Racial/Ethnic Influences on CV and Renal Events in Diabetes
Racial/Ethnic Influences on CV and Renal Events in Diabetes
Severe renal disease requiring renal replacement therapy disproportionately impacts black and Hispanic patients. The explanations for these disparities have included biological differences, access to care, comorbid illnesses, SES, lifestyle habits, and competing risks due to better overall survival among minority CKD patients who happen to be younger. Although these factors leading to disparity are quite important to mitigate among predialysis patients, clinicians should search for novel strategies to prevent disease progression. In a contemporary-treated population with diabetes, CKD, and anemia, we have demonstrated a 53% higher risk of ESRD among black patients despite similar follow-up visits, reasonably controlled hypertension, and well-managed diabetes. This difference persisted after adjusting for demographic differences, clinical conditions, medications, and established surrogate measures of quality of care such as blood pressure control and HbA1C. As an internal control, black and Hispanic patients had similar to lower risks of CV morbidity and death than whites further suggesting that this population was adequately treated.
We also examined eGFR at the time of ESRD, the occurrence of interim CV events and death, and markers of compliance, and none of these factors appeared to explain this excess risk of ESRD among blacks. Among Hispanic patients, the unadjusted risk of ESRD was higher than white patients, but this difference did not remain significant after adjusting for many of these similar factors. As in other studies, the development of ESRD increased the risk of subsequent death almost 4-fold regardless of race.
The use of the trial-based population in TREAT attempts to support the hypothesis that risk for ESRD among blacks extends beyond access to care, blood pressure control, diabetes management, and competing risks of mortality and morbidity, as have been reported widely. Despite the inherent limitations of this population, this ESRD difference would be magnified in the community where these disparities are greater. Several other observations are consistent with our findings. The US Renal Data System has captured virtually every patient who receives treatment for ESRD since 2002 and was linked to the Southern Community Cohort Study, which followed up approximately 80,000 black and white patients enrolled in clinics serving lower SES patients. Black patients had a 3.5-fold increased risk of ESRD compared with whites despite similar SES, and similar predictors of ESRD were confirmed. The African-American Study of Kidney Disease and Hypertension enrolled only black patients and excluded those with diabetes and demonstrated varied progression to ESRD over a 9-year period. The intensity of blood pressure control did not attenuate this progression, although use of ACE inhibitors was required as inclusion criteria for study enrollment. The overall proportion of patients (17%) progressing to ESRD in TREAT was higher than in other clinical trial and population cohorts, likely a reflection of the combination of diabetes and anemia with a mean eGFR at baseline of 34 mL/min per 1.73 m. Our study demonstrates a similar slope of decrements in eGFR in blacks and whites, which is contrary to the findings of an unselected population in Kaiser Permanente. Moreover, the patients who did not develop ESRD had relatively stable renal function during follow-up in all groups, suggesting a cohort of patients who may remain stable for a period of time. A recent study confirmed that even a modest rate of decline in eGFR is a strong predictor of ESRD. Although modest differences in systolic blood pressure existed during follow-up among races, this did not adequately explain the propensity of blacks to develop ESRD. Interestingly, the urinary protein-creatinine ratio increased more in black patients than in other groups, and this event was independently associated with ESRD development. Although proteinuria may be a reflection of vascular-based injuries and confers increased risk for CV and renal events, black patients in TREAT had more proteinuria despite less interim CV events; nevertheless, proteinuria may be an additional marker to identify at-risk black patients earlier in CKD trajectory.
The similar (or better) CV outcomes of blacks in TREAT diminishes the possibility of competing risks as an explanation for the disparity in ESRD, as previously suggested. Most patients did not experience a CV event before ESRD, and these events did not explain the excess risk among blacks or whites with a competing risk analysis. Subsequent mortality post-ESRD was lower in blacks and Hispanics compared to whites, which may be a reflection of predialysis access to care and contributes to recent reports on variable postdialysis risks between blacks and whites. Moreover, the inclusion of younger patients in TREAT supplements findings of studies in the older Medicare population.
Given the persistent risk of ESRD among black patients despite adjusting for many of the factors used to explain these differences in prior publications, continued efforts are required to attenuate this risk. Alternative explanations include genetic factors such as G1 and G2 variants of APOL1, transforming growth factor β, nonmuscle myosin heavy chain type II isoform A, and rheumatologic disorders such as lupus that may lead to inflammation. Apolipoprotein L1 recently identified black patients at risk for more rapid decline in eGFR but is not as predictive of eGFR declines in diabetic kidney disease, a factor that may not be as important given the misclassification of cause of CKD in up to 25% of patients with diabetes. However, even among patients with 2 APOL1 gene risk variants, there may be a role for addressing modifiable risk factors as a strategy to attenuate progression to ESRD. Societal and patient-level factors such as health literacy, stress, maladaptive coping mechanisms, lifestyle habits (including but not limited to nutritional and physical activity pattern), and patient mistrust in the system are proposed as additional factors contributing to the racial differences in ESRD; however, these factors are difficult to measure in large cohorts.
There are several limitations of our study that merit discussion. The patients all had advanced CKD, diabetes, and anemia, which impacts generalizability to a less ill population. Criteria for initiation of renal replacement therapy were not standardized. The follow-up period is relatively short, and there may be alternative factors that influence ESRD risk during long-term follow-up or before enrollment. The lack of consent for DNA extraction makes it difficult to assess genetic factors that may influence risk. Socioeconomic, behavioral, and physiological factors were not assessed in the studied population. Despite similar access to care via protocol-specific visit schedules, residual differences existed with regard to blood pressure and diabetes management and control as well as proteinuria, all of which were adjusted for in the multivariable models; however, other disparities in access to care may persist and cannot be measured. The proportion of the population who was Hispanic was smaller than the other 2 groups and patients who enter clinical trials may not be representative of the general population. Self-reporting of black race might be inaccurate in Latin American countries, although >90% of blacks were in North America; moreover, patients could only check 1 box for race/ethnicity. Finally, factors that influence differential mortality after ESRD is better analyzed in other cohorts due to limited power.
In conclusion, self-reported black patients with diabetes, anemia, and CKD are much more likely to develop ESRD as compared to self-reported white patients, even after adjusting for confounding factors. The excess risk of ESRD in the setting of lower to similar risk of CV morbidity among blacks and reasonably controlled blood pressure and diabetes is concerning. Developing novel strategies for early management of these patients predialysis and for prognostication will be crucial next steps as we attempt to reduce disparities.
Discussion
Severe renal disease requiring renal replacement therapy disproportionately impacts black and Hispanic patients. The explanations for these disparities have included biological differences, access to care, comorbid illnesses, SES, lifestyle habits, and competing risks due to better overall survival among minority CKD patients who happen to be younger. Although these factors leading to disparity are quite important to mitigate among predialysis patients, clinicians should search for novel strategies to prevent disease progression. In a contemporary-treated population with diabetes, CKD, and anemia, we have demonstrated a 53% higher risk of ESRD among black patients despite similar follow-up visits, reasonably controlled hypertension, and well-managed diabetes. This difference persisted after adjusting for demographic differences, clinical conditions, medications, and established surrogate measures of quality of care such as blood pressure control and HbA1C. As an internal control, black and Hispanic patients had similar to lower risks of CV morbidity and death than whites further suggesting that this population was adequately treated.
We also examined eGFR at the time of ESRD, the occurrence of interim CV events and death, and markers of compliance, and none of these factors appeared to explain this excess risk of ESRD among blacks. Among Hispanic patients, the unadjusted risk of ESRD was higher than white patients, but this difference did not remain significant after adjusting for many of these similar factors. As in other studies, the development of ESRD increased the risk of subsequent death almost 4-fold regardless of race.
The use of the trial-based population in TREAT attempts to support the hypothesis that risk for ESRD among blacks extends beyond access to care, blood pressure control, diabetes management, and competing risks of mortality and morbidity, as have been reported widely. Despite the inherent limitations of this population, this ESRD difference would be magnified in the community where these disparities are greater. Several other observations are consistent with our findings. The US Renal Data System has captured virtually every patient who receives treatment for ESRD since 2002 and was linked to the Southern Community Cohort Study, which followed up approximately 80,000 black and white patients enrolled in clinics serving lower SES patients. Black patients had a 3.5-fold increased risk of ESRD compared with whites despite similar SES, and similar predictors of ESRD were confirmed. The African-American Study of Kidney Disease and Hypertension enrolled only black patients and excluded those with diabetes and demonstrated varied progression to ESRD over a 9-year period. The intensity of blood pressure control did not attenuate this progression, although use of ACE inhibitors was required as inclusion criteria for study enrollment. The overall proportion of patients (17%) progressing to ESRD in TREAT was higher than in other clinical trial and population cohorts, likely a reflection of the combination of diabetes and anemia with a mean eGFR at baseline of 34 mL/min per 1.73 m. Our study demonstrates a similar slope of decrements in eGFR in blacks and whites, which is contrary to the findings of an unselected population in Kaiser Permanente. Moreover, the patients who did not develop ESRD had relatively stable renal function during follow-up in all groups, suggesting a cohort of patients who may remain stable for a period of time. A recent study confirmed that even a modest rate of decline in eGFR is a strong predictor of ESRD. Although modest differences in systolic blood pressure existed during follow-up among races, this did not adequately explain the propensity of blacks to develop ESRD. Interestingly, the urinary protein-creatinine ratio increased more in black patients than in other groups, and this event was independently associated with ESRD development. Although proteinuria may be a reflection of vascular-based injuries and confers increased risk for CV and renal events, black patients in TREAT had more proteinuria despite less interim CV events; nevertheless, proteinuria may be an additional marker to identify at-risk black patients earlier in CKD trajectory.
The similar (or better) CV outcomes of blacks in TREAT diminishes the possibility of competing risks as an explanation for the disparity in ESRD, as previously suggested. Most patients did not experience a CV event before ESRD, and these events did not explain the excess risk among blacks or whites with a competing risk analysis. Subsequent mortality post-ESRD was lower in blacks and Hispanics compared to whites, which may be a reflection of predialysis access to care and contributes to recent reports on variable postdialysis risks between blacks and whites. Moreover, the inclusion of younger patients in TREAT supplements findings of studies in the older Medicare population.
Given the persistent risk of ESRD among black patients despite adjusting for many of the factors used to explain these differences in prior publications, continued efforts are required to attenuate this risk. Alternative explanations include genetic factors such as G1 and G2 variants of APOL1, transforming growth factor β, nonmuscle myosin heavy chain type II isoform A, and rheumatologic disorders such as lupus that may lead to inflammation. Apolipoprotein L1 recently identified black patients at risk for more rapid decline in eGFR but is not as predictive of eGFR declines in diabetic kidney disease, a factor that may not be as important given the misclassification of cause of CKD in up to 25% of patients with diabetes. However, even among patients with 2 APOL1 gene risk variants, there may be a role for addressing modifiable risk factors as a strategy to attenuate progression to ESRD. Societal and patient-level factors such as health literacy, stress, maladaptive coping mechanisms, lifestyle habits (including but not limited to nutritional and physical activity pattern), and patient mistrust in the system are proposed as additional factors contributing to the racial differences in ESRD; however, these factors are difficult to measure in large cohorts.
There are several limitations of our study that merit discussion. The patients all had advanced CKD, diabetes, and anemia, which impacts generalizability to a less ill population. Criteria for initiation of renal replacement therapy were not standardized. The follow-up period is relatively short, and there may be alternative factors that influence ESRD risk during long-term follow-up or before enrollment. The lack of consent for DNA extraction makes it difficult to assess genetic factors that may influence risk. Socioeconomic, behavioral, and physiological factors were not assessed in the studied population. Despite similar access to care via protocol-specific visit schedules, residual differences existed with regard to blood pressure and diabetes management and control as well as proteinuria, all of which were adjusted for in the multivariable models; however, other disparities in access to care may persist and cannot be measured. The proportion of the population who was Hispanic was smaller than the other 2 groups and patients who enter clinical trials may not be representative of the general population. Self-reporting of black race might be inaccurate in Latin American countries, although >90% of blacks were in North America; moreover, patients could only check 1 box for race/ethnicity. Finally, factors that influence differential mortality after ESRD is better analyzed in other cohorts due to limited power.
In conclusion, self-reported black patients with diabetes, anemia, and CKD are much more likely to develop ESRD as compared to self-reported white patients, even after adjusting for confounding factors. The excess risk of ESRD in the setting of lower to similar risk of CV morbidity among blacks and reasonably controlled blood pressure and diabetes is concerning. Developing novel strategies for early management of these patients predialysis and for prognostication will be crucial next steps as we attempt to reduce disparities.
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