Tenapanor as Therapy for Hyperphosphatemia in Maintenance Dialysis Patients: Results from the OPTIMIZE Study.

BACKGROUND: OPTIMIZE was a randomized, open-label study evaluating different tenapanor initiation methods. OPTIMIZE evaluated tenapanor alone and in combination with phosphate binders (PBs) to achieve target serum phosphate (P) ≤5.5 mg/dL. METHODS: Patients with inadequately controlled P receiving maintenance dialysis from 42 US locations who were taking PBs with baseline P >5.5 mg/dL and ≤10.0 mg/dL, or were PB-naive with baseline P >4.5 mg/dL and ≤10.0 mg/dL, were included in OPTIMIZE. Participants taking PBs at baseline were randomized to switch from PBs to tenapanor (Straight Switch; n = 151) or reduce PB dosage by ≥50% and add tenapanor (Binder Reduction; n = 152); PB-naive patients started tenapanor alone (Binder-Naive; n = 30). Participants received tenapanor 30 mg twice a day for 10 weeks (part A), followed by an elective, 16-week open-label extension (part B). Outcomes included changes from baseline in P, intact fibroblast growth factor 23 (iFGF23), parathyroid hormone (PTH), serum calcium, and medication burden; patient-reported outcomes; and safety. RESULTS: By part A endpoint, 34.4% (Straight Switch), 38.2% (Binder Reduction), and 63.3% (Binder-Naive) of patients achieved P ≤5.5 mg/dL. Mean P reduction and median pill burden reduction from baseline to part A endpoint were 0.91± 1.7 mg/dL and 4 pills/day for the Straight Switch and 0.99± 1.8 mg/dL and 1 pill/day for the Binder Reduction group. The mean P reduction for Binder-Naive patients was 0.87± 1.5 mg/dL. Among Straight Switch and Binder Reduction patients who completed patient experience questionnaires, 205 of 243 (84.4%) reported an improved phosphate-management routine. Diarrhea was the most common adverse event (133 of 333 [39.9%]). CONCLUSIONS: Tenapanor as monotherapy or in combination with PBs effectively lowered P toward the target range in patients who were PB naïve or who were not at goal despite PB use. FUNDING: Ardelyx, Inc. TRIAL REGISTRATION: NCT04549597.

Difelikefalin in Black/African American Hemodialysis Patients with Moderate-to-Severe Pruritus: Post-hoc Analysis of KALM-1 and KALM-2.

Black and African American (AA) people are over-represented in the kidney failure population; therefore, the safety and efficacy of difelikefalin in Black/AA patients was evaluated. This was a post hoc, pooled exploratory subgroup analysis of the Phase 3 KALM-1 and -2 studies. Patients undergoing hemodialysis (HD) who had moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) at enrollment were stratified into self-reported Black/AA or White subgroups. Patients were randomized (1:1) to receive intravenous (IV) difelikefalin 0.5 µg/kg or placebo for 12 weeks. Difelikefalin efficacy was assessed with validated patient-reported outcome questionnaires: 24-hour Worst Itch Numerical Rating Scale (WI-NRS), 5-D itch, and Skindex 10. There were 249 (29.3%) patients from the KALM studies that self-identified as Black/AA (n=135 difelikefalin; n=114 placebo). Clinically meaningful (≥3-point) reduction in WI-NRS score was achieved by 47.9% of Black/AA patients with difelikefalin versus 24.6% with placebo (P<0.001). More Black/AA patients achieved a ≥5-point 5-D itch total improvement (54.9% vs 35.7%; P=0.013) and a ≥15-point Skindex-10 score improvement with difelikefalin versus placebo (49.0% vs 28.9%; P=0.006) compared with White patients. Incidence of treatment-emergent adverse events (TEAEs) was higher for Black/AA patients (difelikefalin: 78.5%; placebo: 70.8%) versus White patients (difelikefalin: 64.8%; placebo: 61.8%). In this post hoc analysis, difelikefalin was efficacious in the Black/AA population and had an acceptable safety profile.

A phase 3b, multicenter, open-label, single-arm study of roxadustat (ASPEN): Operational learnings within United States dialysis organizations.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). ASPEN evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD in US dialysis organizations. METHODS: This open-label, single-arm study (NCT04484857) comprised a 6-week screening period, followed by 24 weeks of treatment (with optional extension ≤1 year) and a 4-week follow-up. Patients aged ≥18 years, receiving chronic dialysis, with hemoglobin (Hb) 9.0-12.0 g/dL if converting from erythropoiesis-stimulating agents (ESAs), or <10.0 g/dL if receiving ESAs for <6 weeks, received oral roxadustat three times weekly in-center. Primary efficacy endpoints included proportion of patients with mean Hb ≥10 g/dL, averaged over weeks 16-24, and mean Hb change from baseline to the average over weeks 16-24. Safety was also assessed. FINDINGS: Overall, 283 patients were enrolled and treated, 282 (99.6%) were included in the full analysis set, and 216 (76.3%) continued into the extension period. Most patients enrolled were from DaVita sites (71%), with the rest from US Renal Care sites (29%). Mean (standard deviation [SD]) baseline Hb was 10.6 (0.7) g/dL. Nearly all patients were prior ESA users (n = 274; 97.2%). The proportion of patients with mean Hb ≥10 g/dL during weeks 16-24 was 83.7% (95% confidence interval 78.9-88.6). Mean (SD) Hb increase from baseline to the average over weeks 16-24 was 0.2 (1.0) g/dL. During the treatment period, 82 (29.0%) patients reported treatment-emergent serious adverse events (TESAEs). The most common TESAEs were COVID-19 pneumonia (n = 10; 3.5%), acute respiratory failure (n = 9; 3.2%), COVID-19 (n = 7; 2.5%), acute myocardial infarction (n = 7; 2.5%), and fluid overload (n = 6, 2.1%). DISCUSSION: Roxadustat was effective in maintaining Hb in patients with anemia of CKD on dialysis in large, community-based dialysis organizations.

Hypoxia-inducible factor stabilizers: 27 228 patients studied, yet a role still undefined.

With the emergence of hypoxia inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) came the hope that using these oral drugs could improve the treatment of the anemia of kidney disease. In this editorial we discuss the accumulated knowledge on these agents and the clinical context for use.

Evaluation of the effect of sodium zirconium cyclosilicate on arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with hyperkalaemia: protocol for the multicentre, randomised, controlled DIALIZE-Outcomes study.

INTRODUCTION: Patients with kidney failure receiving chronic haemodialysis have elevated risk of arrhythmias potentially increasing the likelihood of sudden cardiac death, stroke and hospitalisation. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an efficacious and well-tolerated treatment for predialysis hyperkalaemia in patients undergoing haemodialysis. The DIALIZE-Outcomes study evaluates the effect of SZC on sudden cardiac death and arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with recurrent hyperkalaemia. METHODS AND ANALYSIS: International, multicentre, randomised, double-blind, placebo-controlled study conducted at 357 study sites across 25 countries. Adults (≥18 years) receiving chronic haemodialysis three times per week with recurrent predialysis serum potassium (K+) ≥5.5 mmol/L post long interdialytic interval (LIDI) are eligible. Patients (~2800) will be randomised 1:1 to SZC or placebo, starting at 5 g orally once daily on non-dialysis days and titrated weekly in 5 g increments (maximum 15 g) to target predialysis serum K+ 4.0-5.0 mmol/L post LIDI. The primary objective is to evaluate efficacy of SZC versus placebo in reducing occurrence of the primary composite endpoint of sudden cardiac death, stroke or arrhythmia-related hospitalisation, intervention or emergency department visit. Secondary endpoints include efficacy of SZC versus placebo in maintaining normokalaemia (serum K+ 4.0-5.5 mmol/L post LIDI) at the 12-month visit, preventing severe hyperkalaemia (serum K+ ≥6.5 mmol/L post LIDI) at the 12-month visit and reducing the incidence of individual cardiovascular outcomes. Safety of SZC will be evaluated. The study is event driven, with participants remaining in the study until 770 primary endpoint events have occurred. Average time in the study is expected to be ~25 months. ETHICS AND DISSEMINATION: Approval was obtained from the relevant institutional review board/independent ethics committee from each participating site (approving bodies in supplementary information). The results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2020-005561-14 and clinicaltrials.gov identifier NCT04847232.

Difelikefalin for the treatment of moderate-to-severe pruritus associated with chronic kidney disease on hemodialysis.

INTRODUCTION: Chronic kidney disease-associated pruritus (CKD-aP) is often experienced by patients with CKD receiving dialysis. Approximately 40% of hemodialysis patients are 'moderately' to 'extremely bothered' by itching, associated with reduced quality of life, poor sleep quality, and depression as well as worse clinical outcomes, including increased medication use, infections, hospitalizations, and mortality. AREAS COVERED: This review covers the pathophysiology and treatment landscape of CKD-aP, and the development, clinical efficacy, and safety profile of difelikefalin. We summarize the existing evidence, and discuss both the position of difelikefalin in the treatment pathway and potential future developments. EXPERT OPINION: Difelikefalin is a kappa opioid receptor agonist, with a primary mode of action that is outside of the central nervous system and provides an improved safety profile compared with other opioid agonists, with limited potential for abuse and dependency. Difelikefalin has demonstrated efficacy, tolerability, and safety profile in several large-scale clinical trials in more than 1,400 hemodialysis patients with CKD-aP treated for up to 64 weeks. Difelikefalin is the only approved treatment for CKD-aP in the U.S.A and Europe; other treatments are used off-label, have limited proof of efficacy in large-scale clinical trials in this patient population, and may present an increased risk of toxicity in patients with CKD.

Use of TIMP-2 and IGFBP-7 for prediction of postoperative acute kidney injury after cardiac surgery.

BACKGROUND: The following cell cycle arrest urinary biomarkers, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7), have been used for early detection of acute kidney injury (AKI) in critically ill patients. The purpose of this study is to validate the use of these urinary biomarkers in patients undergoing open heart surgery. MATERIALS AND METHODS: In a single-center prospective observational study, urine samples were collected in 108 consecutive patients who underwent open heart surgery immediately after separation from cardiopulmonary bypass and on postoperative day 1, and were sent for the biomarker [TIMP-2]*[IGFBP7] analysis. Acute kidney injury was defined based on KDIGO criteria, and levels of [TIMP-2]*[IGFBP7] were analyzed for the ability to predict AKI. RESULTS: Of the 108 patients, 19 (17.6%) patients developed postoperative AKI within 48 hours of surgery. At the threshold of > 0.3 (ng/mL)2/1,000, post-cardiopulmonary bypass [TIMP-2]*[IGFBP-7] had a sensitivity of 13% and specificity of 82% for predicting postoperative AKI. Postoperative day-1 [TIMP-2]*[IGFBP-7] had a sensitivity of 47% and a specificity of 59% for predicting postoperative AKI. There were no differences in [TIMP-2]*[IGFBP-7] values at either timepoint between patients who developed postoperative AKI as compared to those who did not. CONCLUSION: Urinary [TIMP-2]*[IGFBP7] was not predictive of the risk of AKI after cardiac surgery in this single-center study population.

Changes in Iron Availability with Roxadustat in Nondialysis- and Dialysis-Dependent Patients with Anemia of CKD.

Background: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin by stimulating erythropoietin synthesis and improving iron availability through facilitation of iron uptake and/or release from stores. In this exploratory analysis, we assessed the effect of roxadustat treatment on laboratory parameters related to iron metabolism in patients with anemia of chronic kidney disease (CKD). Methods: Data were pooled from pivotal, randomized, phase 3 roxadustat trials: three placebo-controlled, double-blind trials in nondialysis-dependent (NDD) CKD and three open-label, active-comparator (epoetin alfa) trials in dialysis-dependent (DD) CKD. In this exploratory analysis, mean changes from baseline in hemoglobin, iron parameters, and hepcidin, and intravenous (iv) iron use were evaluated. Pooled results in NDD CKD and DD CKD patients are reported. Results: Overall, 4277 patients with NDD CKD and 3890 patients with DD CKD were evaluated. Hemoglobin increases with roxadustat treatment were accompanied by increases in serum iron and total iron-binding capacity (TIBC) and decreases in serum ferritin and hepcidin from baseline through week 52. With epoetin alfa, the hemoglobin increase was accompanied by decreases in serum ferritin and hepcidin, but serum iron decreased, and there was no change in TIBC. With placebo, there were no changes in hemoglobin, iron parameters, or hepcidin. During treatment, iv iron use was reduced with roxadustat versus placebo and epoetin alfa. Conclusions: In patients with NDD CKD and DD CKD, roxadustat treatment is associated with increases in serum iron and TIBC, accompanied by reduced hepcidin and indicative of improved iron kinetics. Patients treated with roxadustat achieved target hemoglobin levels with less iv iron use versus comparators. Practitioners treating patients with anemia of CKD with roxadustat should consider its unique effects when interpreting iron parameters.

Living Well With Kidney Disease and Effective Symptom Management: Consensus Conference Proceedings.

Chronic kidney disease (CKD) confers a high burden of uremic symptoms that may be underrecognized, underdiagnosed, and undertreated. Unpleasant symptoms, such as CKD-associated pruritus and emotional/psychological distress, often occur within symptom clusters, and treating 1 symptom may potentially alleviate other symptoms in that cluster. The Living Well with Kidney Disease and Effective Symptom Management Consensus Conference convened health experts and leaders of kidney advocacy groups and kidney networks worldwide to discuss the effects of unpleasant symptoms related to CKD on the health and well-being of those affected, and to consider strategies for optimal symptom management. Optimizing symptom management is a cornerstone of conservative and preservative management which aim to prevent or delay dialysis initiation. In persons with kidney dysfunction requiring dialysis (KDRD), incremental transition to dialysis and home dialysis modalities offer personalized approaches. KDRD is proposed as the preferred term given the negative connotations of "failure" as a kidney descriptor, and the success stories in CKD journeys. Engaging persons with CKD to identify and prioritize their personal values and individual needs must be central to ensure their active participation in CKD management, including KDRD. Person-centered communication and care are required to ensure diversity, equity, and inclusion; education/awareness that considers the health literacy of persons with CKD; and shared decision-making among the person with CKD, care partners, and providers. By putting the needs of people with CKD, including effective symptom management, at the center of their treatment, CKD can be optimally treated in a way that aligns with their goals.

Safety and Tolerability of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis From the Phase 3 Clinical Trial Program.

Rationale & Objective: We report a pooled safety analysis of intravenous difelikefalin in participants with moderate to severe chronic kidney disease-associated pruritus (CKD-aP) treated by hemodialysis in 4 phase 3 clinical studies. Study Design: KALM-1 and KALM-2 were randomized, double-blind, placebo-controlled, pivotal phase 3 studies; CLIN3101 (52 weeks) and CLIN3105 (12 weeks) were open-label studies. Setting & Participants: Adults with moderate to severe CKD-aP treated by hemodialysis in North America, Europe, and the Asia-Pacific region. Intervention: At least 1 intravenous placebo or difelikefalin dose of 0.5 mcg/kg for up to 64 weeks. Outcomes: Safety. Results: Safety analyses were conducted with 848 participants in the placebo-controlled cohort (424 participants each in the difelikefalin and placebo groups) and in 1,306 participants in the all-difelikefalin-exposure cohort. In the placebo-controlled cohort, the most commonly reported treatment-emergent adverse events (TEAEs), occurring in ≥2% of participants receiving difelikefalin and with a ≥1% higher incidence than placebo, were diarrhea (9.0% and 5.7%, respectively); dizziness (6.8% and 3.8%, respectively); nausea (6.6% and 4.5%, respectively); gait disturbances, including falls (6.6% and 5.4%, respectively), hyperkalemia (4.7% and 3.5%, respectively); headache (4.5% and 2.6%, respectively); somnolence (4.2% and 2.4%, respectively); and mental status changes (3.3% and 1.4%, respectively). These were mostly mild or moderate, with few leading to discontinuation. Incidence rates of TEAEs, serious TEAEs, and discontinuations because of TEAEs did not increase with long-term exposure. Three participants (0.7%) in the difelikefalin group and 5 participants (1.2%) in the placebo group died during the study. Limitations: Pooled data from studies with different designs. Conclusions: Intravenous difelikefalin demonstrated an acceptable safety profile, was generally well tolerated with long-term use, and may address the unmet treatment need for patients with CKD-aP treated by hemodialysis. Funding: Cara Therapeutics, Inc. Trial Registration: KALM-1 is registered as NCT03422653, KALM-2 as NCT03636269, CLIN3101 as NCT03281538, and CLIN3105 as NCT03998163.

Improving Detection and Management of Anemia in CKD.

LEARNING OBJECTIVES: At the end of the activity, participants will be able to:Describe approaches to improve recognition of chronic kidney disease (CKD) and anemia in primary care. Explain the importance of early management of anemia in CKD to reduce adverse outcomes and improve symptoms. Prescribe evidence-based treatment for patients with anemia in CKD who can be managed in the primary care setting. Discuss emerging evidence for new agents being studied for treating anemia in CKD.

Pruritus in chronic kidney disease.

PURPOSE OF REVIEW: Among the many difficult symptoms that patients with kidney disease experience, pruritus is one of the most frequent and troubling. Because a substantial amount of new information has accumulated, we seek here to review the subject. RECENT FINDINGS: Pruritus is not only a common problematic symptom among patients with kidney disease, but its considerably more frequent than nephrologists recognize. The result for patients is not just uncomfortable itch but degraded quality of life as well. The pathogenesis is increasingly understood, but many aspects remain to be fully resolved. Importantly, research is progressing on treatment, leading to the first approved medication in the United States, difelikefalin, in August, 2021. SUMMARY: As nephrology is progressing to a greater focus on patient symptoms, recognition of the importance of pruritus has led to increased interest and improved diagnosis and treatment options.

Ferric pyrophosphate citrate for parenteral administration of maintenance iron: structure, mechanism of action, clinical efficacy and safety.

Anemia is a common complication in patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). Anemia is principally the result of erythropoietin deficiency, inflammation, and iron deficiency. High molecular weight iron oxide nanoparticles (IONP) are routinely administered intravenously to replace iron losses and, although effective, there are lingering concerns about possible safety issues. Ferric pyrophosphate citrate (FPC, Triferic, Triferic AVNU [Triferic and Triferic AVNU are the proprietary name for ferric pyrophosphate citrate. Triferic and Triferic AVNU are registered trademarks of Rockwell medical Inc.]) is a complex iron salt that donates iron directly to plasma transferrin. FPC is devoid of any carbohydrate moiety and is administered via the dialysate or intravenously during each hemodialysis session to replace iron and maintain hemoglobin. Controlled clinical trials of up to 48 weeks in duration have demonstrated the efficacy of regular administration of dialysate FPC for maintaining hemoglobin levels and iron balance in HDD-CKD patients. Clinical data also suggest that dialysate FPC may reduce the dose requirements for and use of erythropoiesis-stimulating agents and IONPs in HDD-CKD patients. Safety data from clinical studies and post-marketing surveillance show that FPC is well tolerated and not associated with an increased risk of infection, inflammation, iron overload, or serious hypersensitivity reactions. FPC represents an effective and well-tolerated choice for iron replacement and maintenance of hemoglobin in the long-term management of HDD-CKD patients.

Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease.

Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.

Course of Hyperkalemia in Patients on Hemodialysis.

Background: Evidence of longitudinal serum potassium (sK+) concentrations in hyperkalemic hemodialysis patients is sparse. Objective: These post hoc analyses of the placebo arm of the phase 3b DIALIZE study (NCT03303521) explored the course of hyperkalemia in hemodialysis patients receiving placebo. Methods: In DIALIZE, 196 patients receiving hemodialysis three times weekly were randomized to placebo or sodium zirconium cyclosilicate 5 g starting dose once daily on nondialysis days for 8 weeks. In these post hoc analyses of placebo patients overall (n = 86) and by predialysis sK+ subgroups at randomization <5.5 mmol/L, 5.5 to <6.0 mmol/L, 6.0 to <6.5 mmol/L, and ≥6.5 mmol/L, we assessed mean predialysis sK+ concentration by visit and the proportions of patients with mean predialysis sK+ ranges of 4.0-5.0 and 4.0-5.5 mmol/L by visit. Results: In placebo patients, the mean predialysis sK+ concentration at randomization was 5.9 mmol/L, and 5.8 mmol/L at the end of the study (day 57). For placebo patients overall and across all predialysis sK+ subgroups, the mean predialysis sK+ concentration remained ≥5.0 mmol/L for all visits over 8 weeks. Overall, 7-21% and 27-62% of placebo patients had predialysis sK+ ranges of 4.0-5.0 and 4.0-5.5 mmol/L, respectively, at any visit. The proportions of placebo patients with either predialysis sK+ range were greatest for those who were least hyperkalemic (<5.5 mmol/L) and generally decreased with increasing predialysis sK+ concentration. Conclusions: Patients receiving placebo and hemodialysis maintained high predialysis sK+ concentrations over 8 weeks following a hyperkalemic event. Most placebo patients remained hyperkalemic and may be at continued risk of adverse events.

Roxadustat Versus Epoetin Alfa for Treating Anemia in Patients with Chronic Kidney Disease on Dialysis: Results from the Randomized Phase 3 ROCKIES Study.

BACKGROUND: Concerns regarding cardiovascular safety with current treatments for anemia in patients with dialysis-dependent (DD)-CKD have encouraged the development of alternatives. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis by increasing endogenous erythropoietin and iron availability. METHODS: In this open-label phase 3 study, patients with DD-CKD and anemia were randomized 1:1 to oral roxadustat three times weekly or parenteral epoetin alfa per local clinic practice. Initial roxadustat dose depended on erythropoiesis-stimulating agent dose at screening for patients already on them and was weight-based for those not on them. The primary efficacy end point was mean hemoglobin change from baseline averaged over weeks 28‒52 for roxadustat versus epoetin alfa, regardless of rescue therapy use, tested for noninferiority (margin, -0.75 g/dl). Adverse events (AEs) were assessed. RESULTS: Among 2133 patients randomized (n=1068 roxadustat, n=1065 epoetin alfa), mean age was 54.0 years, and 89.1% and 10.8% were on hemodialysis and peritoneal dialysis, respectively. Mean (95% confidence interval) hemoglobin change from baseline was 0.77 (0.69 to 0.85) g/dl with roxadustat and 0.68 (0.60 to 0.76) g/dl with epoetin alfa, demonstrating noninferiority (least squares mean difference [95% CI], 0.09 [0.01 to 0.18]; P<0.001). The proportion of patients experiencing ≥1 AE and ≥1 serious AE was 85.0% and 57.6% with roxadustat and 84.5% and 57.5% with epoetin alfa, respectively. CONCLUSIONS: Roxadustat effectively increased hemoglobin in patients with DD-CKD, with an AE profile comparable to epoetin alfa. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis. CLINICALTRIALS: gov Identifier: NCT02174731.

Retraction notice to "Pooled Analysis of Roxadustat for Anemia in Patients With Kidney Failure Incident to Dialysis." Kidney Int Rep. 2021;6:613-623.

[This retracts the article DOI: 10.1016/j.ekir.2020.12.018.].

Potassium responses to sodium zirconium cyclosilicate in hyperkalemic hemodialysis patients: post-hoc analysis of DIALIZE.

BACKGROUND: Sodium zirconium cyclosilicate (SZC) is an effective and well-tolerated treatment for hyperkalemia in maintenance hemodialysis patients. In post-hoc analyses of the phase 3b DIALIZE study, we examined the spectrum of potassium responses to SZC. METHODS: Post-hoc analyses with SZC and placebo included: the number of long interdialytic interval (LIDI) visits during the 4-week evaluation period where patients attained pre-dialysis serum potassium (sK+) concentrations of 4.0-5.0 and 4.0-5.5 mmol/L; potassium gradient (the difference between pre-dialysis sK+ and dialysate potassium) at days 36, 43, 50, and 57, and change from baseline to the end of treatment (EOT) using categories of potassium gradient (1 to < 2, 2 to < 3, 3 to < 4, and ≥ 4 mmol/L). RESULTS: A greater proportion of patients achieved the ranges of pre-dialysis sK+ concentration with SZC versus placebo for ≥1, ≥ 2, ≥ 3, and 4 LIDI visits over 4 weeks; 23.7 and 48.5% of patients in the SZC group achieved pre-dialysis sK+ concentrations of 4.0-5.0 and 4.0-5.5 mmol/L, respectively, at all 4 LIDI visits. Baseline mean potassium gradient was similar with SZC and placebo. At day 57, mean (standard deviation) potassium gradient was 2.78 (0.08) mmol/L with SZC and 3.52 (0.08) mmol/L with placebo; mean difference (95% confidence interval) was - 0.74 mmol/L (- 0.97 to - 0.52). A greater reduction in potassium gradient category from baseline towards lower-risk categories at EOT was observed with SZC versus placebo. CONCLUSIONS: These analyses expand our knowledge of the spectrum of potassium responses with SZC in hyperkalemic hemodialysis patients. TRIAL REGISTRATION: NCT03303521 .