Ethnic disparities in cardiovascular and renal responses to canagliflozin between Asian and White patients with type 2 diabetes mellitus: A post hoc analysis of the CANVAS Program.

AIM: To assess the potential heterogeneity in cardiovascular (CV), renal and safety outcomes of canagliflozin between Whites and Asians, as well as these outcomes in each subgroup. MATERIALS AND METHODS: The CANVAS Program enrolled 10 142 patients with type 2 diabetes, comprising 78.34% Whites and 12.66% Asians. CV, renal and safety outcomes were comprehensively analysed using Cox regression models, while intermediate markers were assessed using time-varying mixed-effects models. Racial heterogeneity was evaluated by adding a treatment-race interacion term. RESULTS: Canagliflozin showed no significant racial disparities in the majority of the CV, renal and safety outcomes. The heterogeneity (p = .04) was observed on all-cause mortality, with reduced risk in Whites (hazard ratio 0.84; 95% confidence interval 0.71-0.99) and a statistically non-significant increased risk in Asians (hazard ratio 1.64; 95% confidence interval 0.94-2.90). There was a significant racial difference in acute kidney injury (p = .04) and a marginally significant racial heterogeneity for the composite of hospitalization for heart failure and CV death (p = .06) and serious renal-related adverse events (p = .07). CONCLUSION: Canagliflozin reduced CV and renal risks similarly in Whites and Asians; however, there was a significant racial discrepancy in all-cause mortality. This distinction may be attributed to the fact that Asian patients exhibited diminished CV protection effects and more renal adverse events with canagliflozin, potentially resulting from the smaller reductions in weight and uric acid. These findings highlight the importance of investigating the impact of race on treatment response to sodium-glucose cotransporter-2 inhibitors and provide more precise treatment strategies.

The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization study.

BACKGROUND: Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry. METHODS: We used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (n = 13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n = 10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n = 57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). FINDINGS: We found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals ß = 1.1 (95% CI [0.411-1.788]; p = 0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR ß = 1.619 (95% CI [0.412-2.826]; p = 0.009). However, the IVW estimate showed that genetically predicted HDL-C ß = -0.164, (95% CI = [-1.329 to 1.00]; p = 0.782), and TG ß = -0.934 (CI = [-2.815 to 0.947]; p = 0.33) were not significantly causally associated with the risk of eGFR. In the multivariable analysis inverse-variance weighted (MVIVW) method, there was evidence for a causal association between LDL and eGFR ß = 1.228 (CI = [0.477-1.979]; p = 0.001). A significant causal effect of Triglycerides (TG) on eGFR in the MVIVW analysis ß = -1.3 ([-2.533 to -0.067]; p = 0.039) was observed as well. All the causal estimates reported reflect a unit change in the outcome per a 1 SD increase in the exposure. HDL showed no evidence of a significant causal association with eGFR in the MVIVW method (ß = -0.117 (95% CI [-1.252 to 0.018]; p = 0.840)). We found no evidence of a reverse causal impact of eGFR on serum lipids. All our sensitivity analyses indicated no strong evidence of pleiotropy or heterogeneity between our instrumental variables for both the forward and reverse MR analysis. INTERPRETATION: In this African ancestry population, genetically predicted higher LDL-C and TC are causally associated with higher eGFR levels, which may suggest that the relationship between LDL, TC and kidney function may be U-shaped. And as such, lowering LDL_C does not necessarily improve risk of kidney disease. This may also imply the reason why LDL_C is seen to be a poorer predictor of kidney function compared to HDL. In addition, this further supports that more work is warranted to confirm the potential association between lipid traits and risk of kidney disease in individuals of African Ancestry. FUNDING: Wellcome (220740/Z/20/Z).

Comparable Cardiorenal Benefits of SGLT2 Inhibitors and GLP-1RAs in Asian and White Populations: An Updated Meta-analysis of Results From Randomized Outcome Trials.

BACKGROUND: Whether the cardiorenal benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) are comparable between White and Asian populations remains unclear. PURPOSE: To compare the cardiorenal benefits of SGLT2 inhibitors and GLP-1RAs between White and Asian populations and to compare the cardiorenal benefits between the two agents in Asian patients. DATA SOURCES: Electronic databases were searched up to 28 March 2021. STUDY SELECTION: We included the cardiovascular (CV) and renal outcome trials of SGLT2 inhibitors and GLP-1RAs where investigators reported major adverse CV events (MACE), CV death/hospitalization for heart failure (HHF), or composite renal outcomes with stratification by race. DATA EXTRACTION: We extracted the hazard ratio of each outcome stratified by race (Asian vs. White populations). DATA SYNTHESIS: In 10 SGLT2 inhibitor trials, there was no significant difference between Asian and White populations for MACE (P = 0.55), CV death/HHF (P = 0.87), or composite renal outcomes (P = 0.97). In seven GLP-1RA trials, we observed a similar MACE benefit between Asian and White populations (P = 0.10). In our networkmeta-analysis we found a comparable benefit for MACE between SGLT2 inhibitors and GLP-1RAs in Asian patients. LIMITATIONS: The data were from stratified analyses. CONCLUSIONS: There appear to be comparable cardiorenal benefits of SGLT2 inhibitors and GLP-1RAs between Asian and White participants enrolled in CV and renal outcome trials; the two therapies seem to have similar CV benefits for Asian participants.

Transplant Clinician Opinions on Use of Race in the Estimation of Glomerular Filtration Rate.

BACKGROUND AND OBJECTIVES: Current race-based eGFR calculators assign a higher eGFR value to Black patients, which could affect the care of kidney transplant candidates and potential living donors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a survey of staff at adult kidney transplant centers in the United States (December 17, 2020 to February 28, 2021) to assess opinions on use of race-based eGFR equations for waitlisting and living donor candidate evaluation, availability of serum cystatin C testing and measured GFR, and related practices. RESULTS: Respondents represented 57% (124 of 218) of adult kidney transplant programs, and the responding centers conducted 70% of recent kidney transplant volume. Most (93%) programs use serum creatinine-based eGFR for listing candidates. However, only 6% of respondents felt that current race-based eGFR calculators are appropriate, with desire for change grounded in concerns for promotion of health care disparities by current equations and inaccuracies in reporting of race. Most respondents (70%) believed that elimination of race would allow more preemptive waitlisting for Black patients, but a majority (79%) also raised concerns that such an approach could incur harms. More than one third of the responding programs lacked or were unsure of availability of testing for cystatin C or measured GFR. At this time, 40% of represented centers did not plan to remove race from eGFR calculators, 46% were planning to remove, and 15% had already done so. There was substantial variability in eGFR reporting and listing of multiracial patients with some Black ancestry. There was no difference in GFR acceptance thresholds for Black versus non-Black living donors. CONCLUSIONS: This national survey highlights a broad consensus that extant approaches to GFR estimation are unsatisfactory, but it also identified a range of current opinions.

Reassessing the Inclusion of Race in Diagnosing Kidney Diseases: An Interim Report from the NKF-ASN Task Force.

For almost two decades, equations that use serum creatinine, age, sex, and race to eGFR have included "race" as Black or non-Black. Given considerable evidence of disparities in health and healthcare delivery in African American communities, some regard keeping a race term in GFR equations as a practice that differentially influences access to care and kidney transplantation. Others assert that race captures important non GFR determinants of serum creatinine and its removal from the calculation may perpetuate other disparities. The National Kidney Foundation (NKF) and American Society of Nephrology (ASN) established a task force in 2020 to reassess the inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and subsequent management of patients with, or at risk for, kidney diseases. This interim report details the process, initial assessment of evidence, and values defined regarding the use of race to estimate GFR. We organized activities in phases: (1) clarify the problem and examine evidence, (2) evaluate different approaches to address use of race in GFR estimation, and (3) make recommendations. In phase one, we constructed statements about the evidence and defined values regarding equity and disparities; race and racism; GFR measurement, estimation, and equation performance; laboratory standardization; and patient perspectives. We also identified several approaches to estimate GFR and a set of attributes to evaluate these approaches. Building on evidence and values, the attributes of alternative approaches to estimate GFR will be evaluated in the next phases and recommendations will be made.

Equity in national policies for Australians with kidney disease.

OBJECTIVE: To describe how the Australian Government Department of Health policies address equity in the management of chronic kidney disease (CKD). METHODS: We searched the websites of the Australian Government Department of Health, Kidney Health Australia, Australian Indigenous HealthInfoNet and the National Rural Health Alliance for policies using the search terms: kidney, renal and chronic. RESULTS: We included 24 policies that addressed groups of people that experience health inequities: 23 addressed Aboriginal and Torres Strait Islander peoples, 18 rural/remote communities, 12 low socioeconomic status groups, six culturally and linguistically diverse communities and four addressed gender disparities. The scope of the policies ranged from broad national frameworks to subsidised access to health services and medicines. Only two policies explicitly addressed equity for patients with CKD. CONCLUSION: CKD outcomes are highly variable across population groups yet Australian Government policies that address access to and the experience of care are limited in both number and their attention to equity issues. Implications for public health: In Australia, some groups of people with CKD have a substantially higher risk of mortality and morbidity than the general CKD population. We advocate for the development and implementation of policies to attain equity for people with CKD.

APOL1 Nephropathy: From Genetics to Clinical Applications.

Rates of many types of severe kidney disease are much higher in Black individuals than most other ethnic groups. Much of this disparity can now be attributed to genetic variants in the apoL1 (APOL1) gene found only in individuals with recent African ancestry. These variants greatly increase rates of hypertension-associated ESKD, FSGS, HIV-associated nephropathy, and other forms of nondiabetic kidney disease. We discuss the population genetics of APOL1 risk variants and the clinical spectrum of APOL1 nephropathy. We then consider clinical issues that arise for the practicing nephrologist caring for the patient who may have APOL1 kidney disease.

Association between goal-striving stress and rapid kidney function decline among African Americans: the Jackson Heart Study.

African Americans (AAs) are disproportionately affected by kidney disease and also report higher psychosocial stressors than other racial groups. Goal-striving stress (GSS) is an understudied psychosocial stressor related to attempting to accomplish one's life goals. Given the numerous social determinants that contribute to health inequities among AAs, stress from goal striving may also disproportionately affect the health of AAs and in particular kidney disease outcomes. The objective of this study was to explore the association between GSS and rapid kidney function decline (RKFD) in an AA cohort. Using examination 1 (2000-2004) and examination 3 (2009-2013) data from the Jackson Heart Study (n=2630), we examined associations of baseline levels of GSS with RKFD among AAs using multivariable Poisson regression models, adjusting for sociodemographics, health behaviors, chronic disease and discrimination. We also explored baseline cortisol as a mediator. The incidence of RKFD in this sample was 7.34% (mean years of follow-up: 8.06±0.84 years). The mean GSS score was 3.80 (±4.88) and total GSS score ranged from 0 to 36. Those who reported high (vs low) GSS were 1.60 times more likely to experience RKFD after full adjustment (incidence rate ratio (IRR) 1.60; 95% CI 1.11 to 2.14, p=0.01). After confirming cortisol as a mediator and adding it to the model, those who reported high (vs low) GSS had 1.58 times the rate of RKFD (IRR 1.58; 95% CI 1.09 to 2.30, p=0.0153). Stress related to not achieving goals was associated with a greater risk of RKFD in this sample of AAs.

COVID-19 and Kidney Disease Disparities in the United States.

Racial, ethnic, socioeconomic, age, and sex-related health disparities in kidney disease are prominent in the United States. The Coronavirus Disease 2019 (COVID-19) pandemic has disproportionately affected marginalized populations. Older adults, people experiencing unstable housing, racial and ethnic minorities, and immigrants are potentially at increased risk for infection and severe complications from COVID-19. The direct and societal effects of the pandemic may increase risk of incident kidney disease and lead to worse outcomes for those with kidney disease. The rapid transition to telemedicine potentially limits access to care for older adults, immigrants, and people experiencing unstable housing. The economic impact of the pandemic has had a disproportionate effect on women, minorities, and immigrants, which may limit their ability to manage kidney disease and lead to complications or kidney disease progression. We describe the impact of COVID-19 on marginalized populations and highlight how the pandemic may exacerbate existing disparities in kidney disease.

Trends in Poor Health Indicators Among Black and Hispanic Middle-aged and Older Adults in the United States, 1999-2018.

Importance: Adults who belong to racial/ethnic minority groups are more likely than White adults to receive a diagnosis of chronic disease in the United States. Objective: To evaluate which health indicators have improved or become worse among Black and Hispanic middle-aged and older adults since the Minority Health and Health Disparities Research and Education Act of 2000. Design, Setting, and Participants: In this repeated cross-sectional study, a total of 4 856 326 records were extracted from the Behavioral Risk Factor Surveillance System from January 1999 through December 2018 of persons who self-identified as Black (non-Hispanic), Hispanic (non-White), or White and who were 45 years or older. Exposure: The 1999 legislation to reduce racial/ethnic health disparities. Main Outcomes and Measures: Poor health indicators and disparities including major chronic diseases, physical inactivity, uninsured status, and overall poor health. Results: Among the 4 856 326 participants (2 958 041 [60.9%] women; mean [SD] age, 60.4 [11.8] years), Black adults showed an overall decrease indicating improvement in uninsured status (ß = -0.40%; P < .001) and physical inactivity (ß = -0.29%; P < .001), while they showed an overall increase indicating deterioration in hypertension (ß = 0.88%; P < .001), diabetes (ß = 0.52%; P < .001), asthma (ß = 0.25%; P < .001), and stroke (ß = 0.15%; P < .001) during the last 20 years. The Black-White gap (ie, the change in ß between groups) showed improvement (2 trend lines converging) in uninsured status (-0.20%; P < .001) and physical inactivity (-0.29%; P < .001), while the Black-White gap worsened (2 trend lines diverging) in diabetes (0.14%; P < .001), hypertension (0.15%; P < .001), coronary heart disease (0.07%; P < .001), stroke (0.07%; P < .001), and asthma (0.11%; P < .001). Hispanic adults showed improvement in physical inactivity (ß = -0.28%; P = .02) and perceived poor health (ß = -0.22%; P = .001), while they showed overall deterioration in hypertension (ß = 0.79%; P < .001) and diabetes (ß = 0.50%; P < .001). The Hispanic-White gap showed improvement in coronary heart disease (-0.15%; P < .001), stroke (-0.04%; P < .001), kidney disease (-0.06%; P < .001), asthma (-0.06%; P = .02), arthritis (-0.26%; P < .001), depression (-0.23%; P < .001), and physical inactivity (-0.10%; P = .001), while the Hispanic-White gap worsened in diabetes (0.15%; P < .001), hypertension (0.05%; P = .03), and uninsured status (0.09%; P < .001). Conclusions and Relevance: This study suggests that Black-White disparities increased in diabetes, hypertension, and asthma, while Hispanic-White disparities remained in diabetes, hypertension, and uninsured status.

Racial Disparities in the Arteriovenous Fistula Care Continuum in Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: Arteriovenous fistulas are the optimal vascular access type for patients on hemodialysis. However, arteriovenous fistulas are used less frequently in Black than in White individuals. The arteriovenous fistula care continuum comprises a series of sequential steps. A better understanding is needed of where disparities exist along the continuum in order to mitigate racial differences in arteriovenous fistula use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using Medicare claims data from the United States Renal Data System, longitudinal analyses of patients ≥67 years initiating hemodialysis with a central venous catheter between July 1, 2010 and June 30, 2012 were performed. Three patient cohorts were identified: patients initiating hemodialysis with a catheter (n=41,814), patients with arteriovenous fistula placement within 6 months of dialysis initiation (n=14,077), and patients whose arteriovenous fistulas were successfully used within 6 months of placement (n=7068). Three arteriovenous fistula processes of care outcomes were compared between Blacks and Whites: (1) arteriovenous fistula creation, (2) successful arteriovenous fistula use, and (3) primary arteriovenous fistula patency after successful use. RESULTS: An arteriovenous fistula was placed within 6 months of dialysis initiation in 37% of patients initiating dialysis with a catheter. Among the patients with arteriovenous fistula placement, the arteriovenous fistula was successfully used for dialysis within 6 months in 48% of patients. Among patients with successful arteriovenous fistula use, 21% maintained primary arteriovenous fistula patency at 3 years. After adjusting for competing risks, Black patients on hemodialysis were 10% less likely to undergo arteriovenous fistula placement (adjusted subdistribution hazard ratio, 0.90; 95% confidence interval, 0.87 to 0.94); 12% less likely to have successful arteriovenous fistula use after placement (adjusted subdistribution hazard ratio, 0.88; 95% confidence interval, 0.83 to 0.93); and 22% less likely to maintain primary arteriovenous fistula patency after successful use (subdistribution hazard ratio, 0.78; 95% confidence interval, 0.74 to 0.84). CONCLUSIONS: Lower arteriovenous fistula use among Blacks older than 67 years of age treated with hemodialysis was attributable to each step along the continuum of arteriovenous fistula processes of care.

Association of APOL1 Genotypes With Measures of Microvascular and Endothelial Function, and Blood Pressure in MESA.

Background APOL1 high-risk genotypes are associated with increased risk for hypertension-attributed kidney disease among Black adults in the United States. Biopsy studies show differences in kidney vasculature by APOL1 status; less is known about the variants' associations with systemic vascular and endothelial function. Whether APOL1 risk variants are associated with blood pressure (BP) is also uncertain. Methods and Results Using linear regression, we examined cross-sectional associations of APOL1 risk genotypes (high=2 risk alleles, low=0 or 1 risk allele) with subclinical measures of vascular function (small arterial elasticity, n=1586; large arterial elasticity, n=1586; ascending aortic distensibility, n=985) and endothelial function (flow-mediated dilation, n=777). Using linear mixed-effects models, we studied longitudinal associations of APOL1 risk genotypes with BP (n=1619), adjusting for age, sex, and African ancestry. Among 1619 (12% APOL1 high-risk) Black participants in MESA (Multi-Ethnic Study of Atherosclerosis), mean age was 62 years old, 58% had hypertension, and mean systolic BP was 131 mm Hg at baseline. At examination 1 (2000-2002), there was no significant difference in small arterial elasticity, large arterial elasticity, ascending aortic distensibility, or flow-mediated dilation in participants with APOL1 high- versus low-risk genotypes (P>0.05 for all). Over a mean follow-up of 7.8 years, relative annual changes in systolic and diastolic BP and pulse pressure did not differ significantly by APOL1 risk status (between-group differences of -0.20, -0.14, and -0.25, respectively; P>0.05 for all). Conclusions Among Black participants in MESA, APOL1 high-risk genotypes were not associated with subclinical vascular and endothelial function or BP trajectories. The relationship of APOL1 with kidney disease may be intrinsic to the kidney rather than through peripheral effects on systemic vasculature or BP.

COVID-19, Racism, and Racial Disparities in Kidney Disease: Galvanizing the Kidney Community Response.

PodcastThis article contains a podcast athttps://www.asn-online.org/media/podcast/JASN/2020_07_21_JASN2020060809.mp3.