The Use of Telemedicine by US Nephrologists for In-Center Hemodialysis Care During the Pandemic: An Analysis of National Medicare Claims.

Rationale & Objective: Because of coronavirus disease 2019 (COVID-19), the US government issued emergency waivers in March 2020 that removed regulatory barriers around the use of telemedicine. For the first time, nephrologists were reimbursed for telemedicine care delivered during in-center hemodialysis. We examined the use of telemedicine for in-center hemodialysis during the first 16 months of the pandemic. Study Design: We ascertained telemedicine modifiers on nephrologist claims. We used multivariable regression to examine time trends and patient, dialysis facility, and geographic correlates of telemedicine use. We also examined whether the estimated effects of predictors of telemedicine use changed over time. Setting & Participants: US Medicare beneficiaries receiving in-center hemodialysis between March 1, 2020, and June 30, 2021. Exposures: Patient, geographic, and dialysis facility characteristics. Outcomes: The use of telehealth for in-center hemodialysis care. Analytic Approach: Retrospective cohort analysis. Results: Among 267,434 Medicare beneficiaries identified, the reported use of telemedicine peaked at 9% of patient-months in April 2020 and declined to 2% of patient-months by June 2021. Telemedicine use varied geographically and was more common in areas that were remote and socioeconomically disadvantaged. Patients were more likely to receive care by telemedicine in areas with higher incidence of COVID-19, although the predictive value of COVID-19 diminished later in the pandemic. Patients were more likely to receive care using telemedicine if they were at facilities with more staff, and the use of telemedicine varied by facility ownership type. Limitations: Limited reporting of telemedicine on claims could lead to underestimation of its use. Reported telemedicine use was higher in an analysis designed to address this limitation by focusing on patients whose physicians used telemedicine at least once during the pandemic. Conclusions: Some US nephrologists continued to use telemedicine for in-center hemodialysis throughout the pandemic, even as the association between COVID-19 incidence and telemedicine use diminished over time. These findings highlight unique challenges and opportunities to the future use of telemedicine in dialysis care.

Emergency waivers issued during the coronavirus disease 2019 pandemic enabled reimbursement to US nephrologists for telemedicine care delivered during in-center hemodialysis. Using modifiers from Medicare claims, we examined telemedicine use in the first 16 months of the pandemic. Reported telemedicine use peaked early in the pandemic and declined subsequently. Telemedicine use was more common in areas that were remote and socioeconomically disadvantaged and at facilities with more staff. Telemedicine use also varied by facility ownership type. Some nephrologists continued to use telemedicine for in-center hemodialysis throughout the pandemic, even as the association between coronavirus disease 2019 incidence and telemedicine use diminished over time. These findings highlight unique challenges and opportunities to the future use of telemedicine in dialysis care.

Prescription and Dispensation of QT-Prolonging Medications in Individuals Receiving Hemodialysis.

Importance: Individuals with dialysis-dependent kidney failure have numerous risk factors for medication-related adverse events, including receipt of care by multiple clinicians and initiation of some QT-prolonging medications with known risk of torsades de pointes (TdP), which is associated with higher risk of sudden cardiac death. Little is known about the prescription and dispensation patterns of QT-prolonging medications among people receiving dialysis, hindering efforts to reduce drug-related harm from these and other medications in this high-risk population. Objective: To examine prescription and dispensation patterns of QT-prolonging medications with known TdP risk and selected interacting medications prescribed to individuals receiving hemodialysis. Design, Setting, and Participants: This cross-sectional study included patients 60 years or older who were enrolled in Medicare Parts A, B, and D receiving in-center hemodialysis from January 1 to December 31, 2019. Analyses were conducted from October 20, 2022, to June 16, 2023. Exposures: New-user prescriptions for the 7 most frequently filled QT-prolonging medications characterized by the timing of the new prescription relative to acute care encounters, the type of prescribing clinician and pharmacy that dispensed the medication, and concomitant use of selected medications known to interact with the 7 most frequently filled QT-prolonging medications with known TdP risk. Main Outcomes and Measures: The main outcomes were the frequencies of the most commonly filled and new-use episodes of QT-prolonging medications; the timing of medication fills relative to acute care events; prescribers and dispensing pharmacy characteristics for new use of medications; and the frequency and types of new-use episodes with concurrent use of potentially interacting medications. Results: Of 20 761 individuals receiving hemodialysis in 2019 (mean [SD] age, 74 [7] years; 51.1% male), 10 992 (52.9%) filled a study drug prescription. Approximately 80% (from 78.6% for odansetron to 93.9% for escitalopram) of study drug new-use prescriptions occurred outside of an acute care event. Between 36.8% and 61.0% of individual prescriptions originated from general medicine clinicians. Between 16.4% and 26.2% of these prescriptions occurred with the use of another QT-prolonging medication. Most potentially interacting drugs were prescribed by different clinicians (46.3%-65.5%). Conclusions and Relevance: In this cross-sectional study, QT-prolonging medications for individuals with dialysis-dependent kidney failure were commonly prescribed by nonnephrology clinicians and from nonacute settings. Prescriptions for potentially interacting medications often originated from different prescribers. Strategies aimed at minimizing high-risk medication-prescribing practices in the population undergoing dialysis are needed.

A Phase II randomized controlled trial evaluated antithrombotic treatment with fesomersen in patients with kidney failure on hemodialysis.

Patients with kidney failure on hemodialysis (KF-HD) are at high risk for both atherothrombotic events and bleeding. This Phase IIb study evaluated the dose-response of fesomersen, an inhibitor of hepatic Factor XI expression, versus placebo, for bleeding and atherothrombosis in patients with KF-HD. Patients were randomized to receive fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months. The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding (MB/CRNMB). Exploratory endpoints included post-dialysis arterio-venous (AV)-access bleeding, major atherothrombotic events (composite of fatal or non-fatal myocardial infarction, ischemic stroke, acute limb ischemia/major amputation, systemic embolism, symptomatic venous thromboembolism), AV-access thrombosis, and clotting of the hemodialysis circuit. Of 308 participants randomized, 307 received study treatment and were analyzed. Fesomersen led to a dose-dependent and sustained reduction of steady-state median FXI levels by 53.6% (40 mg group), 71.3% (80 mg group), 86.0% (120 mg group), versus 1.9% in the placebo group. MB/CRNMB events occurred in 6.5% (40 mg group), 5.1% (80 mg group), 3.9% (120 mg group), and in 4.0% of those receiving placebo (pooled fesomersen versus placebo P = 0.78). Major atherothrombotic events occurred in 1 patient (1.3%) in each treatment arm. MB/CRNMB bleeding and post-dialysis AV-access bleeding were not related to predicted FXI levels. Lower predicted FXI levels were associated with reductions in hemodialysis circuit clotting (P = 0.002) and AV-access thrombosis (P = 0.014). In patients with KF-HD, fesomersen produced a dose-dependent reduction in FXI levels associated with similar rates of major bleeding compared with placebo. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04534114.

Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial.

Individuals with kidney failure undergoing hemodialysis are at elevated risk for thromboembolic events. Factor (F) XI, which is in the intrinsic pathway of coagulation, is emerging as an attractive target for new anticoagulants that may be safer than existing agents. Osocimab-an inhibitory FXIa antibody-is a potential treatment option for such patients. We conducted a phase 2b, double-blind, placebo-controlled trial, in which 704 participants (448 male, 256 female) with kidney failure undergoing hemodialysis were randomized to receive lower- or higher-dose osocimab or placebo. In total, 686 participants (436 male, 250 female) received treatment for ≤18 months (planned minimal treatment period of 6 months). The co-primary outcomes were clinically relevant bleeding (a composite of major and clinically relevant nonmajor bleeding) and a composite of the incidence of moderate, severe or serious adverse events. Clinically relevant bleeding occurred in 16/232 (6.9%) and 11/224 (4.9%) participants who received lower- and higher-dose osocimab, respectively, and in 18/230 participants (7.8%) who received a placebo. For the composite adverse event endpoint, incidences were 51%, 47% and 43% in the lower-dose osocimab, higher-dose osocimab and placebo groups, respectively. These results suggest that osocimab is associated with a low risk of bleeding and is generally well tolerated in this population; findings that require confirmation in larger trials. ClinicalTrials.gov identifier, NCT04523220 .

Intradialytic Hypotension and Mortality in Adolescents and Young Adults With Kidney Failure Receiving Maintenance Hemodialysis.

Rationale & Objective: Intradialytic hypotension (IDH) is associated with mortality in adults with kidney failure requiring hemodialysis (HD); however, large-scale pediatric studies are lacking. Moreover, there is no evidence-based consensus definition of IDH in pediatric literature. We aimed to examine the association of commonly used definitions of IDH with mortality in adolescents and young adults. Study Design: This was a retrospective observational cohort study. Setting & Participants: In total, 1,199 adolescents and young adults (N = 320, aged 10-18 years and N = 879, aged 19-21 years) who initiated HD in a large dialysis organization were included. Exposures: This study used different definitions of IDH. Outcome: The study outcome was 2-year all-cause mortality. Analytical Approach: Several definitions of IDH were selected a priori based on a literature review. Patients were classified as having IDH if it was present in at least 30% of HD treatments during the first 90 days after dialysis initiation. Cox proportional hazards regression was used to test whether IDH associated with 2-year all-cause mortality. Results: Over a 2-year follow-up period, 54 (4.5%) patients died. Dependent on its definition, IDH was present in 2.9%-61.1% of patients. After the multivariable adjustment for sociodemographic and clinical characteristics, we found no association of IDH with mortality. Results were consistent across subgroups stratified by age (aged <18 and 19-21 years) and predialysis systolic blood pressure (<120, 120-150, and >150 mm Hg). We also examined IDH as occurring in <5%, 5%-29%, 30%-50%, and >50% of baseline treatments, and did not find a dose-response association with mortality (P > 0.05). Limitations: Owing to low event rates, our current sample size may have been too small to detect a difference in mortality. Conclusions: Our study found that IDH was not associated with mortality in adolescents and young adults.

Intradialytic hypotension (IDH), or hypotension experienced during dialysis, is common among children and young adults with kidney failure requiring hemodialysis. We examined the association of commonly used definitions of IDH with death in adolescents and young adults with kidney failure receiving hemodialysis. Intradialytic hypotension was present in 2.9%-61.1% of patients, depending on the definition, and over a 2-year follow-up period, 4.5% of the patients died. We found no association of IDH with mortality.

Dialysis Modality, Transplant Characteristics, and Incident Atrial Fibrillation After Kidney Transplant: An Observational Study Using USRDS Data.

Rationale & Objective: Atrial fibrillation is the most common arrhythmia and is increasing in prevalence. The prevalence of atrial fibrillation is high among patients receiving dialysis, affecting ∼21.3% of the patients receiving hemodialysis and 15.5% of those receiving peritoneal dialysis. The association of previous dialysis modality with incident atrial fibrillation in patients after receiving their first kidney transplant has not been studied. Study Design: We used the United States Renal Data System to retrospectively identify adult, Medicare-insured patients who received their first kidney transplant between January 1, 2005, and September 30, 2012 and who had not previously been diagnosed with atrial fibrillation. Setting & Participants: The study included 43,621 patients who were aged 18 years older when receiving a first kidney transplant between January 1, 2005, and September 30, 2012 and whose primary payer was Medicare (parts A and B) at the time of transplantation and the 6 months preceding it. Exposure: Dialysis modality used before transplant. Outcome: Time to incidence of atrial fibrillation up to 3 years posttransplant. Analytical Approach: Multivariable Cox regression was used to estimate HRs. Results: Of 43,621 patients, 84.9% received hemodialysis and 15.1% received peritoneal dialysis before transplant. The mean ± SD age was 51 ± 13.6 years; 60.8% were male, 55.6% White, and 35.8% Black race. The mean dialysis vintage was 4.3 ± 2.8 years. Newly diagnosed atrial fibrillation after kidney transplant occurred in 286 patients (during 15,363 person-years) who had received peritoneal dialysis and in 2,315 patients (during 83,536 person-years) who had received hemodialysis. After multivariable adjustment, atrial fibrillation was 20% (95% CI, 4%-38%) more likely in those who had been receiving hemodialysis versus peritoneal dialysis, regardless of whether death was considered a competing risk or a censoring event. Each year of pretransplant dialysis vintage increased the risk of posttransplant atrial fibrillation by 6% (95% CI, 3%-9%). Limitations: Residual confounding; data from billing claims does not specify the duration of atrial fibrillation or whether it is valvular. Conclusions: Pretransplant hemodialysis, as compared with peritoneal dialysis, was associated with higher risk of newly diagnosed atrial fibrillation after a first kidney transplant. Plain-Language Summary: New-onset atrial fibrillation (AF) occurs in 7% of kidney transplant recipients in the first 3 years posttransplantation. We conducted this study to determine whether pretransplant dialysis modality was associated with posttransplant AF. We identified 43,621 patients; 84.9% used hemodialysis and 15.1% used peritoneal dialysis pretransplant. Multivariable Cox regression was used to estimate hazard ratios. We found that patients receiving hemodialysis pretransplant were at 20% increased risk of developing posttransplant AF as compared with patients receiving peritoneal dialysis. As our understanding of transplant-specific risk factors for AF increases, we may be able to better risk-stratify transplant patients and develop monitoring and management strategies that can improve outcomes.

Market Competition and Anemia Management in the United States Following Dialysis Payment Reform.

BACKGROUND: Whether market competition influences health care provider responses to national reimbursement reforms is unknown. OBJECTIVES: We examined whether changes in anemia management after the expansion of Medicare's dialysis payment bundle varied with market competition. RESEARCH DESIGN: With data from the US dialysis registry, we used a difference-in-differences (DID) design to estimate the independent associations of market competition with changes in anemia management after dialysis reimbursement reform. SUBJECTS: A total of 326,150 patients underwent in-center hemodialysis in 2009 and 2012, representing periods before and after reimbursement reform. MEASURES: Outcomes were erythropoiesis-stimulating agent (ESA) and intravenous iron dosage, the probability of hemoglobin <9 g/dL, hospitalizations, and mortality. We also examined serum ferritin concentration, an indicator of body iron stores. We used a dichotomous market competition index, with less competitive areas defined as effectively having <2 competing dialysis providers. RESULTS: Compared with areas with more competition, patients in less competitive areas had slightly more pronounced declines in ESA dose (60% vs. 57%) following reimbursement reform (DID estimate: -3%; 95% CI, -5% to -1%) and less pronounced declines in intravenous iron dose (-14% vs. -19%; DID estimate: 5%; 95% CI, 1%-9%). The likelihoods of hemoglobin <9 g/dL, hospitalization, and mortality did not vary with market competition. Serum ferritin concentrations in 2012 were 4% (95% CI, 3%-6%) higher in less competitive areas. CONCLUSIONS: After the expansion of Medicare's dialysis payment bundle, ESA use declined by more, and intravenous iron use declined by less in concentrated markets. More aggressive cost-reduction strategies may be implemented in less competitive markets.

Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non-Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Treated Patients.

Rationale & Objective: In the PRO2TECT trials, vadadustat was found to be noninferior to darbepoetin alfa in hematologic efficacy but not for major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction or stroke) in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). We investigated the regional differences in MACE in the PRO2TECT trials. Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial. Setting & Participants: A total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD. Intervention: 1:1 randomization to receive vadadustat or darbepoetin alfa. Outcomes: The primary safety end point was the time to first MACE. Results: At baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (<90 U/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of ≥10 g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region, P = 0.07). In Europe, ESA rescue was associated with a higher risk of MACE in both groups. Limitations: Several analyses are exploratory. Conclusions: In this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group. Funding: Akebia Therapeutics, Inc. Trial Registration: ClinicalTrials.gov identifier: NCT02680574.

Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non-Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Naïve Patients.

Rationale & Objective: Prespecified analyses of the PRO2TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO2TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents. Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial. Setting and Participants: Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD. Intervention: Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa. Outcomes: The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis). Results: In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m2 in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m2 and who may not have had access to dialysis. Limitations: Different regional treatment patterns of patients with NDD-CKD. Conclusions: The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.

Hemodialysis Versus Peritoneal Dialysis Drug Expenditures: A Comparison Within the Private Insurance Market.

Rationale and Objective: Recent initiatives aim to improve patient satisfaction and autonomy by increasing the use of peritoneal dialysis (PD) in the United States. However, limited knowledge is available about the costs of different dialysis modalities, particularly those incurred by private insurers. In this study, we compared the costs of injectable dialysis drugs (and their oral equivalents) paid by insurers between privately insured patients receiving hemodialysis and PD. Study Design: A retrospective cohort study. Setting and Participants: From a private insurance claims database, we identified patients who started receiving PD or in-center hemodialysis between January 1, 2017, and December 31, 2020. Exposure: Patients started receiving PD. Outcomes: Average annual injectable drug and aggregate expenditures and expenditure subcategories. Analytical Approach: Patients who started receiving PD were propensity matched to similar patients who started receiving hemodialysis based on the year of dialysis initiation, patient demographics, health, geography, and comorbidities. Cost ratios (CRs) were estimated from generalized linear models. Results: We matched 284 privately insured patients who started receiving PD 1:1 with patients started receiving in-center hemodialysis. The average annual injectable drug expenditures for hemodialysis were 2-fold higher (CR: 1.99; 95% CI, 1.62-2.44) than that for PD. Compared those receiving PD, patients receiving hemodialysis incurred significantly lower nondrug dialysis-related expenditures (0.85; 95% CI, 0.76-0.94). The average annual expenditures for non-dialysis-dependent outpatient services were significantly higher among patients who underwent in-center hemodialysis (CR: 1.44; 95% CI, 1.10-1.90). Although aggregate and inpatient hospitalization expenditures were higher for in-center hemodialysis, these differences did not reach statistical significance. Limitations: Small sample sizes may have restricted our ability to identify differences in some cost categories. Conclusions: Compared with privately insured patients who started receiving PD, patients starting in-center hemodialysis incurred higher expenditures for injectable dialysis drugs, whereas differences in other expenditure categories varied. Recent increases in the use of PD may lead to reductions in injectable dialysis drug costs among privately insured patients. Plain Language Summary: Recent initiatives aim to improve patient satisfaction and autonomy by increasing the use of peritoneal dialysis (PD) in the United States. However, limited knowledge is available about the costs of different dialysis modalities, particularly those incurred by private insurers. In this study, we compared the costs of injectable dialysis drugs (and their oral equivalents) provided by insurers between privately insured patients receiving hemodialysis and PD. We found that the average annual injectable drug expenditures for hemodialysis were 2.0-fold higher compared with those for PD. These findings suggest that the recent increase in the use of PD may lead to reductions in injectable dialysis drug costs among privately insured patients.

Managing the symptom burden associated with maintenance dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Individuals with kidney failure undergoing maintenance dialysis frequently report a high symptom burden that can interfere with functioning and diminish life satisfaction. Until recently, the focus of nephrology care for dialysis patients has been related primarily to numerical targets for laboratory measures, and outcomes such as cardiovascular disease and mortality. Routine symptom assessment is not universal or standardized in dialysis care. Even when symptoms are identified, treatment options are limited and are initiated infrequently, in part because of a paucity of evidence in the dialysis population and the complexities of medication interactions in kidney failure. In May of 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference-Symptom-Based Complications in Dialysis-to identify the optimal means for diagnosing and managing symptom-based complications in patients undergoing maintenance dialysis. Participants included patients, physicians, behavioral therapists, nurses, pharmacists, and clinical researchers. They outlined foundational principles and consensus points related to identifying and addressing symptoms experienced by patients undergoing dialysis and described gaps in the knowledge base and priorities for research. Healthcare delivery and education systems have a responsibility to provide individualized symptom assessment and management. Nephrology teams should take the lead in symptom management, although this does not necessarily mean taking ownership of all aspects of care. Even when options for clinical response are limited, clinicians should focus on acknowledging, prioritizing, and managing symptoms that are most important to individual patients. A recognized factor in the initiation and implementation of improvements in symptom assessment and management is that they will be based on locally existing needs and resources.

Trends and perspectives for improving quality of chronic kidney disease care: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Chronic kidney disease (CKD) affects over 850 million people globally, and the need to prevent its development and progression is urgent. During the past decade, new perspectives have arisen related to the quality and precision of care for CKD, owing to the development of new tools and interventions for CKD diagnosis and management. New biomarkers, imaging methods, artificial intelligence techniques, and approaches to organizing and delivering healthcare may help clinicians recognize CKD, determine its etiology, assess the dominant mechanisms at given time points, and identify patients at high risk for progression or related events. As opportunities to apply the concepts of precision medicine for CKD identification and management continue to be developed, an ongoing discussion of the potential implications for care delivery is required. The 2022 KDIGO Controversies Conference on Improving CKD Quality of Care: Trends and Perspectives examined and discussed best practices for improving the precision of CKD diagnosis and prognosis, managing the complications of CKD, enhancing the safety of care, and maximizing patient quality of life. Existing tools and interventions currently available for the diagnosis and treatment of CKD were identified, with discussion of current barriers to their implementation and strategies for improving the quality of care delivered for CKD. Key knowledge gaps and areas for research were also identified.

Novel anemia therapies in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Anemia is common in patients with chronic kidney disease and is associated with a high burden of morbidity and adverse clinical outcomes. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline for the diagnosis and management of anemia in chronic kidney disease. Since then, new data from studies assessing established and emerging therapies for the treatment of anemia and iron deficiency have become available. Beginning in 2019, KDIGO planned 2 Controversies Conferences to review the new evidence and its potential impact on the management of anemia in clinical practice. Here, we report on the second of these conferences held virtually in December 2021, which focused on a new class of agents-the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs). This report provides a review of the consensus points and controversies from this second conference and highlights areas that warrant prioritization for future research.

Challenges in the management of the kidney allograft: from decline to failure: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

In March 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a virtual Controversies Conference to address the important but rarely examined phase during which the kidney transplant is failing or has failed. In addition to discussing the definition of a failing allograft, 4 broad areas were considered in the context of a declining functioning graft: prognosis and kidney failure trajectory; immunosuppression strategies; management of medical and psychological complications, and patient factors; and choice of kidney replacement therapy or supportive care following graft loss. Identifying and paying special attention to individuals with failing allografts was felt to be important in order to prepare patients psychologically, manage immunosuppression, address complications, prepare for dialysis and/or retransplantation, and transition to supportive care. Accurate prognostication tools, although not yet widely available, were embraced as necessary to define allograft survival trajectories and the likelihood of allograft failure. The decision of whether to withdraw or continue immunosuppression after allograft failure was deemed to be based most appropriately on risk-benefit analysis and likelihood of retransplantation within a few months. Psychological preparation and support was identified as a critical factor in patient adjustment to graft failure, as was early communication. Several models of care were noted that enabled a medically supportive transition back to dialysis or retransplantation. Emphasis was placed on the importance of dialysis-access readiness before initiation of dialysis, in order to avoid use of central venous catheters. The centrality of the patient to all management decisions and discussions was deemed to be paramount. Patient "activation," which can be defined as engaged agency, was seen as the most effective way to achieve success. Unresolved controversies, gaps in knowledge, and areas for research were also stressed in the conference deliberations.

QT-Prolonging Antibiotics, Serum-to-Dialysate Potassium Gradient, and Risk of Sudden Cardiac Death Among Patients Receiving Maintenance Hemodialysis.

Rationale & Objective: Treatment with certain QT interval-prolonging antibiotics is associated with a higher risk of sudden cardiac death among individuals with hemodialysis-dependent kidney failure. Concurrent exposure to large serum-to-dialysate potassium gradients, which promote large potassium shifts, may augment the proarrhythmic effects of these medications. The primary objective of this study was to examine whether the serum-to-dialysate gradient modifies the cardiac safety of azithromycin, and separately, levofloxacin/moxifloxacin. Study Design: Retrospective observational cohort study using a new-user study design. Setting & Population: Adult in-center hemodialysis patients with Medicare coverage in the US Renal Data System (2007-2017). Exposure: Initiation of azithromycin (or levofloxacin/moxifloxacin) as compared to amoxicillin-based antibiotics (exposure). Serum-to-dialysate potassium gradient (effect modifier). Individual patients could contribute multiple study antibiotic treatment episodes to the analyses. Outcomes: Sudden cardiac death (14 days). Analytical Approach: Inverse probability of treatment-weighted survival models to estimate HRs and robust 95% CIs. Results: The azithromycin versus amoxicillin-based antibiotic cohort included 89,379 unique patients with 113,516 azithromycin and 103,493 amoxicillin-based treatment episodes. Azithromycin versus amoxicillin-based antibiotic treatment was associated with a higher risk of sudden cardiac death overall, HR, 1.68; 95% CI, 1.31-2.16. The risk was numerically higher when the baseline serum-to-dialysate potassium gradient was ≥3 mEq/L compared with <3 mEq/L (HR, 2.22; 95% CI, 1.46-3.40 vs HR, 1.43; 95% CI. 1.04-1.96, P interaction = 0.07). Analogous analyses in a respiratory fluoroquinolone (levofloxacin/moxifloxacin) versus amoxicillin-based antibiotic cohort with 79,449 unique patients and 65,959 respiratory fluoroquinolone and 103,776 amoxicillin-based treatment episodes yielded similar results. Limitations: Residual confounding. Conclusions: Although treatment with azithromycin and, separately, respiratory fluoroquinolones were each associated with a heightened risk of sudden cardiac death, this risk was augmented in the setting of larger serum-to-dialysate potassium gradients. Minimizing the potassium gradient may be an approach to reduce the cardiac risk of these antibiotics.

Vadadustat for treatment of anemia in patients with dialysis-dependent chronic kidney disease receiving peritoneal dialysis.

BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36). RESULTS: Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. CONCLUSIONS: In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.

Defining myocardial infarction in trials of people receiving hemodialysis: consensus report from the SONG-HD MI Expert Working group.

Cardiovascular disease is the leading cause of death in patients receiving hemodialysis. Currently, there is no standardized definition of myocardial infarction (MI) for patients receiving hemodialysis. Through an international consensus process MI was established as the core CVD measure for this population in clinical trials. The Standardised Outcomes in Nephrology Group-Hemodialysis (SONG-HD) initiative convened a multidisciplinary, international working group to address the definition of MI in this population. On the basis of current evidence, the working group recommends using the Fourth Universal Definition of Myocardial Infarction with specific caveats with regard to the interpretation of "ischemic symptoms" and performing a baseline 12-lead electrocardiogram to facilitate interpretation of acute changes on subsequent tracings. The working group does not recommend obtaining baseline cardiac troponin values, though does recommend obtaining serial cardiac biomarkers in settings where ischemia is suspected. The application of an evidence-based uniform definition should increase the reliability and accuracy of trial results.

Physiological Age by Artificial Intelligence-Enhanced Electrocardiograms as a Novel Risk Factor of Mortality in Kidney Transplant Candidates.

BACKGROUND: Mortality risk assessment before kidney transplantation (KT) is imperfect. An emerging risk factor for death in nontransplant populations is physiological age as determined by the application of artificial intelligence to the electrocardiogram (ECG). The aim of this study was to examine the relationship between ECG age and KT waitlist mortality. METHODS: We applied a previously developed convolutional neural network to the ECGs of KT candidates evaluated 2014 to 2019 to determine ECG age. We used a Cox proportional hazard model to examine whether ECG age was associated with waitlist mortality. RESULTS: Of the 2183 patients evaluated, 59.1% were male, 81.4% were white, and 11.4% died during follow-up. Mean ECG age was 59.0 ± 12.0 y and mean chronological age at ECG was 53.3 ± 13.6 y. After adjusting for chronological age, comorbidities, and other characteristics associated with mortality, each increase in ECG age of >10 y than the average ECG age for patients of a similar chronological age was associated with an increase in mortality risk (hazard ratio 3.59 per 10-y increase; 95% confidence interval, 2.06-5.72; P < 0.0001). CONCLUSIONS: ECG age is a risk factor for KT waitlist mortality. Determining ECG age through artificial intelligence may help guide risk-benefit assessment when evaluating candidates for KT.