Association of kidney disease measures with ischemic versus hemorrhagic strokes: pooled analyses of 4 prospective community-based cohorts

Abstract

Background and purpose: Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.

Methods: We pooled individual participant data from 4 community-based cohorts: 3 from the United States and 1 from The Netherlands. GFR was estimated using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of estimated GFR and ACR were compared for each stroke type (ischemic versus intraparenchymal hemorrhagic) using study-stratified Cox regression.

Results: Among 29,595 participants (mean age, 61 [SD 12.5] years; 46% men; 17% black), 1261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low estimated GFR was significantly associated with increased risk of ischemic stroke, but not hemorrhagic stroke, whereas high ACR was associated with both stroke types. Adjusted hazard ratios for ischemic and hemorrhagic stroke at estimated GFR of 45 (versus 95) mL/min per 1.73 m2 were 1.30 (95% confidence interval, 1.01-1.68) and 0.92 (0.47-1.81), respectively. In contrast, the corresponding hazard ratios for ACR of 300 (versus 5) mg/g were 1.62 (1.27-2.07) for ischemic and 2.57 (1.37-4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P=0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.

Conclusions: Whereas albuminuria showed significant association with both stroke types, the association of decreased estimated GFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.

Keywords: cardiovascular; epidemiology; renal insufficiency, chronic; risk factors; stroke.

Figure 1. Adjusted associations of continuous eGFR and ACR with ischemic and hemorrhagic strokes

Top panels show the association of the creatinine and cystatin C combined equation based eGFR with ischemic (A) and hemorrhagic (B) strokes. Bottom panels display the association of ACR with ischemic (C) and hemorrhagic (D) stroke. Diamonds represent the reference points (eGFR=95 mL/min/1.73m², ACR=5 mg/g). Error bars denote 95%CIs of the adjusted hazard ratios, and the black circles denote P <0.05 compared to the reference. Hazard ratios were adjusted for sex, age, black ethnicity, diabetes, current smoking, systolic blood pressure, total cholesterol, history of cardiovascular disease, BMI, statins and antihypertensive drug use. eGFR_CyCr = cystatin C and creatinine combined equation based estimated glomerular filtration rate; ACR= albumin-to-creatinine ratio.

Figure 2. Adjusted risk of ischemic (left) and hemorrhagic (right) stroke according to clinical eGFR and ACR categories

The diamond sizes are proportional to the HRs estimate with full cells corresponding to the highest HRs (i.e. HR=3.2) and empty cells corresponding to HR=1.0 or no data. Hazard ratios were adjusted for sex, age, black ethnicity, diabetes, current smoking, systolic blood pressure, total cholesterol, history of cardiovascular disease, BMI, statins and antihypertensive drug use. The dark-gray diamond color corresponds to P<0.05. eGFR_CyCr = combined cystatin C and creatinine based equation estimated glomerular filtration rate; ACR= albumin-to-creatinine ratio.

Figure 3. Adjusted association of traditional cardiovascular risk factors (panel A) versus kidney measures (panel B) with ischemic and hemorrhagic strokes

*CKD was defined as eGFR_CyCr <60 mL/min/1.73m² and/or ACR ≥30 mg/g; eGFR_CyCr= Cystatin C and creatinine combined estimated glomerular filtration rate. 1 SD of age = 12.5 years; 1SD of BMI = 5.3 kg/m²; 1 SD of systolic blood pressure = 20.3 mmHg; and 1SD of cholesterol = 1.0 mmol/L. eGFR_CysC = cystatin C based estimated glomerular filtration rate; eGFR_Creat = creatinine based estimated glomerular filtration rate; ACR = albumin-to-creatinine ratio; CVD = cardiovascular disease; BMI = body mass index; SBP = systolic blood pressure. Estimates in panel A were obtained from a single multivariable model with additional adjustment for eGFR_CyCr and ACR. Estimates in panel B were adjusted for traditional cardiovascular risk factors shown in panel A and either eGFR_CyCr or ACR as appropriate. P-diff = P for difference between ischemic and hemorrhagic stroke. The size of the box around the hazard ratio estimates is proportional to the inverse of the hazard ratio variance.

Figure 3. Adjusted association of traditional cardiovascular risk factors (panel A) versus kidney measures (panel B) with ischemic and hemorrhagic strokes

*CKD was defined as eGFR_CyCr <60 mL/min/1.73m² and/or ACR ≥30 mg/g; eGFR_CyCr= Cystatin C and creatinine combined estimated glomerular filtration rate. 1 SD of age = 12.5 years; 1SD of BMI = 5.3 kg/m²; 1 SD of systolic blood pressure = 20.3 mmHg; and 1SD of cholesterol = 1.0 mmol/L. eGFR_CysC = cystatin C based estimated glomerular filtration rate; eGFR_Creat = creatinine based estimated glomerular filtration rate; ACR = albumin-to-creatinine ratio; CVD = cardiovascular disease; BMI = body mass index; SBP = systolic blood pressure. Estimates in panel A were obtained from a single multivariable model with additional adjustment for eGFR_CyCr and ACR. Estimates in panel B were adjusted for traditional cardiovascular risk factors shown in panel A and either eGFR_CyCr or ACR as appropriate. P-diff = P for difference between ischemic and hemorrhagic stroke. The size of the box around the hazard ratio estimates is proportional to the inverse of the hazard ratio variance.