American Board of Internal Medicine Nephrology Procedure Requirements for Initial Certification: Time for a Change and Pursuing Consensus in the Nephrology Community.

In 1988, the American Board of Internal Medicine (ABIM) defined essential procedural skills in nephrology, and candidates for ABIM certification were required to present evidence of possessing the skills necessary for placement of temporary dialysis vascular access, hemodialysis, peritoneal dialysis, and percutaneous renal biopsy. In 1996, continuous renal replacement therapy was added to the list of nephrology requirements. These procedure requirements have not been modified since 1996 while the practice of nephrology has changed dramatically. In March 2021, the ABIM Nephrology Board embarked on a policy journey to revise the procedure requirements for nephrology certification. With the guidance of nephrology diplomates, training program directors, professional and patient organizations, and other stakeholders, the ABIM Nephrology Board revised the procedure requirements to reflect current practice and national priorities. The approved changes include the Opportunity to Train standard for placement of temporary dialysis catheters, percutaneous kidney biopsies, and home hemodialysis which better reflects the current state of training in most training programs, and the new requirements for home dialysis therapies training will align with the national priority to address the underuse of home dialysis therapies. This perspective details the ABIM process for considering changes to the certification procedure requirements and how ABIM collaborated with the larger nephrology community in considering revisions and additions to these requirements.

Racial and Ethnic Disparities in Kidney Replacement Therapies Among Adults With Kidney Failure: An Observational Study of Variation by Patient Age.

RATIONALE & OBJECTIVE: Non-Hispanic Black and Hispanic patients present with kidney failure at younger ages than White patients. Younger patients are also more likely to receive transplants and home dialysis than in-center hemodialysis (ICHD), but it is unknown whether racial and ethnic disparities in treatment differ by age. We compared use of kidney replacement therapies between racial and ethnic groups among patients with incident kidney failure overall and by age. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 830,402 US adult (age >21 years) patients initiating kidney failure treatment during the period of 2011-2018. EXPOSURES: Patient race and ethnicity (non-Hispanic Black, non-Hispanic White, Hispanic, or other) and age group (22-44, 45-64, 65-74, or 75-99 years). OUTCOME: Treatment modality (transplant, peritoneal dialysis [PD], home hemodialysis [HHD], or ICHD) as of day 90 of treatment. ANALYTICAL APPROACH: Differences in treatment modalities were quantified for patient subgroups defined by race and ethnicity and by age. Log-binomial regression models were fit to estimate adjusted risk ratios. RESULTS: 81% of patients were treated with ICHD, 3.0% underwent transplants (85% preemptive, 57% living-donor), 10.5% were treated with PD, and 0.7% were treated with HHD. Absolute disparities in treatment were most pronounced among patients aged 22-44 years. Compared with non-Hispanic White patients, whose percentages of treatment with transplant, PD, and HHD were 10.9%, 19.0%, and 1.2%, respectively, non-Hispanic Black patients were less commonly treated with each modality (unadjusted percentages, 1.8%, 13.8%, and 0.6%, respectively), as were Hispanic patients (4.4%, 16.9%, and 0.5%, respectively; all differences P < 0.001). After adjustment, the largest relative disparities were observed for transplant among the 22-44-year age group; compared with non-Hispanic White patients, the adjusted risk ratios for non-Hispanic Black and Hispanic patients were 0.21 (95% CI, 0.19-0.23) and 0.47 (95% CI, 0.43, 0.51), respectively. LIMITATIONS: Race and ethnicity data not self-reported. CONCLUSIONS: Among adults with incident kidney failure, racial and ethnic disparities in transplant and home dialysis use are most pronounced among the youngest adult patient age group.

Epidemiology of COVID-19 Infection in Hospitalized End-Stage Kidney Disease Patients in a Predominantly African-American Population.

BACKGROUND: End-stage kidney disease patients on dialysis are particularly susceptible to COVID-19 infection due to comorbidities, age, and logistic constraints of dialysis making social distancing difficult. We describe our experience with hospitalized dialysis patients with COVID-19 and factors associated with mortality. METHODS: From March 1, 2020, to May 31, 2020, all dialysis patients admitted to 4 Emory Hospitals and tested for COVID-19 were identified. Sociodemographic information and clinical and laboratory data were obtained from the medical record. Death was defined as an in-hospital death or transfer to hospice for end-of-life care. Patients were followed until discharge or death. RESULTS: Sixty-four dialysis patients with COVID-19 were identified. Eighty-four percent were African-American. The median age was 64 years, and 59% were males. Four patients were on peritoneal dialysis, and 60 were on hemodialysis for a median time of 3.8 years, while 31% were obese. Fever (72%), cough (61%), and diarrhea (22%) were the most common symptoms at presentation. Thirty-three percent required admission to intensive care unit, and 23% required mechanical ventilation. The median length of stay was 10 days, while 11 patients (17%) died during hospitalization and 17% were discharged to a temporary rehabilitation facility. Age >65 years (RR 13.7, CI: 1.9-100.7), C-reactive protein >100 mg/dL (RR 8.3, CI: 1.1-60.4), peak D-dimer >3,000 ng/mL (RR 4.3, CI: 1.03-18.2), bilirubin >1 mg/dL (RR 3.9, CI: 1.5-10.4), and history of peripheral vascular disease (RR 3.2, CI: 1.2-9.1) were associated with mortality. Dialysis COVID-19-infected patients were more likely to develop thromboembolic complications than those without COVID-19 (RR 3.7, CI: 1.3-10.1). CONCLUSION: In a predominantly African-American population, the mortality of end-stage kidney disease patients admitted with COVID-19 infection was 17%. Age, C-reactive protein, D-dimer, bilirubin, and history of peripheral vascular disease were associated with worse survival.

COVID-19 infection control measures and outcomes in urban dialysis centers in predominantly African American communities.

BACKGROUND: Emory Dialysis serves an urban and predominantly African American population at its four outpatient dialysis facilities. We describe COVID-19 infection control measures implemented and clinical characteristics of patients with COVID-19 in the Emory Dialysis facilities. METHODS: Implementation of COVID-19 infection procedures commenced in February 2020. Subsequently, COVID-19 preparedness assessments were conducted at each facility. Patients with COVID-19 from March 1-May 31, 2020 were included; with a follow-up period spanning March-June 30, 2020. Percentages of patients diagnosed with COVID-19 were calculated, and characteristics of COVID-19 patients were summarized as medians or percentage. Baseline characteristics of all patients receiving care at Emory Dialysis (i.e. Emory general dialysis population) were presented as medians and percentages. RESULTS: Of 751 dialysis patients, 23 (3.1%) were diagnosed with COVID-19. The median age was 67.0 years and 13 patients (56.6%) were female. Eleven patients (47.8%) were residents of nursing homes. Nineteen patients (82.6%) required hospitalization and 6 patients (26.1%) died; the average number of days from a positive SARS-CoV-2 (COVID) test to death was 16.8 days (range 1-34). Two patients dialyzing at adjacent dialysis stations and a dialysis staff who cared for them, were diagnosed with COVID-19 in a time frame that may suggest transmission in the dialysis facility. In response, universal masking in the facility was implemented (prior to national guidelines recommending universal masking), infection control audits and re-trainings of PPE were also done to bolster infection control practices. CONCLUSION: We successfully implemented recommended COVID-19 infection control measures aimed at mitigating the spread of SARS-CoV-2. Most of the patients with COVID-19 required hospitalizations. Dialysis facilities should remain vigilant and monitor for possible transmission of COVID-19 in the facility.

Long-term outcomes among Medicare patients readmitted in the first year of hemodialysis: a retrospective cohort study.

BACKGROUND: Readmission within 30 days of hospital discharge is common and costly among end-stage renal disease (ESRD) patients. Little is known about long-term outcomes after readmission. We estimated the association between hospital admissions and readmissions in the first year of dialysis and outcomes in the second year. METHODS: Data on incident dialysis patients with Medicare coverage were obtained from the United States Renal Data System (USRDS). Readmission patterns were summarized as no admissions in the first year of dialysis (Admit-), at least one admission but no readmissions within 30 days (Admit+/Readmit-), and admissions with at least one readmission within 30 days (Admit+/Readmit+).We used Cox proportional hazards models to estimate the association between readmission pattern and mortality, hospitalization, and kidney transplantation, accounting for demographic and clinical covariates. RESULTS: Among the 128,593 Medicare ESRD patients included in the study, 18.5% were Admit+/Readmit+, 30.5% were Admit+/Readmit-, and 51.0% were Admit-. Readmit+/Admit+ patients had substantially higher long-term risk of mortality (HR = 3.32 (95% CI, 3.21-3.44)), hospitalization (HR = 4.46 (95% CI, 4.36-4.56)), and lower likelihood of kidney transplantation (HR = 0.52 (95% CI, 0.44-0.62)) compared to Admit- patients; these associations were stronger than those among Admit+/Readmit- patients. CONCLUSIONS: Patients with readmissions in the first year of dialysis were at substantially higher risk of poor outcomes than either patients who had no admissions or patients who had hospital admissions but no readmissions. Identifying strategies to both prevent readmission and mitigate risk among patients who had a readmission may improve outcomes among this substantial, high-risk group of ESRD patients.

Delivery of a patient-friendly functioning report to improve patient-centeredness of dialysis care: a pilot study.

BACKGROUND: Provider recognition of level of functioning may be suboptimal in the dialysis setting, and this lack of recognition may lead to less patient-centered care. We aimed to assess whether delivery of an app-based, individualized functioning report would improve patients' perceptions of patient-centeredness of care. METHODS: In this pre-post pilot study at three outpatient dialysis facilities in metropolitan Atlanta, an individualized functioning report-including information on physical performance, perceived physical functioning, and community mobility-was delivered to patients receiving hemodialysis (n = 43) and their providers. Qualitative and quantitative approaches were used to gather patient and provider feedback to develop and assess the report and app. Paired t test was used to test for differences in patient perception of patient-centeredness of care (PPPC) scores (range, 1 = most patient-centered to 4 = least patient-centered) 1 month after report delivery. RESULTS: Delivery of the reports to both patients and providers was not associated with a subsequent change in patients' perceptions of patient-centeredness of their care (follow-up vs. baseline PPPC scores of 2.35 vs. 2.36; P > 0.9). However, patients and providers generally saw the potential of the report to improve the patient-centeredness of care and reacted positively to the individualized reports delivered in the pilot. Patients also reported willingness to undergo future assessments. However, while two-thirds of surveyed providers reported always or sometimes discussing the reports they received, most (98%) participating patients reported that no one on the dialysis care team had discussed the report with them within 1 month. CONCLUSIONS: Potential lack of fidelity to the intervention precludes definitive conclusions about effects of the report on patient-centeredness of care. The disconnect between patients' and providers' perceptions of discussions of the report warrants future study. However, this study introduces a novel, individualized, multi-domain functional report that is easily implemented in the setting of hemodialysis. Our pilot study provides guidance for improving its use both clinically and in future pragmatic research studies, both within and beyond the dialysis population.

Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial.

BACKGROUND: Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS: SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS: Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION: Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. FUNDING: Medtronic.

Burden and correlates of readmissions related to pulmonary edema in US hemodialysis patients: a cohort study.

Background: Pulmonary edema is prevalent and may be a common cause of hospital readmissions in hemodialysis patients. We aimed to estimate the national burden of, and identify correlates of, readmissions related to pulmonary edema among hemodialysis patients. Methods: In this retrospective cohort study using national registry data, we identified prevalent US hemodialysis patients (n = 215 251) with index admissions while under Medicare primary coverage in 2011-13. We defined readmissions as admissions occurring within 30 days of the index discharge and pulmonary edema-related readmissions as readmissions with discharge diagnoses of fluid overload, heart failure or pulmonary edema. Multivariable logistic regression models were used to determine odds ratios (ORs) for pulmonary edema-related readmissions by patient and index admission characteristics. Results: About one-quarter (23%) of index hospital admissions were followed by a readmission, with nearly half (44%) of the readmissions being associated with pulmonary edema. The strongest independent correlate of pulmonary edema-related readmission was a pulmonary edema-related index admission [OR = 2.32; 95% confidence interval (CI) 2.22-2.41]. With the exception of dialysis vintage <1 year (OR = 1.18; 95% CI 1.14-1.22), chronic obstructive pulmonary disease (OR = 1.34; 95% CI 1.29-1.38), dialysis non-compliance (OR = 1.53; 95% CI 1.41-1.64) and congestive heart failure (OR = 1.85; 95% CI 1.77-1.93), patient characteristics were not generally associated with higher risk of pulmonary edema-related readmission. Conclusions: Readmissions related to pulmonary edema are common in hemodialysis patients. Interventions aimed at preventing such readmissions could have a substantial impact on readmissions overall, particularly targeted at incident hemodialysis patients with a prior history of heart failure and patients initially admitted for pulmonary edema.

Association of social worker-assessed psychosocial factors with 30-day hospital readmissions among hemodialysis patients.

BACKGROUND: Evidence regarding the effect of psychosocial factors on hospital readmission in the setting of hemodialysis is limited. We examined whether social worker-assessed factors were associated with 30-day readmission among prevalent hemodialysis patients. METHODS: Data on 14 factors were extracted from the first available psychosocial assessment performed by social workers at three metropolitan Atlanta dialysis centers. Index admissions (first admission preceded by ≥30 days without a previous hospital discharge) were identified in the period 2/1/10-12/31/14, using linked national administrative hospitalization data. Readmission was defined as any admission within 30 days after index discharge. Associations of each of the psychosocial factors with readmission were assessed using multivariable logistic regression with adjustment for patient and index admission characteristics. RESULTS: Among 719 patients with index admissions, 22.1% were readmitted within 30 days. No psychosocial factors were statistically significantly associated with readmission risk. However, history of substance abuse vs. none was associated with a 29% higher risk of 30-day readmission [OR: 1.29, 95% CI: 0.75-2.23], whereas depression/anxiety was associated with 20% lower risk [OR: 0.80, 95% CI: 0.47-1.36]. Patients who were never married and those who were divorced, or widowed had 38 and 17% higher risk of 30-day readmission, respectively, than those who were married [OR: 1.38, 95% CI: 0.84-2.72; OR: 1.17, 95% CI: 0.73-1.90]. CONCLUSIONS: Results suggest that psychosocial issues may be associated with risk of 30-day readmission among dialysis patients. Despite the limitations of lack of generalizability and potential misclassification due to patient self-report of psychosocial factors to social workers, further study is warranted to determine whether addressing these factors through targeted interventions could potentially reduce readmissions among hemodialysis patients.

Post-hospitalization dialysis facility processes of care and hospital readmissions among hemodialysis patients: a retrospective cohort study.

BACKGROUND: Both dialysis facilities and hospitals are accountable for 30-day hospital readmissions among U.S. hemodialysis patients. We examined the association of post-hospitalization processes of care at hemodialysis facilities with pulmonary edema-related and other readmissions. METHODS: In a retrospective cohort comprised of electronic medical record (EMR) data linked with national registry data, we identified unique patient index admissions (n = 1056; 2/1/10-7/31/15) that were followed by ≥3 in-center hemodialysis sessions within 10 days, among patients treated at 19 Southeastern dialysis facilities. Indicators of processes of care were defined as present vs. absent in the dialysis facility EMR. Readmissions were defined as admissions within 30 days of the index discharge; pulmonary edema-related vs. other readmissions defined by discharge codes for pulmonary edema, fluid overload, and/or congestive heart failure. Multinomial logistic regression to estimate odds ratios (ORs) for pulmonary edema-related and other vs. no readmissions. RESULTS: Overall, 17.7% of patients were readmitted, and 8.0% had pulmonary edema-related readmissions (44.9% of all readmissions). Documentation of the index admission (OR = 2.03, 95% CI 1.07-3.85), congestive heart failure (OR = 1.87, 95% CI 1.07-3.27), and home medications stopped (OR = 1.81, 95% CI 1.08-3.05) or changed (OR = 1.69, 95% CI 1.06-2.70) in the EMR post-hospitalization were all associated with higher risk of pulmonary edema-related vs. no readmission; lower post-dialysis weight (by ≥0.5 kg) after vs. before hospitalization was associated with 40% lower risk (OR = 0.60, 95% CI 0.37-0.96). CONCLUSIONS: Our results suggest that some interventions performed at the dialysis facility in the post-hospitalization period may be associated with reduced readmission risk, while others may provide a potential existing means of identifying patients at higher risk for readmissions, to whom such interventions could be efficiently targeted.

Early hospital readmission among hemodialysis patients in the United States is associated with subsequent mortality.

Dialysis providers in the United States may soon be held accountable for their patients' 30-day hospital readmissions. However, few studies have evaluated the timing of readmissions, which determines the window in which dialysis providers could act to prevent readmission. We therefore examined the timing of readmissions of hemodialysis patients in the United States and its association with mortality among 285,795 prevalent adult Medicare-primary hemodialysis patients from a national registry. Patients had at least one hospitalization in 2010-2013 (first index) and survived for 30 days or more. Readmission timing was defined as 0-7, 8-14, or 15-30 days after the index discharge. Multivariable Cox proportional hazards models were used to estimate the association between readmission timing (referent no readmission) and mortality, censored at one year. Overall, 23.1% of patients had readmissions within 30 days of the index discharge, of which over one-third (35.9%) were within the first week. Regardless of timing, patients with readmissions had a higher risk of death within one year, compared to those with no readmissions, with hazard ratios of 2.04 (95% confidence interval 2.00-2.09) for being readmitted within 15-30 days; 1.98 (1.93-2.04) for being readmitted within 8-14 days; and 1.76 (1.71-1.80) for being readmitted within 0-7 days. Thus, opportunities for dialysis providers to intervene and prevent early readmission may be limited. Regardless of the timing, readmission appears independently associated with a substantially increased risk of mortality in this population.

Past Decline Versus Current eGFR and Subsequent Mortality Risk.

A single determination of eGFR associates with subsequent mortality risk. Prior decline in eGFR indicates loss of kidney function, but the relationship to mortality risk is uncertain. We conducted an individual-level meta-analysis of the risk of mortality associated with antecedent eGFR slope, adjusting for established risk factors, including last eGFR, among 1.2 million subjects from 12 CKD and 22 other cohorts within the CKD Prognosis Consortium. Over a 3-year antecedent period, 12% of participants in the CKD cohorts and 11% in the other cohorts had an eGFR slope <-5 ml/min per 1.73 m(2) per year, whereas 7% and 4% had a slope >5 ml/min per 1.73 m(2) per year, respectively. Compared with a slope of 0 ml/min per 1.73 m(2) per year, a slope of -6 ml/min per 1.73 m(2) per year associated with adjusted hazard ratios for all-cause mortality of 1.25 (95% confidence interval [95% CI], 1.09 to 1.44) among CKD cohorts and 1.15 (95% CI, 1.01 to 1.31) among other cohorts during a follow-up of 3.2 years. A slope of +6 ml/min per 1.73 m(2) per year also associated with higher all-cause mortality risk, with adjusted hazard ratios of 1.58 (95% CI, 1.29 to 1.95) among CKD cohorts and 1.43 (95% CI, 1.11 to 1.84) among other cohorts. Results were similar for cardiovascular and noncardiovascular causes of death and stronger for longer antecedent periods (3 versus <3 years). We conclude that prior decline or rise in eGFR associates with an increased risk of mortality, independent of current eGFR.

APOL1 renal-risk genotypes associate with longer hemodialysis survival in prevalent nondiabetic African American patients with end-stage renal disease.

Relative to European Americans, evidence supports that African Americans with end-stage renal disease (ESRD) survive longer on dialysis. Renal-risk variants in the apolipoprotein L1 gene (APOL1), associated with nondiabetic nephropathy and less subclinical atherosclerosis, may contribute to dialysis outcomes. Here, APOL1 renal-risk variants were assessed for association with dialytic survival in 450 diabetic and 275 nondiabetic African American hemodialysis patients from Wake Forest and Emory School of Medicine outpatient facilities. Outcomes were provided by the ESRD Network 6-Southeastern Kidney Council Standardized Information Management System. Dates of death, receipt of a kidney transplant, and loss to follow-up were recorded. Outcomes were censored at the date of transplantation or through 1 July 2015. Multivariable Cox proportional hazards models were computed separately in patients with nondiabetic and diabetic ESRD, adjusting for the covariates age, gender, comorbidities, ancestry, and presence of an arteriovenous fistula or graft at dialysis initiation. In nondiabetic ESRD, patients with 2 (vs. 0/1) APOL1 renal-risk variants had significantly longer dialysis survival (hazard ratio 0.57), a pattern not observed in patients with diabetes-associated ESRD (hazard ratio 1.29). Thus, 2 APOL1 renal-risk variants are associated with longer dialysis survival in African Americans without diabetes, potentially relating to presence of renal-limited disease or less atherosclerosis.

The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease.

Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 × 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10(-7) and 3.70 × 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants.

Lack of Association of the APOL1 G3 Haplotype in African Americans with ESRD.

Apolipoprotein L1 gene (APOL1) G1 and G2 variants are strongly associated with progressive nondiabetic nephropathy in populations with recent African ancestry. Selection for these variants occurred as a result of protection from human African trypanosomiasis (HAT). Resequencing of this region in 10 genetically and geographically distinct African populations residing in HAT endemic regions identified eight single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium and comprising a novel G3 haplotype. To determine whether the APOL1 G3 haplotype was associated with nephropathy, G1, G2, and G3 SNPs and 70 ancestry informative markers spanning the genome were genotyped in 937 African Americans with nondiabetic ESRD, 965 African Americans with type 2 diabetes-associated ESRD, and 1029 non-nephropathy controls. In analyses adjusting for age, sex, APOL1 G1/G2 risk (recessive), and global African ancestry, the G3 haplotype was not significantly associated with ESRD (P=0.05 for nondiabetic ESRD, P=0.57 for diabetes-associated ESRD, and P=0.27 for all-cause ESRD). We conclude that variation in APOL1 G3 makes a nominal, if any, contribution to ESRD in African Americans; G1 and G2 variants explain the vast majority of nondiabetic nephropathy susceptibility.

Association Analysis of the Reticulon 1 Gene in End-Stage Kidney Disease.

BACKGROUND: The reticulon 1 gene (RTN1) encodes reticulons, endoplasmic reticulum stress proteins recently implicated in kidney disease progression. METHODS: RTN1 single nucleotide polymorphisms (SNPs) were tested for association with type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) in African Americans (AAs) and European Americans (EAs), and AAs with non-diabetic ESKD. RTN1 SNPs that were associated with T2D-ESKD in AA cases compared to non-nephropathy controls were identified from a discovery genome-wide association study (n=1,797), then tested for replication in 1,847 additional AA T2D-ESKD cases and controls. RESULTS: Three intronic RTN1 variants were nominally associated with T2D-ESKD in both discovery and replication analyses: rs1952034, rs12431381 and rs12434215 (additive models); combined T2D-ESKD (discovery+replication) p values were 0.015-3.0×10(-4) (ORs 0.67-0.77; minor alleles protective). In addition, rs12434215 was weakly associated with T2D-ESKD in 557 EA T2D-ESKD cases contrasted with 753 EA non-nephropathy controls (p=0.019; OR 0.69, dominant model). Nominal association extended to non-diabetic causes of ESKD in 1,459 additional AA cases (rs12431381 and rs12434215 p values 0.014-0.015; OR 0.77). An all-cause ESKD association analysis contrasted the 3,594 AA ESKD cases with 1,489 AA non-nephropathy controls and detected association with rs12434215 (p=6.7×10(-4), OR 0.73) and rs12431381 (p=7.5×10(-4), OR 0.75) in dominant models. Of the 3 SNPs, only rs12434215 was weakly associated with T2D per se when contrasting T2D non-nephropathy cases with non-diabetic controls (additive model p=0.032 AAs; p=0.048 EAs). CONCLUSIONS: These results suggest evidence of genetic association between common variants in RTN1 and ESKD in AAs and EAs.

Complement factor H gene associations with end-stage kidney disease in African Americans.

BACKGROUND: Mutations in the complement factor H gene (CFH) region associate with renal-limited mesangial proliferative forms of glomerulonephritis including IgA nephropathy (IgAN), dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Lack of kidney biopsies could lead to under diagnosis of CFH-associated end-stage kidney disease (ESKD) in African Americans (AAs), with incorrect attribution to other causes. A prior genome-wide association study in AAs with non-diabetic ESKD implicated an intronic CFH single nucleotide polymorphism (SNP). METHODS: Thirteen CFH SNPs (8 exonic, 2 synonymous, 2 3'UTR, and the previously associated intronic variant rs379489) were tested for association with common forms of non-diabetic and type 2 diabetes-associated (T2D) ESKD in 3770 AAs (1705 with non-diabetic ESKD, 1305 with T2D-ESKD, 760 controls). Most cases lacked kidney biopsies; those with known IgAN, DDD or C3GN were excluded. RESULTS: Adjusting for age, gender, ancestry and apolipoprotein L1 gene risk variants, single SNP analyses detected 6 CFH SNPs (5 exonic and the intronic variant) as significantly associated with non-diabetic ESKD (P = 0.002-0.01), three of these SNPs were also associated with T2D-ESKD. Weighted CFH locus-wide Sequence Kernel Association Testing (SKAT) in non-diabetic ESKD (P = 0.00053) and T2D-ESKD (P = 0.047) confirmed significant evidence of association. CONCLUSIONS: CFH was associated with commonly reported etiologies of ESKD in the AA population. These results suggest that a subset of cases with ESKD clinically ascribed to the effects of hypertension or glomerulosclerosis actually have CFH-related forms of mesangial proliferative glomerulonephritis. Genetic testing may prove useful to identify the causes of renal-limited kidney disease in patients with ESKD who lack renal biopsies.

Kidney Transplantation Contraindications: Variation in Nephrologist Practice and Training Vintage.

Introduction: Health system leaders aim to increase access to kidney transplantation in part by encouraging nephrologists to refer more patients for transplant evaluation. Little is known about nephrologists' referral decisions and whether nephrologists with older training vintage weigh patient criteria differently (e.g., more restrictively). Methods: Using a novel, iteratively validated survey of US-based nephrologists, we examined how nephrologists assess adult patients' suitability for transplant, focusing on established, important criteria: 7 clinical (e.g., overweight) and 7 psychosocial (e.g., insurance). We quantified variation in nephrologist restrictiveness-proportion of criteria interpreted as absolute or partial contraindications versus minor or negligible concerns-and tested associations between restrictiveness and nephrologist age (proxy for training vintage) in logistic regression models, controlling for nephrologist-level and practice-level factors. Results: Of 144 nephrologists invited, 42 survey respondents (29% response rate) were 85% male and 54% non-Hispanic White, with mean age 52 years, and 67% spent ≥1 day/wk in outpatient dialysis facilities. Nephrologists interpreted patient criteria inconsistently; consistency was lower for psychosocial criteria (intraclass correlation coefficient: 0.28) than for clinical criteria (intraclass correlation coefficient: 0.43; P < 0.01). With each additional 10 years of age, nephrologists' odds of interpreting criteria restrictively (top tertile) doubled (adjusted odds ratio [aOR] 1.96; 95% confidence interval [CI]: 0.95-4.07), with marginal statistical significance. This relationship was significant when interpreting psychosocial criteria (aOR: 3.18; 95% CI: 1.16-8.71) but not when interpreting clinical criteria (aOR: 1.12; 95% CI: 0.52-2.38). Conclusion: Nephrologists interpret evaluation criteria variably when assessing patient suitability for transplant. Guideline-based educational interventions could influence nephrologists' referral decision-making differentially by age.

Intensive blood-pressure control in hypertensive chronic kidney disease.

BACKGROUND: In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients. METHODS: We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years. RESULTS: During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01). CONCLUSIONS: In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)

Proportion of Hemodialysis Treatments with High Ultrafiltration Rate and the Association with Mortality.

Background: Rapid fluid removal during hemodialysis has been associated with increased mortality. The limit of ultrafiltration rate (UFR) monitored by the Centers for Medicare & Medicaid Services is 13 ml/kg per hour. It is not clear if the proportion of treatments with high UFR is associated with higher mortality. We examined the association of proportion of dialysis treatments with high UFR and mortality in end stage kidney failure patients receiving hemodialysis. Methods: This was a retrospective study of incident patients initiating hemodialysis between January 1, 2010, and December 31, 2019, at Emory dialysis centers. The proportion of treatments with high UFR (>13 ml/kg per hour) per patient was calculated using data from the initial 3 months of dialysis therapy. Patients were categorized on the basis of quartiles of proportion of dialysis sessions with high UFR. Risk of death and survival probabilities were calculated and compared for all quartiles. Results: Of 1050 patients eligible, the median age was 59 years, 56% were men, and 91% were Black. The median UFR was 6.5 ml/kg per hour, and the proportion of sessions with high UFR was 5%. Thirty-one percent of patients never experienced high UFR. Being a man, younger age, shorter duration of hemodialysis sessions, lower weight, diabetic status, higher albumin, and history of heart failure were associated with a higher proportion of sessions with high UFR. Patients in the higher quartile (26% dialysis with high UFR, average UFR 9.8 ml/kg per hour, median survival of 5.6 years) had a higher risk of death (adjusted hazard ratio 1.54; 95% CI, 1.13 to 2.10) compared with those in the lower quartile (0% dialysis with high UFR, average UFR 4.7 ml/kg per hour, median survival 8.8 years). Conclusions: Patients on hemodialysis who did not experience frequent episodes of elevated UFR during the first 3 months of their dialysis tenure had a significantly lower risk of death compared with patients with frequent episodes of high UFR.