- Meng Lee, visiting scholar and instructor13,
- Jeffrey L Saver, director and professor1,
- Kuo-Hsuan Chang, instructor4,
- Hung-Wei Liao, director5,
- Shen-Chih Chang, epidemiologist6,
- Bruce Ovbiagele, associate professor12
- 1Stroke Center, 710 Westwood Plaza, University of California, Los Angeles, CA 90095, USA
- 2Department of Neurology, University of California, Los Angeles
- 3Department of Neurology, Chang Gung Memorial Hospital at Chiayi, Chang Gung University College of Medicine, Taiwan
- 4Department of Neurology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine
- 5Ching-Ten Clinic, Taiwan
- 6Department of Epidemiology, School of Public Health, University of California
- Correspondence to: B Ovbiagele
- Accepted 25 June 2010
Objective To qualitatively and quantitatively investigate the link between a low estimated glomerular filtration rate (eGFR) at baseline and risk of future stroke.
Design Systematic review and meta-analysis of prospective studies.
Data sources PubMed (1966-October 2009) and Embase (1947-October 2009).
Selection criteria Inclusion criteria were studies that prospectively collected data within cohort studies or clinical trials, estimated glomerular filtration rate at baseline using the modification of diet in renal disease or Cockcroft-Gault equations, assessed incident stroke, had a follow-up of at least one year, and reported quantitative estimates of multivariate adjusted relative risk and 95% confidence interval for stroke associated with an eGFR of 60-90 ml/min/1.73 m2 or <60 ml/min/1.73 m2.
Data abstraction Two investigators independently abstracted data from eligible studies. Estimates were combined using a random effects model. Heterogeneity was assessed by P value of χ2 statistics and I2. Publication bias was assessed by visual examination of funnel plots.
Results 21 articles derived from 33 prospective studies: 14 articles assessed eGFR <60 ml/min/1.73 m2 and seven assessed eGRF at both <60 ml/min/1.73 m2 and 60-90 ml/min/1.73 m2 for a total of 284 672 participants (follow-up 3.2-15 years) with 7863 stroke events. Incident stroke risk increased among participants with an eGFR <60 ml/min/1.73 m2 (relative risk 1.43, 95% confidence interval 1.31 to 1.57; P<0.001) but not among those with an eGFR of 60-90 ml/min/1.73 m2 (1.07, 0.98 to 1.17; P=0.15). Significant heterogeneity existed between estimates among patients with an eGFR <60 ml/min/1.73 m2 (P<0.001). In subgroup analyses among participants with an eGFR <60 ml/min/1.73 m2, heterogeneity was significant in Asians compared with non-Asians (1.96, 1.73 to 2.23 v 1.25, 1.16 to 1.35; P<0.001), and those with an eGFR of 40-60 ml/min/1.73 m2 v <40 ml/min/1.73 m2 (1.28, 1.04 to 1.56 v 1.77, 1.32 to 2.38; P<0.01).
Conclusions A baseline eGFR <60 ml/min/1.73 m2 was independently related to incident stroke across a variety of participants and study designs. Prompt and appropriate implementation of established strategies for reduction of vascular risk in people with know renal insufficiency may prevent future strokes.
Chronic kidney disease and cardiovascular disease are major public health problems worldwide and often share the same pathophysiological mechanisms.1 Indeed, the prevalence of traditional cardiovascular risk factors can be high in those with impaired kidney function,2 and most patients with an estimated glomerular filtration rate (eGFR) lower than 60 ml/min/1.73 m2 die of cardiovascular causes and not progression to end stage renal disease.3 As such, averting future vascular events in patients with a low eGFR should be a primary goal.4
A systematic review of observational studies showed that a reduced eGFR was associated with an increased risk of coronary heart disease,5 and a recent meta-analysis showed that a low eGFR was linked to all cause and cardiovascular mortality in the general population.6 The effect of reduced eGFR on incident stroke, however, has not been well delineated in a qualitative or quantitative manner using the totality of published data. As stroke is a leading cause of mortality and morbidity worldwide, and several strategies, such as blood pressure control and use of statins and aspirin, may reduce subsequent cardiovascular disease in patients with chronic kidney disease, it is important to identify people at potential high risk, then appropriate therapy can be applied.7 8 We carried out a systematic review and meta-analysis to determine whether a link exists between reduced eGFR and incident stroke and the magnitude of any relation.
The search strategy was done according to the recommendations of the Meta-analysis of Observational Studies in Epidemiology.9 We searched PubMed (1966 to October 2009) and Embase (1947 to October 2009) using the search strategy “glomerular filtration rate” OR “renal disease” OR “chronic kidney disease” AND “stroke” OR “cerebrovascular disease” OR “cerebrovascular attack” OR “cerebral infarct” OR “intracranial hemorrhage” AND “prospective” OR “cohort” OR “observational” OR “post hoc” (see web extra fig 1). We restricted the search to studies in humans. No language restrictions were applied. Further information was retrieved through a manual search of references from recent reviews and relevant published original studies.
Study selection and data abstraction
We included studies that prospectively collected data within cohort studies or clinical trials, used the modification of diet in renal disease or Cockcroft-Gault equations to estimate glomerular filtration rate at baseline, assessed incident stroke, had a follow-up of at least one year, and reported quantitative estimates of the multivariate adjusted relative risk and 95% confidence interval for stroke associated with an eGFR of 60-90 ml/min/1.73 m2 or <60 ml/min/1.73 m2, or both. We excluded studies that had a cross sectional, case-control, or retrospective cohort study; that had mostly participants with end stage renal disease (by history of dialysis or an eGFR <15 ml/min/1.73 m2) or kidney transplant; that only reported unadjusted or age and sex adjusted relative risk; that did not report 95% confidence intervals; and that were duplicated. Studies that used slightly varying eGFR intervals were included if they were otherwise comparable. Two investigators (ML and K-HC) independently abstracted data from eligible studies. Discrepancies were resolved by discussion with a third investigator (BO) and by referencing the original report.
We assessed the quality of eligible studies. Assessment was based on guidelines developed by the US Preventive Task Force as well as the modified checklist used in previous studies.10 11 12 We assessed eight characteristics: prospective study design, maintenance of comparable groups, adjustment of potential confounders, documented loss of follow-up rate, assessor of outcome blinded to exposure status, clear definition of exposures (eGFR) and outcomes (stroke), temporality (eGFR measured at baseline, not at time of outcomes assessment), and follow-up of at least one year. Studies were graded as good quality if they met at least seven of eight criteria, fair if they met four to six, and poor if they met fewer than four.
For data analysis we used multivariate adjusted outcome data (expressed as relative risks and 95% confidence intervals). When articles provided estimates based on both the modification of diet in renal disease and the Cockcroft-Gault equations, we used estimates from the more informative, expert recommended modification of diet in renal disease equation4 for primary analysis. In each study we converted these values by using their natural logarithms, and we calculated the standard errors from these logarithmic numbers and their corresponding 95% confidence intervals. For the statistical analysis we combined log relative risks and standard errors using the inverse variance approach. We used a random effect model and explored for sources of inconsistency (I2) and heterogeneity. A fixed effect model was also used for comparison with the random effects model on the overall risk estimate. Reported P values were two sided, with significance set at less than 0.05. Heterogeneity was assessed by P value of χ2 statistics and I2, which describes the percentage of variability in the effect estimates that is due to heterogeneity rather than to chance.13 14 Based on the suggestion of the Cochrane Collaboration we regarded heterogeneity as possibly unimportant when the I2 value was less than 40% and considerable when more than 75%.15 RevMan 5 was used for the meta-analysis of observational studies.16 17
The leading outcomes of interest were relative risks of incident stroke in patients with an eGFR of 60-90 ml/min/1.73 m2 and <60 ml/min/1.73 m2. Publication bias was assessed by visual examination of funnel plots. Subgroup analyses for eGFRs <60 ml/min/1.73 m2 were done according to normal references (studies using an eGFR >60 ml/min/1.73 m2 as the normal reference versus studies using >90 ml/min/1.73 m2 as normal), study population type (general or hypertension only versus established cardiovascular disease or high cardiovascular risk at entry), study design (ordinary cohorts versus secondary analysis of clinical trials), ethnicity (Asians v non-Asians), follow-up (<7 years v ≥7 years), number of participants (<10 000 v ≥10 000), equation used to determine eGFR (modification of diet in renal disease v Cockcroft-Gault), end points (fatal v fatal plus non-fatal stroke), stroke subtype (ischaemic v haemorrhagic stroke), sex (men v women), degree of eGFR impairment (eGFR 40-60 ml/min/1.73 m2 or nearest equivalent v <40 ml/min/1.73 m2 or nearest equivalent), level of adjustment (age and sex adjusted v multivariate adjusted), and study quality (good v fair). We also explored the interaction between eGFR and albuminuria by using as a reference those groups with an eGFR of >60 ml/min/1.73 m2 without albuminuria.
The literature review identified 83 full articles for detailed assessment, of which 53 were excluded for having no multivariate adjusted stroke estimate, six for being duplicated studies, and three for having a retrospective cohort design. Our final primary analysis included 21 articles derived from 33 prospective studies18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38: 14 articles assessed eGFR <60 ml/min/1.73 m2 only and seven assessed both <60 ml/min/1.73 m2 and 60-90 ml/min/1.73 m2 (fig 1⇓). The table⇓ shows the characteristics of the included studies. Overall, 284 672 participants had a total of 7863 stroke events. Among the 21 articles, one contained 10 community cohorts from Japan30 and the other four community cohorts from the United States.36 Participants were derived from ordinary cohorts in 13 articles and clinical trials in eight. On a scale of 8 the overall quality of studies was good (median score 7, range 5-8). Follow-up ranged from 3.222 to 15 years.20 Glomerular filtration rate was estimated by the modification of diet in renal disease equation in 15 articles and by the Cockcroft-Gault equation in six. Nineteen articles reported fatal plus non-fatal stroke as a primary end point, whereas two reported fatal stroke as a primary end point.20 24 One study used thromboembolic events as a primary end point, but ischaemic stroke constituted over 94% of total thromboembolic events.23 Transient ischaemic attacks were only included as end points in three studies.22 26 34
Pooling results from the random effects model showed that incident stroke increased among patients with an eGFR <60 ml/min/1.73 m2 (relative risk 1.43, 95% confidence interval 1.31 to 1.57, P<0.001; fig 2⇓). The risk of incident stroke did not, however, increase significantly among patients with an eGFR of 60-90 ml/min/1.73 m2 (1.07, 0.98 to 1.17, P=0.15; fig 2). Significant heterogeneity existed between estimates among patients with an eGFR <60 ml/min/1.73 m2 (P<0.001, I2=69%) but not among those with an eGFR of 60-90 ml/min/1.73 m2 (P=0.06, I2=38%). The estimates were similar between the fixed effects model and random effect model.
An eGFR <60 ml/min/1.73 m2 was associated with an increased risk of subsequent stroke in all subgroups when estimates were stratified by eGFR reference group, study population type, study design, ethnicity, duration of follow-up, number of participants, equation used to determine eGFR, end points, sex, stroke subtype, different eGFR intervals <60 ml/min/1.73 m2, study quality, and level of adjustment (fig 3⇓). Significant heterogeneity between pooled analyses were noted for studies using an eGFR >60 ml/min/1.73 m2 as the normal reference compared with studies using >90 ml/min/1.73 m2 as normal (1.29, 1.18 to 1.41 v 1.82, 1.53 to 2.16, P for heterogeneity among subgroups <0.001), cohort studies compared with clinical trials (1.59, 1.40 to 1.81 v 1.25, 1.13 to 1.38, P<0.01), Asians compared with non-Asians (1.96, 1.73 to 2.23 v 1.26, 1.16 to 1.35, P<0.001), fatal compared with fatal plus non-fatal stroke (1.97, 1.63 to 2.38 v 1.38, 1.26 to 1.51, P<0.001), eGFR 40-60 ml/min/1.73 m2 v <40 ml/min/1.73 m2 (1.28, 1.04 to 1.56 v 1.77, 1.32 to 2.38, P<0.01), and good study quality compared with fair study quality (1.35, 1.23 to 1.49 v 1.62, 1.33 to 1.97, P=0.01).
A total of 11 studies reported adjusted estimates of the strength of the association, first by age and sex then by other known cardiovascular risk factors—for example, blood pressure, smoking, lipids levels, diabetes. The overall age and sex adjusted summary estimate was 1.64 (95% confidence interval 1.45 to 1.85), which after further adjustment of other known cardiovascular risk factors was reduced to 1.45 (1.26 to 1.68; P for heterogeneity among subgroups 0.01).
Otherwise no obvious heterogeneity found between baseline risk populations (general or hypertension only v high cardiovascular risk), duration of follow-up, number of participants, equation used to determine eGFR, stroke subtypes, and sex. Based on the few papers that provided information on the interaction between proteinuria and eGFR, proteinuria did not substantially increase the risk of stroke in patients with an eGFR of <60 or >60 ml/min/1.73 m2 (fig 4⇓).
The funnel plots showed no major asymmetry except for a small degree of publication bias, with a slight under-representation of small studies showing neutral or unexpected protective effects (see web extra fig 2).
In this meta-analysis of 21 articles derived from 33 prospective studies of generally good quality, among over 280 000 people experiencing almost 8000 stroke events, we found that patients with a baseline estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m2 had a risk of future stroke that was 43% greater than those with a normal baseline eGFR. This relation was consistent across diverse population subgroups—that is, those with or without traditional cardiovascular risk factors. The size and inclusion of only prospectively collected data strengthened the robustness of our findings, as selection bias, recall bias, and reverse causality were unlikely. In addition, all studies included in our meta-analysis reported a multivariate adjusted relative risk, which probably mitigated the possibility of known confounding influencing our results.
We used subgroup analyses to assess the varying influence of several factors on the association between eGFR <60 ml/min/1.73 m2 and risk of stroke. The magnitude of risk was larger when studies used an eGFR >90 ml/min/1.73 m2 as reference compared with >60 ml/min/1.73 m2, which raised the possibility that an eGFR of 60-90 ml/min/1.73 m2 may increase the risk of stroke compared with an eGFR >90 ml/min/1.73 m2. Our formal meta-analysis did not, however, show significantly increased risk of incident stroke among patients with an eGFR of 60-90 ml/min/1.73 m2. The explanation could be that such a rate is not sensitive enough as a marker of kidney disease to discriminate risk of stroke. We did, however, find a possible dose-response relation between eGFR and stroke at levels <60 ml/min/1.73 m2—that is, the risk of stroke was significantly greater for eGFR <40 ml/min/1.73 m2 than for levels of 40-60 ml/min/1.73 m2.
A meta-analysis based on observational studies cannot prove causality. However, based on these results it may not be unreasonable to regard the presence of a low eGFR as a marker for increased risk of stroke, prompting optimal application of established vascular risk reduction strategies such as control of blood pressure, statin use, and antiplatelet therapy.7
Interestingly we found that Asian people with a low baseline eGFR seemed to be at higher risk of future stroke. Indeed, in Asian populations, hypertension is a major risk factor of both stroke and death from renal causes,39 40 chronic kidney disease further increases the association of blood pressure with stroke,25 and meta-analysis showed that the risk of stroke associated with hypertension is consistently and significantly greater in Chinese than in white people.41 Furthermore, it has been suggested that Asian people tend to develop hypertension at earlier ages than other races,42 and it is conceivable that a longer history of hypertension may cause more profound damage of end organs and vessels thereby leading to a higher likelihood of vascular events within a given study period. A systematic review that linked reduced eGFR with increased risk of coronary heart disease was only among participants in Western countries and so did not have the means of exploring this issue.5 Although most of the studies we analysed adjusted for hypertension or blood pressure, none adjusted for the duration of hypertension, thereby limiting the extent to which we could fully adjust for hypertension as a confounder. As such, this potential disparity between races will need to be more comprehensively explored in future studies.
We also observed that the effect of reduced eGFR was more profound on the risk of fatal stroke than on all strokes, which probably points to the association of compromised kidney function with risk factors for generally poor clinical outcomes such as oxidative stress, widespread inflammation, electrolyte derangements, procoagulation, and presence of uraemic toxins.3 In fact, kidney disease even of mild severity has been shown to be an independent predictor of poorer clinical outcomes among people with stroke, including higher risk of all cause mortality and cardiovascular mortality.43 44 Also of note, the presence of albuminuria did not substantially further increase the risk of stroke among patients with a baseline eGFR of <60 or >60 ml/min/1.73 m2. Our result should be interpreted with caution, however, as it was based on just three studies and the rate of albuminuria is low in people without diabetes. A recent meta-analysis showed that compared with people without albuminuria or a low eGFR, those with either condition had a higher risk of cardiovascular death and those with both conditions had the highest risk of cardiovascular death.6 Furthermore, meta-analyses have shown that albuminuria was independently associated with a higher risk of stroke even when the included studies had adjusted for eGFR or serum creatinine level.45 46
Limitations of this meta-analysis
Limitations of this meta-analysis must be considered. Firstly, meta-analyses may be biased if the literature search fails to identify all relevant studies or the selection criteria for including a study are applied in a subjective manner. To minimise these risks we carried out thorough searches across different databases using explicit criteria for study selection, data abstraction, and data analysis. Secondly, compared with studies of good quality, those of fair quality showed a stronger association between reduced eGFR and stroke. When we restricted analysis to good quality studies, the estimate of association slightly decreased. Thirdly, a large amount of heterogeneity was observed in the results of the various studies. Although subanalyses were done to identify this, heterogeneity persisted in many subgroups, suggesting that other factors might explain this result. Meta-regression by average baseline eGFR and other variables could have been a better way of exploring potential sources of heterogeneity. However, most included articles did not provide average baseline eGFR in each eGFR category, which prevented us from exploring further. In those studies that provided both age and sex adjusted and multivariate unadjusted estimates, the association between reduced eGFR and stroke was slightly, but significantly, attenuated after further adjustment. Such an attenuation in effect size suggests that residual confounding may have remained and that the summary result presented here may be a slight overestimation of the true magnitude of the association between reduced eGFR and risk of stroke. Despite these limitations, the results of this systematic review represent the most precise and accurate estimate of the strength of the relation between reduced eGFR and incident stroke currently available.
Our formal meta-analysis found a significant association between eGFR <60 ml/min/1.73 m2 and increased incident stroke across various populations, after adjustment for established cardiovascular risk factors. None the less, these results possibly underestimated the magnitude of this relation because a reduced eGFR often simultaneously exists with several traditional and novel vascular risk factors. Of major public health interest were our findings that Asian patients with a low eGFR were at higher risk for stroke than their non-Asian counterparts, that below an eGFR level of 60 ml/min/1.73 m2 a dose-response relation with risk of stroke might exist, and that fatal strokes were especially associated with low baseline eGFR.
At this juncture, a low baseline eGFR should be seen simply as a risk marker. Established evidence based strategies already proved to mitigate vascular risk, such as reduction of blood pressure, when promptly and appropriately applied are likely to avert future strokes in people with renal insufficiency. Specific patient subgroups with a low eGFR, such as people of Asian race, may particularly benefit.
What is already known on this topic
Most patients with an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 die of cardiovascular causes and not progression to end stage renal disease
A recent meta-analysis showed that an eGFR <60 ml/min/1.73 m2 was associated with all cause and cardiovascular mortality in the general population
What this study adds
People with a baseline eGFR <60 ml/min/1.73 m2 had an independent risk of future stroke that was 43% greater than those with a normal baseline eGFR
A dose-response relation between eGFR <60 ml/min/1.73 m2 and risk of stroke was observed, with risk of stroke being significantly greater for levels <40 ml/min/1.73 m2 compared with 40-60 ml/min/1.73 m2
Asian patients with an eGFR <60 ml/min/1.73 m2 were at higher risk of stroke than people of non-Asian ethnicity
Cite this as: BMJ 2010;341:c4249
We thank Yueh Lee for retrieving the papers.
Contributors: ML and BO conceived the study. ML, S-CC, and BO design the inclusion and exclusion criteria. ML, and K-HC participated in the study search and data collection and extraction. ML did the statistical analysis with guidance from JLS, S-CC, and BO. ML wrote the first draft of the report, and JLS, H-WL, and BO did the major revision and made comments. All other authors commented on the draft and approved the final version. ML and BO had full access to all the data and had the final decision to submit for publication. They are guarantors.
Funding: ML was supported by a grant from Chang Gung Memorial Hospital, Taiwan (CMRPG 660311, Taiwan). JLS was supported by the specialised programme on translational research in acute stroke (SPOTRIAS) award (P50 NS044378) from the National Institutes of Health, and BO was supported by University of California, Los Angeles-Resource Centers for Minority Aging Research under National Institutes of Health/National Institutes on Aging grant No P30-AG021684. The sponsors played no role in the study design, data collection and analysis, or decision to submit the article for publication.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any company for the submitted work; no financial relationships with any companies that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: Not required.
Data sharing: No additional data available.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.