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Epidemiology and Outcomes |




* Center for Clinical Epidemiology and Biostatistics and the Department of Biostatistics and Epidemiology, and
Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and
Arbor Research Collaborative for Health, Ann Arbor, Michigan
Address correspondence to: Dr. Bruce M. Robinson, Department of Medicine, University of Pennsylvania School of Medicine, 700 CRB, 415 Curie Boulevard, Philadelphia, PA 19104-6021. Phone: 215-573-1830; Fax: 215-898-0189; E-mail: brurobinson{at}msn.com
Received for publication October 18, 2005. Accepted for publication August 4, 2006.
| Abstract |
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| Introduction |
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The association with longer survival among racial and ethnic minority groups on HD exists even though they have generally higher prevalence than non-Hispanic white patients of social characteristics that do much to explain poorer health outcomes among racial and ethnic minority groups in numerous other health care settings (1723). Moreover, racial or ethnic minority group patients, particularly black patients, have longer survival on HD than non-Hispanic white patients despite higher prevalence of many intermediate dialysis outcomes that are linked to increased mortality (18,2427).
On the other hand, racial and ethnic minority group patients lack access to the most effective therapies to treat chronic kidney disease and to avoid the need for dialysis. Although genetics may be contributory, potentially correctable social disparitieswith respect to the prevention of mortality before ESRD, the prevention of ESRD, and the treatment of ESRD by kidney transplantationmay yield a racial and ethnic minority group HD population that is systematically healthier than the non-Hispanic white HD population (1,18,20,2637).
Despite the probable influence of social disparities on the selection of healthier racial and ethnic minority group patients for HD, the HD survival data nonetheless may be interpreted to indicate that individual racial and ethnic minority group patients somehow tolerate or are better suited to HD than are non-Hispanic white patients (9,18). We therefore sought to clarify understanding of the survival advantage for racial and ethnic minority group HD patients by determining to what extent it can be explained by measurable factors, including case-mix and treatment characteristics that are associated with mortality. We hypothesized that the unadjusted associations of Hispanic and racial minority group patients with improved survival would be substantially attenuated or lost after comprehensive covariate adjustment. We performed the analysis using data from the American arm of the first phase of the Dialysis Outcomes and Practice Patterns Study (DOPPS I), a large contemporary cohort of HD patients for whom detailed comorbidity, psychosocial, laboratory, and dialysis care data were available at study entry and for up to 5 yr of follow-up.
| Materials and Methods |
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Patient-level DOPPS data were abstracted from the medical record, supplemented by personal knowledge, by a study coordinator in each participating HD facility. Pertinent to this analysis were a detailed enrollment medical summary and interval medical summaries that were completed approximately every 4 mo until departure from DOPPS I. For time-varying variables, values recorded were the most recent available before each medical summary. Dates and details of hospitalizations, outpatient medical interventions, vascular access events, and departures were recorded. Patient information was collected without patient identifiers, and patient consent was obtained in compliance with local institutional review boards.
Study Data
Mortality and Censoring Events.
The outcome for the study was time to all-cause mortality. Censoring events are listed in Table 1.
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Patients also were asked to self-report a single racial and a single ethnic designation in a separate DOPPS patient questionnaire. Although self-reporting has been considered the most reliable method to collect race and ethnicity data (22), we did not use this classification in our analyses because of a higher proportion of missing values. The proportion of agreement of ethnicity in the medical questionnaire with self-reported ethnicity was 0.93 (
= 0.87), and among patients who did not self-identify as Hispanic, the proportion of agreement of race in the medical questionnaire with self-reported race was 0.94 (
= 0.80).
Other Variables.
Because our primary analytic goal was to estimate the associations of racial/ethnic categories with mortality after adjusting for variables that might explain the association, we identified numerous patient-level DOPPS variables that plausibly were associated with mortality. To replicate and then add to previous published analysis of the associations of race and/or ethnicity with mortality (115), we assigned each of these variables to one of seven covariate groups (Tables 2 and 3).
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In a third approach, values that were assigned to time-varying variables equaled the values that were recorded for the DOPPS enrollment medical summary or the first interval medical summary with complete variable characterization. In the survival models, this approach yields hazard ratios (HR) that reflect the predicted course over a more extended follow-up than our primary approach using time-updated values, but it may attenuate the influence of time-varying variables during any shorter time interval that they may affect mortality most directly (39).
Because DOPPS I enrolled both incident and prevalent ESRD patients with ESRD, both the time-updated and enrollment approaches to characterizing time-varying variables captured values of these variables from a combination of incident and prevalent ESRD patients. We chose not to limit the analyses to incident ESRD patients to take advantage of the DOPPS design to characterize more fully the relationships of the racial/ethnic categories to survival across a wide range of ESRD duration (ESRD vintage). The possibility that the associations with survival changed with increasing ESRD vintage was examined by testing for an interaction of racial/ethnic category with ESRD vintage; this possibility also was studied less directly using the alternative analytic approaches described above.
Patient Eligibility.
Multivariable model inclusion required complete covariate characterization, because missing data were not imputed. Patients were required to remain in DOPPS I for at least 3 mo, or 1 mo for the model that characterized medical events over the most recent 1 mo. No other exclusion criteria were applied.
Statistical Analyses
Our analyses of the probability of mortality as a function of racial/ethnic category used Cox proportional hazards models (39). The time at risk was from 3 mo after DOPPS enrollment (or 1 mo after DOPPS enrollment for the model that characterized medical events over 1 mo). Because some patients enrolled in the DOPPS at ESRD onset, the earliest time at risk was 3 mo after ESRD onset (or 1 mo after ESRD onset for the model that characterized medical events over 1 mo). The time at risk ended on the date of death or censoring. Because modeling survival in prevalent cohorts using biologically arbitrary time scales such as days since study entry can be subject to left-truncation bias, we used ESRD vintage as the time scale for all analyses (40,41). We stratified by center to account for the possibility of systematic, otherwise uncaptured differences among the DOPPS facilities.
Beginning with a model for the unadjusted association of racial/ethnic categories with mortality, we built a series of progressively more comprehensive multivariable models by sequentially adding each of the seven covariate groups to the model. At each step, we used backward elimination to exclude those newly added covariates for which the association with mortality had P > 0.10 (42,43). Unless otherwise stated, P < 0.05 was the criterion for statistical significance. All analyses used Stata version 8.2 (44).
| Results |
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Among the 6677 patients, the median time between ESRD onset and the start of the time at risk was 9.3 mo (range 3.0 mo to 30.0 yr). The median total time at risk was 15.3 mo (range 0.2 mo to 5.1 yr); the total person-time at risk was 10374 yr; 2444 deaths occurred; and the death rate was 0.24 per patient-year.
The unadjusted Kaplan-Meier survivor function for survival on HD by racial/ethnic category among these 6677 patients (Figure 1) demonstrates lower survival among non-Hispanic white patients than all five racial/ethnic minority categories (P < 0.001 by log rank test). In unadjusted proportional hazards analysis (Table 3), the HR (95% confidence interval [CI]) for mortality compared with non-Hispanic white patients was 0.72 (0.61 to 0.85) for Hispanic patients; among non-Hispanic patients, HR (95% CI) were 0.63 (0.57 to 0.71) for black patients, 0.68 (0.50 to 0.93) for Asian patients, 0.62 (0.35 to 1.11) for Native American patients, and 0.74 (0.52 to 1.07) for patients of other races (overall P < 0.001).
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Of 37 patient characteristics other than race/ethnicity that were plausibly associated with mortality, all but two had P
0.20 for the unadjusted association with mortality and were tested for inclusion in the multivariable model. Table 2 shows the distribution of these 35 characteristics at enrollment within racial/ethnic categories. Compared with patients of all five minority racial/ethnic categories, white patients had distributions that were associated with higher mortality for 14 characteristics but distributions that were associated with lower mortality for only two characteristics. These characteristics are identified in Table 2. Each of these characteristics had P < 0.001 for overall distribution by race/ethnicity.
Multivariable Analyses
Table 3 shows that the associations of racial/ethnic minority categories with lower mortality were attenuated or lost in progressively more comprehensive multivariable models. In the final multivariable model (model 8), the HR (95% CI) for mortality compared with non-Hispanic white patients was 0.86 (0.72 to 1.03) for Hispanic patients; among non-Hispanic patients, the HR (95% CI) were 0.97 (0.85 to 1.11) for black patients, 0.82 (0.56 to 1.20) for Asian patients, 0.95 (0.52 to 1.73) for Native American patients, and 0.95 (0.60 to 1.50) for patients of other races (overall P = 0.66). Twenty-five other variables (identified in Table 3) met inclusion criteria for the final multivariable model (P
0.10), and all but one of these (cause of ESRD, P = 0.02) had P
0.01 for the adjusted association with mortality. Model diagnostics revealed no evidence of substantial multiple collinearity. There were no statistically significant interactions between racial/ethnic category and variables that were indicative of overall health status among HD patients, including categorized levels of albumin (P = 0.16), creatinine (P = 0.48), ferritin (P = 0.99), and hemoglobin (P = 0.32), as well as erythropoietin dosing (P = 0.97).
As evidence that the adjusted associations of race/ethnicity with survival did not change with increasing ESRD vintage, there was no statistically significant interaction between racial/ethnic category and ESRD vintage (P = 0.21 and 0.58 for untransformed and log-transformed ESRD vintage, respectively) in the final multivariable model. Consistent with this finding, the adjusted associations of race/ethnicity with survival in a model that was restricted to patients with ESRD vintage <12 mo at DOPPS enrollment were similar to those in the primary analysis, although the precision of estimates for the least common racial/ethnic categories notably was limited by the small sample size and number of events.
Analyses that used the DOPPS enrollment values for time-varying covariates yielded similar adjusted associations between racial/ethnic category and mortality as the primary modeling approach using time-updated values. In a multivariable model that was analogous to the final multivariable model (model 8) in Table 3 but using DOPPS enrollment values, the HR (95% CI) for mortality compared with non-Hispanic white patients was 0.91 (0.76 to 1.08) for Hispanic patients; among non-Hispanic patients, the HR (95% CI) were 0.92 (0.81 to 1.04) for black patients, 0.81 (0.58 to 1.13) for Asian patients, 0.85 (0.49 to 1.48) for Native American patients, and 1.06 (0.73 to 1.55) for patients of other races (overall P = 0.52).
Analyses that added time from months 1 to 3 after DOPPS enrollment also yielded similar adjusted associations between racial/ethnic category and mortality. In a multivariable model that was analogous to the final multivariable model (model 8) in Table 3 but including 7025 patients, the HR (95% CI) for mortality compared with non-Hispanic white patients was 0.87 (0.73 to 1.04) for Hispanic patients; among non-Hispanic patients, the HR (95% CI) were 0.96 (0.85 to 1.09) for black patients, 0.82 (0.58 to 1.16) for Asian patients, 0.98 (0.57 to 1.69) for Native American patients, and 0.80 (0.51 to 1.25) for patients of other races (overall P = 0.58).
Explaining Survival Differences by Race/Ethnicity
We considered the possibility that the unadjusted survival advantage for racial/ethnic minority categories on HD might be due in part to violation of the independent censoring assumption. Table 1 shows that the proportion of patients who were censored because of transplantation, renal function recovery, or change in renal replacement therapy modality (all potentially informative censoring events) was low overall and was similar across racial/ethnic groups. To assess the limits of these censoring events on the unadjusted associations with mortality by race/ethnicity, we modeled the HR for mortality under the extreme assumption that all patients who were censored for these reasons survived until the studys end. Extending the total person-time at risk by 1981 years (19%), the unadjusted HR (95% CI) for survival compared with non-Hispanic white patients was 0.74 (0.62 to 0.89) for Hispanic patients; among non-Hispanic patients, the unadjusted HR (95% CI) were 0.68 (0.60 to 0.76) for black patients, 0.62 (0.44 to 0.87) for Asian patients, 0.61 (0.33 to 1.12) for Native American patients, and 0.80 (0.52 to 1.22) for patients of other races (overall P < 0.001). These HR were similar to the unadjusted HR in Table 3. Likewise, HR in adjusted analyses that incorporated the same assumption were similar to the adjusted HR in Table 3. Because we know of no data to suggest that non-Hispanic white patients who were censored because of transplantation, renal function recovery, or change in renal replacement therapy modality would be expected to survive longer if they remained on HD than racial or ethnic minority group patients who were censored for these reasons, we did not perform analyses that accounted for this possibility.
Next, we identified the influence of each variable in the multivariable model on the statistical associations of race/ethnicity with mortality. To do so, we used seemingly unrelated estimation (45,46) to estimate and formally test the effect of excluding each variable individually from the final multivariable model on the associations of each racial/ethnic category with mortality (data not shown). Consistent with the "unfavorable" unadjusted distributions among white patients for numerous patient characteristics in Table 2, the survival advantages for racial/ethnic minority categories compared with non-Hispanic white patients most notably were explained (attenuated) in the multivariable model by the combined effect of small but statistically significant contributions of many different variables.
Among these variables, younger age was a key explanatory variable for each racial/ethnic minority category, and nutritional indicators had sizable but variable influences among the racial/ethnic minority categories. For example, higher creatinine levels attenuated much of the survival advantage for non-Hispanic black and Asian patients; adjustment for albumin levels attenuated the survival advantage for Asian and Native American patients but accentuated the survival advantage for Hispanic patients; and adjustment for body weight accentuated the survival advantages compared with non-Hispanic white patients for all racial/ethnic minority categories except non-Hispanic black patients.
| Discussion |
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In contrast to our study, these disparate previous studies of HD recipients in the United States or Canada reported that adjustment for case-mix and laboratory variables yielded persistent survival advantages for racial/ethnic minority groups (116). The overall adjusted point estimates for survival relative to white or non-Hispanic white patients were 0.78 (9) and 0.92 (3) for nonwhite patients; 0.55 (5), 0.60 (8), 0.66 (12), 0.75 (11), 0.78 (4), 0.84 (2), 0.87 (15), and 0.90 (6) for African-American, black, or non-Hispanic black patients; 0.47 (6) and 0.67 (8) for Mexican-American patients; 0.76 (12) for Hispanic patients; 0.73 (11) for South Asian patients; 0.61 (11) for Southeast Asian patients; 0.75 (10) for Asian American patients; and 0.60 (16) for Asian and Pacific Islander patients. All were statistically significant except for the 0.90 (6) and 0.92 (3) estimates for black and nonwhite patients, respectively.
Using more comprehensive covariate adjustment, our results (Table 3) are notably different. The unadjusted survival advantage compared with non-Hispanic white patients was nearly lost for non-Hispanic black patients (0.97 [95% CI 0.85 to 1.11]) and was more substantially attenuated than previously reported for Hispanic (0.86 [95% CI 0.72 to 1.03]) and Asian patients (0.82 [95% CI 0.56 to 1.20]). We also report marked attenuation of the point estimate for the survival advantage for Native American patients, although the small sample size limits interpretation of this finding. Overall, these results provide several key insights into the longer survival of Hispanic and racial minority group patients receiving maintenance HD.
Most clearly, the results demonstrate that individual racial minority group or Hispanic patients should not be expected to survive much or any longer than otherwise "identical" non-Hispanic white patients (identical, at least, with respect to all case-mix and treatment characteristics for which we adjusted). As a result, there is no rationale for the patient-level treatment biases, conscious or otherwise, that may exist because of the widely known population-level survival advantages for Hispanic and racial minority group HD patients. Proposed biases include complacent treatment of racial and ethnic minority group patients on the basis of the contention that they somehow tolerate HD better and may be less apt to benefit from transplantation than non-Hispanic white patients (18), as well as less attentive treatment of non-Hispanic white HD patients because of the sense that their racial or ethnic classification dooms many of them to poor survival irrespective of care provided (3).
In addition to this predictive inference, our results yield insight into the causes of longer survival among racial and ethnic minority group HD patients. First, their survival advantage is not substantially explained by possible informative censoring events, including transplantation among patients who are already on HD. This finding results principally from relatively low rates of transplantation among HD patients and modest absolute rate differences by race/ethnicity (Table 1), despite the widely known racial and ethnic disparities in access to kidney transplantation (1,18,20,2737). Transplantation that is undertaken preemptively before dialysis initiation is unobservable with the DOPPS data.
Second, the descriptive analyses that we present (Figure 1 and related text) indicate that the survival advantage for racial/ethnic minority group HD patients exists at or very soon after ESRD onset, a finding that is consistent with USRDS data (1). Because the survival advantage that we observed for racial/ethnic minority categories on HD largely is lost by covariate adjustment, racial and ethnic minority group patients selected for HD at ESRD onset are healthier in measurable ways than non-Hispanic white patients. In turn, the health advantage among racial and ethnic minority groups at later ESRD vintages likely is because they are healthier at ESRD onset. An alternative adverse influence of HD on non-Hispanic white patients that is unrelated to health status at ESRD onset cannot be ruled out, but we know of no biologic rationale for this possibility.
Third, the survival advantages for racial/ethnic minority categories compared with non-Hispanic white patients were explained (attenuated) in the multivariable survival model by the combined influences of many different variables. Whereas the influences of younger age (across racial/ethnic minority categories) and higher creatinine levels (among black patients) on the associations with lower mortality are widely known (1,3), the influences across racial/ethnic categories of other case-mix variables, such as pulmonary and psychiatric comorbidity (data not shown), are novel. The variable direction of the effect of nutritional indicatorsincluding creatinine level, albumin level, and weighton the associations of various racial/ethnic categories with mortality merits further investigation.
We caution that the identification of these variables that explain the statistical associations of race/ethnic category with survival may be a biased means to understand the reasons for differences in survival by race and ethnicity (47,48). Unbalanced distributions of variables (e.g., age, creatinine level) by racial/ethnic categories may have social or biologic (genetic) causes or both. For most clinical outcomes, social attributes explain racial and ethnic differences more completely than biologic attributes (2123). In this context, we believe that a combination of social causes that yield a healthier minority racial/ethnic population at ESRD onset more plausibly explains the survival advantages for disparate racial and ethnic minority groups on HD than a combination of biologic causes before and possibly after ESRD onset. However, these analyses cannot distinguish directly the relative contribution of biologic and social causes to the survival differences on HD by race and ethnicity.
| Conclusion |
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| Acknowledgments |
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This study was presented in abstract form at the annual meeting of the American Society of Nephrology; November 8 through 13, 2005; Philadelphia, PA.
| Footnotes |
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| References |
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