chart detailing the process of study identification and selection is shown in Fig 1, and characteristics of the included studies are listed in Table 2. Two studies5, 19 reported the effects of macroalbuminuria compared with

Discussion

The key finding from this systematic overview, which included data for more than 3,000 stroke events in 140,000 participants, is that the presence of proteinuria confers a 50% to 70% greater risk of stroke. This association was uniformly consistent across important subgroups characterized by sex, ethnicity, and diabetes status and was apparent in studies that had adjusted for known cardiovascular risk factors, most notably blood pressure. Although the potential for residual confounding remains,

Acknowledgements

Support: None.

Financial Disclosure: Toshiharu Ninomiya 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; Vlado Perkovic holds a fellowship of Heart Foundation of Australia and the Royal Australasian College of Physicians Pfizer Cardiovascular Research fellowship; Alan Cass holds a Senior Research Fellowship from the NHMRC of Australia; and Craig Anderson holds

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    Originally published online as doi:10.1053/j.ajkd.2008.08.032 on December 15, 2008.

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