Proteinuria as an independent predictor of stroke: Systematic review and meta-analysis

Abstract

Background Proteinuria has emerged as an important vascular risk factor for adverse cardiovascular events including stroke. Hypertension has been proposed as the principal confounder of this relationship but its role has not been systematically examined. Aim We aimed to determine if proteinuria remains an independent predictor of stroke after more complete adjustment for blood pressure. Summary of review We performed a systematic review, searching MEDLINE and EMBASE (to February 2018) for cohort studies or randomized controlled trials that reported stroke incidence in adults according to baseline proteinuria ± glomerular filtration rate. Study and participant characteristics and relative risks were extracted. Estimates were combined using a random effects model. Heterogeneity was assessed by χ 2 statistics and I2, and by subgroup strata and meta-regression, with a particular focus on the impact of more complete adjustment for blood pressure on the association. The quality of cohort studies and post hoc analyses was assessed using the Newcastle–Ottawa Scale. We identified 38 studies comprising 1,735,390 participants with 26,405 stroke events. Overall, the presence of any level of proteinuria was associated with greater stroke risk (18 studies; pooled crude relative risk 2.00, 95%CI 1.63–2.46; p < 0.001) even after adjustment for established cardiovascular risk factors (33 studies; pooled adjusted relative risk 1.72, 1.51–1.95; p < 0.001), albeit with considerable heterogeneity between studies (p < 0.001; I2 = 77.3%). Moreover, the association did not substantially attenuate with more thorough adjustment for hypertension: single baseline blood pressure measure (10 studies; pooled adjusted relative risk = 1.92, 1.39–2.66; p < 0.001); history or treated hypertension (four studies; pooled adjusted relative risk = 1.76, 1.13–2.75, p = 0.013); multiple blood pressure measurements over months to years (four studies; relative risk = 1.68, 1.33–2.14; p < 0.001). Conclusions Even after extensive adjustment for hypertension, proteinuria is strongly and independently associated with incident stroke risk, possibly indicating a shared renal and cerebral susceptibility to vascular injury that is not fully explained by traditional vascular risk factors.

Associations of blood biomarkers with glomerular filtration rate in patients with TIA and stroke: population-based study

“…Fourth, urine albumin was not measured in this study and we have previously shown that the relationship between albuminuria and stroke may be mechanistically different to that of low eGFR and stroke. 45 …”

“…Fourth, urine albumin was not measured in this study and we have previously shown that the relationship between albuminuria and stroke may be mechanistically different to that of low eGFR and stroke. 45 As the global burden of CKD rises, 46 so too will its potential contribution to stroke mechanisms and its prevalence in stroke survivors. However, disentangling the pathophysiology of stroke in CKD and the importance of non-traditional or renal-specific risk factors has been challenging.…”

Metformin Use and Risk of All-Cause Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease—A Systematic Review and Meta-Analysis

“…and M.L. with a 9-star Newcastle–Ottawa scale ( 20 , 21 ), and high quality was implied by a score > 6 stars. The evidence quality of each outcome among the enrolled articles was assessed as deficient, low, modest or high by YH and ML independently according to Grading of Recommended Assessment, Development and Evaluation ( 22 ).…”

Impact of multimorbidity on risk and outcome of stroke: Lessons from chronic kidney disease

“…The “strain vessel hypothesis” has been proposed whereby juxtamedullary afferent arterioles in the kidney and cerebral perforating arteries in the brain are both small, short vessels exposed to the large pressure gradients and therefore most vulnerable to hypertensive vascular injury, manifest as albuminuria and cerebrovascular disease, respectively. 53 In a systematic review and meta-analysis of nearly 2 million participants undertaken to study the impact of hypertension on the relationship between proteinuria and stroke risk, 8 the presence of proteinuria conferred a 70% greater risk of stroke compared to that in those without it. However, in contrast to low eGFR and stroke, the risk association between proteinuria and stroke did not substantially vary or attenuate even with the extensive adjustment for blood pressure.…”

“…The methodology of our systematic reviews of stroke and CKD has previously been published. 7 , 8 Briefly, we searched MEDLINE and EMBASE databases (from inception to May 2020) using a search strategy developed by a specialized librarian that combined text word and medical subject headings without language restrictions. Additionally, we searched references from relevant articles.…”