Risk Factors for Incident Stroke Among Patients with End-Stage Renal Disease

J Am Soc Nephrol 14: 2623–2631, 2003 Risk Factors for Incident Stroke among Patients with End-Stage Renal Disease

STEPHEN L. SELIGER,* DANIEL L. GILLEN,† DAVID TIRSCHWELL,‡ HAIMANOT WASSE,* BRYAN R. KESTENBAUM,* and CATHERINE O. STEHMAN-BREEN§ *Division of Nephrology, University of Washington, Seattle, Washington; †Department of Biostatistics, University of Washington School of Public Health and Community Medicine, Seattle, Washington; ‡Department of Neurology, University of Washington, Seattle, Washington; and §Division of Nephrology, Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, Washington

Abstract. Although patients with ESRD experience markedly were associated with the risk of stroke—serum albumin (per higher rates of stroke, no studies in the US have identified 1 g/dl decrease, hazard ratio [HR] ϭ 1.43), height-adjusted risk factors associated with stroke in this population. It was body weight (per 25% decrease, HR ϭ 1.09), and a subjec- hypothesized that black race, malnutrition, and elevated BP tive assessment of undernourishment (HR ϭ 1.27)—as was would be associated with the risk of stroke among patients higher mean BP (per 10 mmHg, HR ϭ 1.11). The associa- with ESRD. Data from the United States Renal Data Sys- tion between black race varied by cardiac disease status, tems were used. Adult Medicare-insured hemodialysis and with blacks estimated to be at lower risk than whites among peritoneal dialysis patients without a history of stroke or individuals with cardiac disease (HR ϭ 0.74), but at higher transient ischemic attack (TIA) were considered for analy- risk among individuals without cardiac disease (HR ϭ sis. The primary outcome was hospitalized or fatal stroke. 1.24). This study confirms the extraordinarily high rates of Cox proportional hazards models were used to determine the stroke in ESRD patients on dialysis and identifies high mean associations between the primary predictor variables and BP and malnutrition as potentially modifiable risk factors. stroke. The rate of incident stroke was 33/1,000 person- The association between black race and stroke differs by years in the study sample. After adjustment for age and cardiac disease status; the reasons for this differing effect of other patient characteristics, three markers of malnutrition race deserve further investigation.

Patients with ESRD experience markedly advanced atheroscle- not be generalizable to the US dialysis population. In addition, rotic disease of the cerebral vasculature (1–4). Although we although blacks have much higher rates of stroke in the general recently reported a 5- to 10-fold risk of hospitalized ischemic population, no previous studies have examined black race as a and hemorrhagic stroke among ESRD patients compared with risk factor for incident stroke in the dialysis population. We non-ESRD individuals (5), little is known regarding potential used data collected by the United States Renal Data System stroke risk factors among the ESRD population. Risk factors (USRDS) to identify patient characteristics associated with the for stroke in this population are likely to differ from those in risk of hospitalized or fatal stroke in dialysis patients, with the non-ESRD population. For example, elevated BP and body specific focus on black race, hypertension, and malnutrition as mass index are risk factors for stroke in the general population, risk factors. whereas in the dialysis population, they are associated with a lower risk of adverse outcomes such as all-cause and cardiac Materials and Methods death (6–9). Only one small study, conducted in a Japanese Study Population dialysis population, has examined risk factors for stroke (10), We used data from the USRDS Dialysis Morbidity and Mortality identifying hypertension as the only significant predictor. Studies, Waves 2 to 4 (DMMS-2 to -4). Details of the studies per- However, the study had limited power, and results from the formed by the USRDS are described elsewhere (12). Briefly, the younger and healthier Japanese dialysis population (11) may USRDS collects demographic and clinical data on all patients who have survived Ͼ90 d of renal replacement therapy for ESRD. DMMS-2 was a prospective observational study of a sample of adult Received January 27, 2003. Accepted July 15, 2003. patients who initiated dialysis in 1996 and early 1997, with deliberate Correspondence to Dr. Stephen L. Seliger, Division of Nephrology, Box oversampling of patients on peritoneal dialysis. DMMS-3 and -4 were 356521, University of Washington, Seattle, WA 98102. Phone: 206-543-3792; retrospective studies of random samples of hemodialysis patients who Fax: 206-685-8661; E-mail: [email protected] were alive on December 31, 1993. Data collection techniques and 1046-6673/1410-2623 content were kept consistent across the three studies, allowing them to Journal of the American Society of Nephrology be combined for use in epidemiologic research. The study population Copyright © 2003 by the American Society of Nephrology for this analysis included all patients who were in DMMS-2 to -4 and DOI: 10.1097/01.ASN.0000088722.56342.A8 treated with dialysis and were Medicare-insured with no previous 2624 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2623–2631, 2003 history of stroke or transient ischemic attack. Following the recom- Statistical Analyses mendations of the USRDS for studies of hospitalization rates (13), The Cox proportional hazards model for censored survival data was patients for whom fee-for-service Medicare was not the primary used to assess the association between the primary risk factors of insurer were excluded from our analysis, because hospitalization data interest and incident stroke after adjustment for potential confounders. for these patients are incomplete in the USRDS database (see the Primary predictor variables of interest included race (white, black, Outcome section). Asian, other), mean BP (MBP; calculated as [systolic BP ϩ 2*diastolic BP]/3), and markers of malnutrition (serum albumin, body weight, and a subjective assessment of undernourishment). Adjust- Ascertainment of Baseline Patient Characteristics ment variables to control confounding were a priori chosen on the Baseline patient data were abstracted by dialysis facility personnel basis of their potential relationship with the outcome of interest. from each patient’s medical record and through patient interview. Cigarette smoking was not included as an adjustment covariate in the Patient characteristics ascertained included demographic (age, gender, primary model because of the high degree of missing information and race), laboratory (albumin, cholesterol, hemoglobin, calcium, (15%) for this variable in the USRDS; rather, the potential confound- parathyroid hormone, and phosphorous), clinical (cause of renal dis- ing effect of smoking was assessed in an exploratory analysis. Renal ease, history of cardiovascular disease (CVD), history of stroke or replacement modality (hemodialysis, peritoneal dialysis, transplant) transient ischemic attack (TIA), dialysis vintage, smoking status, and was modeled as time-dependent covariates, allowing patients to a subjective assessment of undernourishment), and other measure- switch risk groups over the course of follow-up. All models were ments (height, weight, and BP). Previous CVD was defined as any further adjusted for DMMS study via stratification. diagnosis of coronary artery disease, myocardial infarction, coronary Following recommendations from the USRDS (13), incident pa- artery bypass, angioplasty, cardiac arrest, or congestive heart failure. tients were not considered at risk for hospitalizations until day 90 of The average of up to three measurements of BP during three consec- ESRD. Patients were followed from day 90 of ESRD or (for prevalent utive dialysis sessions, recorded either before dialysis (in hemodial- patients) from the DMMS study start date and were censored at loss ysis patients) or randomly (in peritoneal dialysis patients), were used to follow-up, nonstroke death, or the end of the study period (Decem- in this analysis. For DMMS-2 patients, only single measurements of ber 31, 1999). laboratory variables were available. For patients in DMMS-3 and -4, Formal and graphic techniques were used to confirm the presence multiple values for laboratory measurements were available for up to of proportional hazards and to identify potential outliers. We hypoth- 3 mo preceding the start of the study; for these patients, all available esized that all continuous covariates would be linearly related to the values were averaged before inclusion into a statistical model. outcome of interest; however, exploratory residual analyses were performed to investigate functional form further. In particular, we explored linear and nonlinear forms of MBP to determine whether Outcome there was a “U”-or“J”-shaped relationship between BP and stroke. The primary outcome was defined as first hospitalized stroke or Effect modification by age, gender, CVD, and DMMS wave was fatal nonhospitalized stroke. Hospitalization for stroke was deter- explored and tested via stratification and the use of multiplicative mined by linking Medicare hospital billing records to each patient interactions. through unique identifier codes supplied by the USRDS. Diagnosis of stroke was based on the International Classification of Diseases, 9th Results Revision, Clinical Modification (ICD-9-CM) diagnosis codes con- Study Population tained in these billing records. On the basis of previous studies that A total of 13,716 patients were included in DMMS-2 to -4. examined the relative accuracy of different ICD-9-CM diagnosis A total of 712 patients were excluded because their DMMS codes in identifying patients with actual hospitalized stroke (14–18), study start date was missing or implausible (n ϭ 120) or we a priori considered the following five codes to identify acute because they did not have information on mortality or treat- stroke: 430 (subarachnoid hemorrhage), 431 (intracerebral hemor- ment history (n ϭ 365), were younger than 18 yr (n ϭ 22), did rhage), 433.X1 (occlusion of precerebral arteries with infarction), ϭ 434.X1 (occlusion of cerebral arteries with infarction), and 436 (acute not survive until day 90 of ESRD care (n 125), had a ϭ cerebrovascular attack), where “X” can be any integer from 0 to 9 and functioning transplant at the study start date (n 30), or had refers to specific arterial syndromes. A hospitalization in which one of other errors in their baseline data collection (n ϭ 50). Finally, these five diagnosis codes was listed in either the primary or the nine because we were interested in risk factors for incident stroke secondary positions reported by the USRDS was considered stroke only, we excluded 1958 patients with a reported history of related. stroke or TIA before study start date. After these exclusions, For information on fatal stroke, survival status and cause of death 11,046 patients remained. Of these, 2126 (19%) patients did were linked to the DMMS data from the USRDS Patients Standard not have Medicare as a primary insurer at the start of follow-up Analysis File via unique patient identifiers. The date and cause of and were excluded. Baseline characteristics of the final study death listed in a patient’s Standard Analysis File was obtained from cohort of 8920 patients are presented in Table 1. There were information submitted to the USRDS by the patient’s nephrologist 6862 patients with complete data available for inclusion in the (form HCFA 2746). Fatal nonhospitalized stroke was defined as a primary cause of death from either “cerebrovascular disease” or fully adjusted multivariate models; baseline characteristics “cerebrovascular accident including intracranial hemorrhage” without were similar in this group compared with the total cohort a preceding hospitalization for stroke. (Table 1). Secondary outcomes included hospitalized hemorrhagic stroke (ICD-9 codes 430, 431) and ischemic stroke (codes 433.X1, 434.X1, All Strokes or 436). Data on hospitalization and mortality were available through In the total cohort, 915 hospitalized or fatal nonhospitalized December 31, 1999. strokes occurred over a median follow-up of 3.1 yr, with an J Am Soc Nephrol 14: 2623–2631, 2003 Stroke Risk Factors in ESRD 2625

Table 1. Characteristics of study cohort at baselinea

Study Cohort Included in Total Cohort c (N ϭ 8920)b Multivariate Model Patient Characteristic (N ϭ 6862)

N (%) or Mean (SD)

Gender male 4589 (51.4%) 3562 (51.9%) female 4331 (48.6%) 3300 (48.1%) Race white 4484 (52.9%) 3664 (53.4%) black 3371 (39.8%) 2711 (39.5%) Asian 160 (1.9%) 128 (1.9%) other 453 (5.4%) 359 (5.2%) Age (yr) 60.0 (15.8) 60.0 (15.7) Primary renal disease diabetes 2861 (34.1%) 2285 (33.3%) HTN 2510 (29.9%) 2085 (30.4%) other 1350 (16.1%) 1068 (15.6%) primary GN 965 (11.5%) 592 (8.6%) PKD 710 (8.5%) 832 (12.1%) Treatment modality at study start hemodialysis 7907 (88.7%) 6139 (89.5%) peritoneal dialysis 1012 (11.4%) 723 (10.5%) Time on dialysis before start of study incident (90 d) 2129 (23.9%) 1715 (25.0%) 91 d–1 yr 1306 (14.6%) 967 (14.1%) 1–2 yr 1375 (15.4%) 1046 (15.3%) 2ϩ yr 4110 (46.1%) 3134 (45.7%) Smoker current 2140 (28.2%) 1746 (27.5%) former 1419 (18.7%) 1220 (19.2%) never 4031 (53.1%) 3389 (53.3%) Previous CVDd (yes) 4381 (53.8%) 3716 (54.2%) Undernourished (yes) 1154 (14.4%) 964 (14.1%) Serum albumin (g/dl) 3.68 (0.45) 3.68 (0.45) Total cholesterol (mg/dl) 179.4 (49.3) 179.3 (49.4) Hemoglobin (g/dl; median, IQR) 10.1 (9.0–11.1) 10.1 (9.0–11.1) Mean BPe (mmHg) 103.4 (14.0) 103.5 (14.1) Weight (kg; median, IQR) 68.5 (58.5–80) 68.9 (58.6–80.5) Height (cm) 167.5 (11.0) 167.6 (11.0)

a HTN, hypertension; GN, glomerulonephritis; PKD, polycystic kidney disease; IQR, interquartile range; CVD, cardiovascular disease. b Subgroup numbers may not add up to total because of missing data. c Patients with missing covariate values were excluded from the multivariate model. d Defined as a previous diagnosis of coronary artery disease, myocardial infarction, coronary artery bypass, angioplasty, cardiac arrest, or congestive heart failure. e Mean BP ϭ (systolic BP ϩ 2*diastolic BP)/3. BP measurements were performed predialysis (for hemodialysis patients) or randomly (for peritoneal dialysis patients). incidence density of 33/1000 person-years (95% confidence blacks were estimated to be at higher risk of stroke when interval [CI]: 31 to 35). Model-based unadjusted and adjusted compared with whites (hazard ratio [HR] ϭ 1.24; 95% CI ϭ estimates of the association of patient characteristics with 0.96 to 1.6), whereas among patients with prevalent CVD, incident stroke are presented in Table 2. The association be- blacks were at significantly lower risk (HR ϭ 0.74; 95% CI ϭ tween race and incident stroke differed significantly among 0.60 to 0.92). Patients of other races were not found to have individuals with and without prevalent CVD (P ϭ 0.001 for experienced a significantly different risk of stroke, regardless test of interaction). Among patients without prevalent CVD, of CVD status (Table 2). 2626 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2623–2631, 2003

Table 2. Patient characteristics associated with incident strokea

Unadjusted Hazard Ratio Adjusted Hazard Ratio Covariate (95% CI) (N ϭ 8920, 915 (95% CI) (N ϭ 6862, 684 P Value Strokes) Strokes)

Raceb among patients without CVDc white Referent Referent black 1.20 (0.96–1.50) 1.24 (0.96–1.60) 0.1 Asian 0.71 (0.29–1.74) 0.56 (0.21–1.53) 0.26 other 0.98 (0.60–1.61) 0.76 (0.42–1.39) 0.4 among patients with CVDc white Referent Referent black 0.70 (0.58–0.85) 0.74 (0.60–0.92) 0.007 Asian 0.77 (0.38–1.56) 0.54 (0.24–1.23) 0.15 other 0.66 (0.42–1.04) 0.76 (0.48–1.23) 0.3 Markers of malnutrition undernourished 1.62 (1.33–1.97) 1.27 (1.01–1.61) 0.04 serum albumin (per 1 g/dl decrease) 1.72 (1.58–2.00) 1.43 (1.17–1.74) Ͻ0.001 weight (25% relative decrease) 1.14 (1.07–1.21) 1.09 (1.00–1.18) 0.057 Mean BP (10 mmHg increase)d 1.00 (0.95–1.05) 1.11 (1.05–1.18) Ͻ0.001 Gender (female versus male) 1.33 (1.17–1.52) 0.96 (0.79–1.17) 0.7 Age (per decade) 1.42 (1.36–1.49) 1.34 (1.26–1.42) Ͻ0.001 Renal disease primary GN Referent Referent hypertension 1.41 (1.10–1.81) 1.14 (0.87–1.50) 0.3 diabetes 1.97 (1.55–2.50) 1.36 (1.04–1.78) 0.02 PKD 0.96 (0.67–1.39) 1.03 (0.76–1.40) 0.8 other 1.09 (0.83–1.44) 0.72 (0.47–1.08) 0.1 Renal replacement modality hemodialysis Referent Referent peritoneal dialysis 1.04 (0.82–1.31) 1.08 (0.79–1.47) 0.6 transplant 0.21 (0.13–0.33) 0.34 (0.20–0.57) Ͻ0.001

a The multivariate model is adjusted for all variables listed in the table and is further adjusted for age, height, dialysis vintage, and DMMS study (wave 2, 3, or 4). Patients with missing covariate values were excluded from the multivariate model. b There was significant interaction between race and prevalent cardiovascular disease (P ϭ 0.001). c Prevalent CVD is defined as a previous diagnosis of coronary artery disease, myocardial infarction, coronary artery bypass, angioplasty, cardiac arrest, or congestive heart failure. d Mean BP ϭ (systolic BP ϩ 2*diastolic BP)/3. BP measurements were taken predialysis (for hemodialysis patients) or randomly (for peritoneal dialysis patients).

Among our other predictors of interest, markers of malnu- incident stroke was similar among hemodialysis (when mea- trition all were strongly associated with a higher risk of stroke. sured before dialysis) and peritoneal dialysis patients (mea- Patients who were described by dialysis staff as being under- sured randomly) and among patients of different races, types of nourished were estimated to have a 27% higher risk of stroke renal disease, and duration of ESRD (P Ͼ 0.05 for all tests of (HR ϭ 1.27; 95% CI ϭ 1.01 to 1.61). A 1-g/dl decrement in interaction; data not shown). Among hemodialysis patients, serum albumin was associated with a 43% higher risk of stroke postdialysis MBP was not significantly associated with inci- (HR ϭ 1.43; 95% CI ϭ 1.17 to 1.74), and there was a trend dent stroke (per 10 mmHg increment, HR ϭ 1.03; 95% CI ϭ toward higher risk of stroke associated with low body weight, 0.95 to 1.12), and adjustment for this BP measurement did not after adjustment for height (per 25% relative decrease, HR ϭ meaningfully change the HR estimate for predialysis MBP. 1.08; 95% CI ϭ 1.00 to 1.18; P ϭ 0.057). Further adjustment for smoking status did not materially MBP was also predictive of incident stroke with an increase change the associations between any of the primary predictors of 10 mmHg in MBP associated with an 11% increased risk of and stroke, and smoking was not a significant independent stroke (HR ϭ 1.11; 95% CI ϭ 1.05 to 1.18). There was no predictor of stroke (data not shown). evidence of excess risk at very low BP (e.g.,MBPϽ75 In exploratory analyses, we assessed the association with mmHg), although there were relatively few patients in this stroke of other laboratory parameters that could possibly con- category (n ϭ 183, eight strokes). The association of MBP with tribute to the risk of stroke in the dialysis population. There J Am Soc Nephrol 14: 2623–2631, 2003 Stroke Risk Factors in ESRD 2627 was no relationship between baseline cholesterol (per 10 mg/dl 95% CI ϭ 1.21 to 3.98). Among individuals without CVD, increment, HR ϭ 1.00), serum calcium, phosphorous, or para- however, blacks had much lower rates of hemorrhagic stroke thyroid hormone and incident stroke (data not shown). Among (HR ϭ 0.52; 95% CI ϭ 0.24 to 1.10). hemodialysis patients, the change in MBP from predialysis to Higher MBP was associated with a higher stroke risk (per 10 postdialysis was not associated with incident stroke (P ϭ 0.7). mmHg increase, HR ϭ 1.32; 95% CI ϭ 1.15 to 1.53). Among Hemoglobin levels were modestly associated with stroke, after the markers of malnutrition, undernourishment showed a trend adjustment for other covariates. In comparison with patients toward an association with a higher stroke rate (HR ϭ 1.76; with hemoglobin levels of 10 to 12 g/dl, those with very low 95% CI ϭ 0.98 to 3.18); serum albumin and height-adjusted hemoglobin (Ͻ9 g/dl) were at a 22% higher risk for stroke (HR weight were not predictive of stroke. Patients with polycystic ϭ 1.22, 95% CI ϭ 1.00 to 1.49). kidney disease were at a 2.5-fold risk for hemorrhagic stroke compared with patients with primary glomerulonephritis (HR Hemorrhagic Strokes ϭ 2.55; 95% CI ϭ 0.94 to 6.86), although this association was A total of 131 incident hospitalized hemorrhagic strokes short of statistical significance (P ϭ 0.07). occurred during the follow-up period, with an estimated incidence density of 4.6 per 1000 person-years (95% CI ϭ 3.9 to Ischemic Stroke 5.5). Patient characteristics associated with risk of hemorrhagic There were 700 incident hospitalized ischemic strokes ob- stroke are shown in Table 3. The association between race and served over the course of follow-up, corresponding to an hemorrhagic stroke differed significantly among individuals incidence density of 25.2/1000 person-years (95% CI ϭ 23.4 to with and without prevalent CVD (P ϭ 0.002 for test of inter- 27.1). For ischemic stroke, the effects of the major predictors action). Compared with whites without CVD, blacks without of interest differed among patients with and without prevalent CVD had twice the rate of hemorrhagic stroke (HR ϭ 2.19; CVD (P Ͻ 0.05 for interaction terms), so separate multivariate

Table 3. Patient characteristics associated with incident hemorrhagic strokea

Adjusted Hazard Ratio (95% CI) P Value (N ϭ 6862, 101 Strokes)

Raceb among patients without CVD white Referent black 2.19 (1.21–3.99) 0.01 Asian 1.11 (0.15–8.45) 0.9 other 1.15 (0.33–4.02) 0.8 among patients with CVD white Referent black 0.52 (0.24–1.10) 0.09 Asian 0.96 (0.13–7.29) 0.97 other 2.59 (1.03–6.53) 0.04 Markers of malnutrition undernourished 1.76 (0.98–3.18) 0.06 serum albumin (per 1 g/dl decrease) 1.31 (0.79–2.18) 0.3 weight (25% relative increase) 1.19 (0.96–1.48) 0.1 Mean BP (10 mmHg increase)c 1.32 (1.15–1.53) Ͻ0.001 Gender (female versus male) 0.58 (0.35–0.96) 0.03 Renal disease primary GN Referent hypertension 1.83 (0.84–4.01) 0.13 diabetes 1.84 (0.84–4.09) 0.13 PKD 2.55 (0.94–6.86) 0.07 other 1.97 (0.84–4.61) 0.12

a Adjusted for DMMS study, age, dialysis vintage, smoking history, height, renal replacement modality (time-dependent - hemodialysis, peritoneal dialysis, or transplant), and prevalent CVD, in addition to the other covariates in this table. Patients with missing covariate values were excluded from the multivariate model. b There was significant interaction between race and prevalent CVD (P ϭ 0.002). c Mean BP ϭ (systolic BP ϩ 2*diastolic BP)/3. BP measurements were taken predialysis (for hemodialysis patients) or randomly (for peritoneal dialysis patients). 2628 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2623–2631, 2003 models were developed for these two subgroups (Table 4). Most studies of stroke in the general population have found Among patients with prevalent CVD, blacks were at 23% that blacks are at a 50 to 200% higher risk than whites lower risk of ischemic stroke when compared with whites (HR (14,15,19–24). This increased risk seems to be independent of ϭ 0.77; 95% CI ϭ 0.60 to 0.98), and there were no significant traditional stroke risk factors such as hypertension and diabetes associations between BP and stroke. Among the markers of (14,20,24). To our knowledge, no study has examined whether malnutrition, only a subjective assessment of undernourish- these racial differences in stroke rate differ by cardiac disease ment was associated with higher stroke risk (HR ϭ 1.40; 95% status. In the dialysis population, although racial differences in CI ϭ 1.02 to 1.92). Among patients without prevalent CVD, stroke incidence have not been assessed, previous studies re- blacks were at equal risk to whites, and higher MBP was ported a lower rate of all-cause mortality, cardiac-specific associated with an increased risk for ischemic stroke (HR per mortality (25), cerebrovascular mortality (26), and coronary 10 mmHg increment, HR ϭ 1.16; 95% CI ϭ 1.04 to 1.30). artery disease prevalence (27). Our finding of a significant and Low serum albumin levels in this subgroup were also associ- large interaction between race and prevalent cardiac disease on ated with a higher ischemic stroke risk (per 1-g/dl decrease, the risk of stroke raises the question of whether a similar HR ϭ 1.84; 95% CI ϭ 1.28 to 2.64), although height-adjusted interaction exists with regard to other important outcomes. body weight was not. The reason for this interaction is unclear. One possible explanation is a nondifferential misclassification of cardiac Discussion disease between blacks and whites. Information on comorbid In a cohort of incident and prevalent US dialysis patients, the illness in DMMS was obtained by dialysis facility personnel incidence of hospitalized and fatal stroke was 33/1000 person- from the patients themselves and from notation in the medical years. Markers of malnutrition (low height-adjusted body record available in the dialysis centers; there was no indepen- weight, hypoalbuminemia, and undernourishment) and ele- dent verification of comorbid status. If cardiac disease was less vated MBP were predictive of incident stroke, as was low accurately characterized among black patients (as a result of hemoglobin. Stroke risk among blacks relative to whites dif- less self-knowledge of their medical conditions or because of fered among those with and without clinical cardiac disease: lower rates of screening for cardiac disease) than among their risk was somewhat higher among individuals without whites, then resulting selective misclassification would create cardiac disease but was significantly lower among individuals the appearance of an interaction between black race and car- with cardiac disease. diac disease.

Table 4. Baseline patient characteristics associated with incident ischemic stroke, stratified by the presence of clinical CVDa

Prevalent CVDb No Prevalent CVDb (N ϭ 3716, 330 Strokes) (N ϭ 3146, 195 Strokes)

Adjusted Hazard Ratio (95% CI)

Race white Referent Referent black 0.77 (0.60–0.98) 1.08 (0.79–1.47) Asian 0.43 (0.16–1.17) 0.59 (0.18–1.89) other 0.60 (0.33–1.08) 0.84 (0.43–1.64) Markers of malnutrition undernourished 1.40 (1.02–1.92) 0.53 (0.28–1.00) serum albumin (1 g/dl decrease) 1.30 (0.97–1.73) 1.84 (1.28–2.64) weight (25% relative decrease) 1.07 (0.95–1.21) 1.04 (0.89–1.21) Mean BP (10 mmHg increase)c 1.03 (0.94–1.18) 1.16 (1.04–1.30) Renal disease primary GN Referent Referent hypertension 1.30 (0.92–2.13) 0.85 (0.54–1.35) diabetes 1.63 (1.08–2.46) 1.19 (0.75–1.89) PKD 1.24 (0.77–2.00) 0.67 (0.39–1.16) other 0.79 (0.42–1.50) 0.58 (0.28–1.18)

a Adjusted for DMMS study, age, gender, dialysis vintage, smoking history, height, and renal replacement modality (time-dependent - hemo-, peritoneal dialysis, or transplant), in an addition to the other covariates in this table. Patients with missing covariate values were excluded from the multivariate model. b Prevalent CVD is defined as any of the following conditions at study start: coronary artery disease, myocardial infarction, coronary artery bypass, angioplasty, cardiac arrest, or congestive heart failure. c Mean BP ϭ (systolic BP ϩ 2*diastolic BP)/3. BP measurements were taken predialysis (for hemodialysis patients) or randomly (for peritoneal dialysis patients). J Am Soc Nephrol 14: 2623–2631, 2003 Stroke Risk Factors in ESRD 2629

If the observed interaction between race and CVD is not due In the current study, several markers of malnutrition, includ- to bias, then one interpretation of this interaction is that blacks ing low serum albumin, low height-adjusted body weight, and are less “susceptible” to the adverse effects of CVD on risk of a subjective assessment of undernourishment, were associated stroke. Some authors have suggested that a selection process with a higher risk of incident stroke. This is in contrast to the occurs in which blacks who have early renal disease and general population, in which obesity, rather than malnutrition, survive long enough to reach ESRD represent a relatively confers a higher stroke risk (40). However, malnutrition has healthier subgroup, as a result of a competing risk between a been well recognized as a strong risk factor for total (41–44) premature death and ESRD among blacks (28). In this sce- and cardiovascular-specific (9) mortality in the dialysis popu- nario, blacks with cardiac disease and early renal insufficiency lation. Several authors have suggested that malnutrition in would be more likely to have a premature death before reach- ESRD patients reflects not merely poor nutrient intake but also ing ESRD than whites with similar cardiac disease, such that the effects of a chronic microinflammatory state (45,46). Ele- only blacks who are in some way more “resistant” to the effects vated inflammatory markers have been associated with higher of this cardiac disease would survive to ESRD. Although this rates of stroke in the general population (47–49). It is possible is a plausible hypothesis, there is currently neither supporting that the mechanism that leads to the association of inflamma- nor refuting evidence. tion and stroke in the general population exerts a similar effect Consistent with data from the general population (29–32), in the dialysis population and might explain the observed elevated BP was associated with an increased risk for stroke. association between malnutrition and stroke in the present We found no evidence of a U- or J-shaped effect of MBP. Our study. finding is also in agreement with those of Iseki et al. (10), who This study has a number of limitations. First, acute strokes reported a 120% increased stroke risk associated with hyper- were detected through hospital discharge diagnosis codes and tension in a Japanese dialysis cohort. The effect of BP on ESRD cause-of-death forms; it was not possible to validate stroke risk seems to differ from its effect on all-cause mortality, as suggested by several studies in which predialysis BP these events in the data sources used. It therefore is likely that (especially systolic BP) was inversely related to mortality risk, some patients in this study were misclassified with regard to with an excess risk at low BP (6–8). Among hemodialysis their stroke status. However, the combination of ICD-9-CM patients, we did not find an association between postdialysis codes used to identify stroke hospitalizations in our study has BP and stroke, in contrast to previous reports suggesting a been shown to have high sensitivity and specificity in identi- U-shaped association between postdialysis BP and mortality fying true hospitalized stroke in the general population (18). In (6,7). addition, one would expect such misclassification to be non- The finding of a positive relationship between BP and stroke differential with regard to baseline patient characteristics, should be interpreted with some caution. Our analysis did not which would result in an underestimation of the true relative distinguish those patients using antihypertensive medications, risk of stroke associated with specific risk factors. Our study and it is possible that the effect of BP is confounded by the use excluded patients for whom fee-for-service Medicare was not of these medications or differs among patients according to the primary insurer, and therefore the results cannot be gener- their use of antihypertensives. In addition, the observed effect alized to this generally healthier and younger subgroup of of BP could be biased by a competing risk between mortality dialysis patients. However, the overwhelming majority (81%) and stroke, in which patients with low BP are less likely to of patients in the DMMS studies had fee-for-service Medicare survive long enough to be at risk for stroke. as the primary insurer. In an exploratory analysis, profound anemia (hemoglobin Despite these limitations, this is the first study to examine Ͻ9.0 g/dl) was associated with a significant 22% increase risk risk factors for incident stroke among the US dialysis popula- of stroke, compared with a hemoglobin level of 10 to 12 g/dl. tion. Because the study cohort included a national sample of This is in strong contrast to findings from the general popula- dialysis patients, the results of this study are not limited to a tion, in which high, not low, hemoglobin was associated with single center or geographic region. These results confirm the an increased risk (33–36). However, these studies may have extraordinarily high rates of stroke in this population and had insufficient power to detect an association between very identify several modifiable risk factors, including malnutrition, low hemoglobin levels and stroke given the low prevalence of anemia, and hypertension, as potential targets for preventive severe anemia in the non-ESRD population. Our findings may therapies. represent a type I error, given that several secondary risk factors were tested for association with incident stroke. How- ever, an increased risk of stroke from profound anemia in Acknowledgments ESRD is biologically plausible and could be mediated either This study was supported by a Veterans Affairs Career Develop- through the direct effects of low oxygen-carrying capacity in ment Award and PHS grants (DK07721-6 and DK63079-01) from the regions of the brain already poorly perfused from vascular National Institutes of Health, Bethesda, MD. The data reported here disease or dialysis-related hypotension or through the detri- have been supplied by the USRDS. The interpretation and reporting of mental effects of chronic anemia on arterial and cardiac hy- these data are the responsibility of the authors and in no way should pertrophy (37), which are associated with increased stroke risk be seen as an official policy of or interpretation by the US in the non-ESRD population (38,39). government. 2630 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2623–2631, 2003

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