Faculty Bibliography

The HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis (HOPE Trial) is a multicenter randomized trial addressing chronic pain among patients receiving maintenance hemodialysis for end-stage kidney disease. The trial uses a sequential, multiple assignment design with a randomized component for all participants (Phase 1) and a non-randomized component for a subset of participants (Phase 2). During Phase 1, participants are randomized to Pain Coping Skills Training (PCST), an intervention designed to increase self-efficacy for managing pain, or Usual Care. PCST consists of weekly, live, coach-led cognitive behavioral therapy sessions delivered by video- or tele-conferencing for 12 weeks followed by daily interactive voice response sessions delivered by telephone for an additional 12 weeks. At 24 weeks (Phase 2), participants in both the PCST and Usual Care groups taking prescription opioid medications at an average dose of ≥20 morphine milligram equivalents per day are offered buprenorphine, a partial opioid agonist with a more favorable safety profile than full-agonist opioids. All participants are followed for 36 weeks. The primary outcome is pain interference ascertained at 12 weeks for the primary analysis. Secondary outcomes include additional patient-reported measures and clinical outcomes including falls, hospitalizations, and death. Exploratory outcomes include acceptability, tolerability, and efficacy of buprenorphine. The enrollment target of 640 participants was met 27 months after trial initiation. The findings of the trial will inform the management of chronic pain, a common and challenging issue for patients treated with maintenance hemodialysis. NCT04571619.

KEY POINTS:Women are under-represented in high-impact nephrology trials. Trends remain consistent over the past 20 years and on the basis of target condition. Addressing the imbalanced enrollment of women in trials could improve disparities in care and outcomes of kidney disease. BACKGROUND:Gender disparities in the incidence and complications of kidney diseases are well described. However, analysis to elucidate gender disparities in enrollment in nephrology randomized clinical trials (RCTs) has not been performed. METHODS:) kidney transplantation. We summarized trial characteristics according to reporting and enrollment of participants, enrollment site, publication year, trial category, and intervention type. Outcomes of interest include the proportion of enrolled male and female participants overall and according to trial category. In addition, we compared enrollment trends in the United States and globally to estimates of kidney disease prevalence. RESULTS:=133,082). Male participants formed most of trial cohorts in AKI (65%), CKD (62%), dialysis (55%), and transplant trials (65%), whereas women were majority enrollees in GN trials (61%). CKD trials under-represented women in both US trials and worldwide. CONCLUSIONS:Women are under-represented in high-impact nephrology trials with the exception of GN trials. This imbalance may contribute to disparities in outcomes and gaps in the care of women with kidney disease.

INTRODUCTION/UNASSIGNED:Chronic kidney disease (CKD) and left ventricular (LV) dysfunction are risk factors for cardiovascular events. We explore whether the association of LV ejection fraction (LVEF) with cardiac arrest, heart failure hospitalization, and all-cause mortality differs across stages of kidney impairment. METHODS/UNASSIGNED:and without end-stage kidney disease (ESKD). Cox regression models, incorporating an interaction term for eGFR and LVEF, were fit and adjusted for relevant covariates. RESULTS/UNASSIGNED:-interaction 0.26). CONCLUSION/UNASSIGNED:, the association of LVEF with cardiac arrest and heart failure hospitalization is attenuated at lower levels of kidney function. Further research is required to elucidate what factors beyond LVEF drive these observations.

RATIONALE & OBJECTIVE/UNASSIGNED:Conservative kidney management (CKM) is a viable treatment option for many patients with chronic kidney disease. However, CKM practices and resources in the United States are not well described. We undertook this study to gain a better understanding of factors influencing uptake of CKM by describing: (1) characteristics of patients who choose CKM, (2) provider practice patterns relevant to CKM, and (3) CKM resources available to providers. STUDY DESIGN/UNASSIGNED:Cross-sectional study. SETTING & PARTICIPANTS/UNASSIGNED:(n=1018) and available information on whether a decision had been made to pursue CKM at the time of kidney failure, patient (n=407) reports of discussions about forgoing dialysis, and provider (n=26) responses about CKM delivery and available resources in their health systems. ANALYTICAL APPROACH/UNASSIGNED:Descriptive statistics were used to report patient demographics, clinical information, provider demographics, and clinic characteristics. RESULTS/UNASSIGNED:Among data from 1018 patients, 68 (7%) were recorded as planning for CKM. These patients were older, had more comorbidities, and were more likely to require assistance with transfers. Of the 407 patient surveys, 18% reported a conversation about forgoing dialysis with their nephrologist. A majority of providers felt comfortable discussing CKM; however, no clinics had a dedicated clinic or protocol for CKM. LIMITATIONS/UNASSIGNED:Inconsistent survey terminology and unlinked patient and provider responses. CONCLUSIONS/UNASSIGNED:Few patients reported discussion of forgoing dialysis with their providers and even fewer anticipated a choice of CKM on reaching kidney failure. Most providers were comfortable discussing CKM, but practiced in clinics that lacked dedicated resources. Further research is needed to improve the implementation of a CKM pathway. PLAIN-LANGUAGE SUMMARY/UNASSIGNED:For older comorbid adults with kidney failure, conservative kidney management (CKM) can be an appropriate treatment choice. CKM is a holistic approach with treatment goals of maximizing quality of life and preventing progression of chronic kidney disease (CKD) without initiation of dialysis. We investigated US CKM practices and found that among 1018 people with CKD, only 7% were planning for CKM. Of 407 surveyed patients, 18% reported a conversation with their provider about forgoing dialysis. In contrast, most providers felt comfortable discussing CKM; however, none reported working in an environment with a dedicated CKM clinic or protocol. Our data show the need for further CKM education in the United States as well as dedicated resources for its delivery.

INTRODUCTION/UNASSIGNED:Excessive dialytic potassium (K) and acid removal are risk factors for arrhythmias; however, treatment-to-treatment dialysate modification is rarely performed. We conducted a multicenter, pilot randomized study to test the safety, feasibility, and efficacy of 4 point-of-care (POC) chemistry-guided protocols to adjust dialysate K and bicarbonate (HCO3) in outpatient hemodialysis (HD) clinics. METHODS/UNASSIGNED:Participants received implantable cardiac loop monitors and crossed over to four 4-week periods with adjustment of dialysate K or HCO3 at each treatment according to pre-HD POC values: (i) K-removal minimization, (ii) K-removal maximization, (iii) Acidosis avoidance, and (iv) Alkalosis avoidance. The primary end point was percentage of treatments adhering to the intervention algorithm. Secondary endpoints included pre-HD K and HCO variability, adverse events, and rates of clinically significant arrhythmias (CSAs). RESULTS/UNASSIGNED:Nineteen subjects were enrolled in the study. HD staff completed POC testing and correctly adjusted the dialysate in 604 of 708 (85%) of available HD treatments. There was 1 K ≤3, 29 HCO3 <20 and 2 HCO3 >32 mEq/l and no serious adverse events related to study interventions. Although there were no significant differences between POC results and conventional laboratory measures drawn concurrently, intertreatment K and HCO3 variability was high. There were 45 CSA events; most were transient atrial fibrillation (AF), with numerically fewer events during the alkalosis avoidance period (8) and K-removal maximization period (3) compared to other intervention periods (17). There were no significant differences in CSA duration among interventions. CONCLUSION/UNASSIGNED:Algorithm-guided K/HCO3 adjustment based on POC testing is feasible. The variability of intertreatment K and HCO3 suggests that a POC-laboratory-guided algorithm could markedly alter dialysate-serum chemistry gradients. Definitive end point-powered trials should be considered.

AIMS/OBJECTIVE:To assess whether the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin affects risk of non-genital skin and soft tissue infections (SSTIs). MATERIALS AND METHODS/METHODS:We performed a post hoc pooled individual participant analysis of the CANVAS Program and CREDENCE trials that randomized people with type 2 diabetes at high cardiovascular risk and/or with chronic kidney disease to either canagliflozin or placebo. Investigator-reported adverse events were assessed by two blinded authors following predetermined criteria for non-genital SSTIs. Risks of non-genital SSTIs, overall and within prespecified subgroups, and risk of non-genital fungal SSTIs, were analysed using Cox regression models. Factors associated with non-genital SSTIs were assessed using multivariable Cox regression models. RESULTS:Overall, 903 of 14 531 participants (6%) experienced non-genital SSTIs over a median follow-up of 26 months. No difference was observed in non-genital SSTI rates between canagliflozin and placebo (24.0 events/1000 person-years vs. 23.9 events/1000 person-years, respectively; hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85-1.11; P = 0.70), with consistent results across subgroups (all P interaction > 0.05). The risk of recurrent events and non-genital fungal infection also did not differ significantly between canagliflozin and placebo (HR 1.06, 95% CI 0.94-1.19 [P = 0.32] and HR 1.18, 95% CI 0.88-1.60 [P = 0.27], respectively). Baseline factors independently associated with non-genital SSTIs were younger age, male sex, higher body mass index, higher glycated haemoglobin, lower estimated glomerular filtration rate (eGFR), established peripheral vascular disease, and history of neuropathy. CONCLUSIONS:Canagliflozin did not affect risk of non-genital SSTIs or non-genital fungal SSTIs compared with placebo. These findings suggest that any SGLT2 inhibitor-mediated change in skin microenvironment is unlikely to have meaningful clinical consequences.

SIGNIFICANCE STATEMENT:Racial and ethnic disparities in clinical trial enrollment are well described. However, whether these disparities are present in nephrology randomized clinical trials has not been previously reported. We performed a systematic review and meta-analysis of 380 randomized clinical trials involving different aspects of kidney disease published between 2000 and 2021. Our results indicate that worldwide reporting of race and ethnicity is poor and that White individuals account for most of the randomized participants with decreased enrollment of Black participants in more recent trials. However, trials conducted in the United States have representation of Black and Hispanic participants consistent with the population prevalence of disease and under-representation of Asian participants. BACKGROUND:Under-representation of racial and ethnic minorities in clinical trials could worsen disparities, but reporting and enrollment practices in nephrology randomized clinical trials have not been described. METHODS:PubMed was searched to capture randomized clinical trials for five kidney disease-related conditions published between 2000 and 2021 in ten high-impact journals. We excluded trials with <50 participants and pilot trials. Outcomes of interest were the proportion of trials reporting race and ethnicity and the proportions of enrolled participants in each race and ethnicity category. RESULTS:Among 380 trials worldwide, race was reported in just over half and ethnicity in 12%. Most enrolled participants were White, and Black individuals accounted for ≤10% of participants except in dialysis trials where they accounted for 26% of participants. However, Black participants were enrolled at high proportions relative to disease and population prevalence in US CKD, dialysis, and transplant trials representing 19% of participants in AKI, 26% in CKD, 44% in GN, 40% in dialysis, and 26% in transplant trials. Enrollment of Asian participants was low worldwide except in GN trials with marked under-representation in US CKD, dialysis, and transplant trials. Hispanic individuals represented only 13% of participants in US dialysis trials compared with 29% of US dialysis population. CONCLUSION:More complete reporting of race and ethnicity in nephrology trials is needed. Black and Hispanic patients are well-represented in kidney disease trials in the United States. Asian patients are poorly represented in kidney trials both globally and in the United States.

RATIONALE & OBJECTIVE/OBJECTIVE:It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the CREDENCE study. STUDY DESIGN/METHODS:Secondary analysis of a randomized controlled trial. SETTING & PARTICIPANTS/METHODS:Participants in the CREDENCE trial. INTERVENTION/METHODS:Participants were randomly assigned to canagliflozin 100 mg daily or placebo. OUTCOMES/RESULTS:Primary composite outcome of kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease. Pre-specified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and ≥70 years) and sex in the intention-to-treat population using Cox regression models. RESULTS:=0.8). No differences in safety outcomes by age group or sex were observed. LIMITATIONS/CONCLUSIONS:This was a post hoc analysis with multiple comparisons. CONCLUSIONS:Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. Owing to higher background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.