Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

A Randomized Trial of the Impact of Ferric Citrate on Erythropoietin and Intravenous Iron Use in Patients Receiving Dialysis.

INTRODUCTION: Ferric citrate (FC) is an FDA-approved iron-based phosphate binder for adults with dialysis-dependent chronic kidney disease. This study investigated the impact of FC as the primary phosphate-lowering therapy on utilization of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron. METHODS: In this randomized, open-label, active-controlled, multicenter study (NCT04922645), patients on dialysis and receiving ESAs were randomized to receive FC or remain on standard of care (SOC) phosphate-lowering therapy for up to 6 months. Primary endpoints were the difference in change from baseline to efficacy evaluation period (EEP) in mean monthly ESA and IV iron doses. Secondary endpoints included treatment differences in hemoglobin, phosphate, TSAT, and ferritin levels. RESULTS: Two hundred nine patients were randomized to FC and had a day 1 dosing visit (n = 103) or SOC (n = 106). The two groups had similar baseline laboratory characteristics; however, atherosclerotic CV disease, peripheral vascular disease, and congestive heart failure were more common in the SOC group. The mean treatment difference in ESA monthly dose was -30.8 µg (FC vs. SOC; p = 0.02). An absolute though non-statistically significant change in mean monthly IV iron dose of -37.2 mg (p = 0.17) was observed with FC. Mean hemoglobin, TSAT, and ferritin all increased from baseline to the EEP with FC versus SOC. Serious adverse events occurred in 28% of patients receiving FC versus 37% in those receiving SOC. CONCLUSIONS: In patients receiving dialysis, treatment with FC as compared to remaining on SOC phosphate binders resulted in reductions in mean monthly ESA and IV iron dose.

SARS-CoV-2 Vaccine Antibody Response and Breakthrough Infection in Patients Receiving Dialysis.

BACKGROUND: Whether breakthrough SARS-CoV-2 infections after vaccination are related to the level of postvaccine circulating antibody is unclear. OBJECTIVE: To determine longitudinal antibody-based response and risk for breakthrough infection after SARS-CoV-2 vaccination. DESIGN: Prospective study. SETTING: Nationwide sample from dialysis facilities. PATIENTS: 4791 patients receiving dialysis. MEASUREMENTS: Remainder plasma from a laboratory processing routine monthly tests was used to measure qualitative and semiquantitative antibodies to the receptor-binding domain (RBD) of SARS-CoV-2. To evaluate whether peak or prebreakthrough RBD values were associated with breakthrough infection, a nested case-control analysis matched each breakthrough case patient to 5 control patients by age, sex, and vaccination month and adjusted for diabetes status and region of residence. RESULTS: Of the 4791 patients followed with monthly RBD assays, 2563 were vaccinated as of 14 September 2021. Among the vaccinated patients, the estimated proportion with an undetectable RBD response increased from 6.6% (95% CI, 5.5% to 7.8%) 14 to 30 days after vaccination to 20.2% (CI, 17.0% to 23.3%) 5 to 6 months after vaccination. Estimated median index values decreased from 91.9 (CI, 78.6 to 105.2) 14 to 30 days after vaccination to 8.4 (CI, 7.6 to 9.3) 5 to 6 months after vaccination. Breakthrough infections occurred in 56 patients, with samples collected a median of 21 days before breakthrough infection. Compared with prebreakthrough index RBD values of 23 or higher (equivalent to ≥506 binding antibody units per milliliter), prebreakthrough RBD values less than 10 and values from 10 to less than 23 were associated with higher odds for breakthrough infection (rate ratios, 11.6 [CI, 3.4 to 39.5] and 6.0 [CI, 1.5 to 23.6], respectively). LIMITATIONS: Single measure of vaccine response; ascertainment of COVID-19 diagnosis from electronic health records. CONCLUSION: The antibody response to SARS-CoV-2 vaccination wanes rapidly in persons receiving dialysis. In this population, the circulating antibody response is associated with risk for breakthrough infection. PRIMARY FUNDING SOURCE: Ascend Clinical Laboratory.

Systematic Review and Meta-Analyses of the Effects of Phosphate-Lowering Agents in Nondialysis CKD.

BACKGROUND: Benefits of phosphate-lowering interventions on clinical outcomes in patients with CKD are unclear; systematic reviews have predominantly involved patients on dialysis. This study aimed to summarize evidence from randomized controlled trials (RCTs) concerning benefits and risks of noncalcium-based phosphate-lowering treatment in nondialysis CKD. METHODS: We conducted a systematic review and meta-analyses of RCTs involving noncalcium-based phosphate-lowering therapy compared with placebo, calcium-based binders, or no study medication, in adults with CKD not on dialysis or post-transplant. RCTs had ≥3 months follow-up and outcomes included biomarkers of mineral metabolism, cardiovascular parameters, and adverse events. Outcomes were meta-analyzed using the Sidik-Jonkman method for random effects. Unstandardized mean differences were used as effect sizes for continuous outcomes with common measurement units and Hedge's g standardized mean differences (SMD) otherwise. Odds ratios were used for binary outcomes. Cochrane risk of bias and GRADE assessment determined the certainty of evidence. RESULTS: In total, 20 trials involving 2498 participants (median sample size 120, median follow-up 9 months) were eligible for inclusion. Overall, risk of bias was low. Compared with placebo, noncalcium-based phosphate binders reduced serum phosphate (12 trials, weighted mean difference -0.37; 95% CI, -0.58 to -0.15 mg/dl, low certainty evidence) and urinary phosphate excretion (eight trials, SMD -0.61; 95% CI, -0.90 to -0.31, low certainty evidence), but resulted in increased constipation (nine trials, log odds ratio [OR] 0.93; 95% CI, 0.02 to 1.83, low certainty evidence) and greater vascular calcification score (three trials, SMD, 0.47; 95% CI, 0.17 to 0.77, very low certainty evidence). Data for effects of phosphate-lowering therapy on cardiovascular events (log OR, 0.51; 95% CI, -0.51 to 1.17) and death were scant. CONCLUSIONS: Noncalcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion, but there was an unclear effect on clinical outcomes and intermediate cardiovascular end points. Adequately powered RCTs are required to evaluate benefits and risks of phosphate-lowering therapy on patient-centered outcomes.

SARS-CoV-2 Infection during the Omicron Surge among Patients Receiving Dialysis: The Role of Circulating Receptor-Binding Domain Antibodies and Vaccine Doses.

BACKGROUND: It is unclear whether circulating antibody levels conferred protection against SARS-CoV-2 infection among patients receiving dialysis during the Omicron-dominant period. METHODS: We followed monthly semiquantitative SARS-CoV-2 RBD IgG index values in a randomly selected nationwide cohort of patients receiving dialysis and ascertained SARS-CoV-2 infection during the Omicron-dominant period of December 25, 2021 to January 31, 2022 using electronic health records. We estimated the relative risk for documented SARS-CoV-2 infection by vaccination status and by circulating RBD IgG using a log-binomial model accounting for age, sex, and prior COVID-19. RESULTS: Among 3576 patients receiving dialysis, 901 (25%) received a third mRNA vaccine dose as of December 24, 2021. Early antibody responses to third doses were robust (median peak index IgG value at assay limit of 150). During the Omicron-dominant period, SARS-CoV-2 infection was documented in 340 (7%) patients. Risk for infection was higher among patients without vaccination and with one to two doses (RR, 2.1; 95% CI, 1.6 to 2.8, and RR, 1.3; 95% CI, 1.0 to 1.8 versus three doses, respectively). Irrespective of the number of vaccine doses, risk for infection was higher among patients with circulating RBD IgG <23 (506 BAU/ml) (RR range, 2.1 to 3.2, 95% CI, 1.3 to 3.4 and 95% CI, 2.2 to 4.5, respectively) compared with RBD IgG ≥23. CONCLUSIONS: Among patients receiving dialysis, a third mRNA vaccine dose enhanced protection against SARS-CoV-2 infection during the Omicron-dominant period, but a low circulating RBD antibody response was associated with risk for infection independent of the number of vaccine doses. Measuring circulating antibody levels in this high-risk group could inform optimal timing of vaccination and other measures to reduce risk of SARS-CoV-2 infection.

SARS-CoV-2 Vaccine Acceptability in Patients on Hemodialysis: A Nationwide Survey.

BACKGROUND: Patients on dialysis are at increased risk for COVID-19-related complications. However, a substantial fraction of patients on dialysis belong to groups more likely to be hesitant about vaccination. METHODS: With the goal of identifying strategies to increase COVID-19 vaccine uptake among patients on hemodialysis, we conducted a nationwide vaccine acceptability survey, partnering with a dialysis network to distribute an anonymized English and Spanish language online survey in 150 randomly selected facilities in the United States. We used logistic regression to evaluate characteristics of vaccine-hesitant persons. RESULTS: A total of 1515 (14% of eligible) patients responded; 20% of all responders, 29% of patients aged 18-44 years, and 29% of Black responders reported being hesitant to seek the COVID-19 vaccine, even if the vaccine was considered safe for the general population. Odds of vaccine hesitancy were higher among patients aged 18-44 years versus those 45-64 years (odds ratio [OR], 1.5; 95% confidence interval [95% CI], 1.0 to 2.3), Black patients versus non-Hispanic White patients (OR, 1.9; 95% CI, 1.3 to 2.7), Native Americans or Pacific Islanders versus non-Hispanic White patients (OR, 2.0; 95% CI, 1.1 to 3.7), and women versus men (OR, 1.6; 95% CI, 1.2 to 2.0). About half (53%) of patients who were vaccine hesitant expressed concerns about side effects. Responders' main information sources about COVID-19 vaccines were television news and dialysis staff (68% and 38%, respectively). CONCLUSIONS: A substantial proportion of patients receiving in-center hemodialysis in the United States are hesitant about seeking COVID-19 vaccination. Facilitating uptake requires outreach to younger patients, women, and Black, Native American, or Pacific Islander patients, and addressing concerns about side effects. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/JASN/2021_07_07_JASN2021010104.mp3.

Cardiovascular safety and efficacy of vadadustat for the treatment of anemia in non-dialysis-dependent CKD: Design and baseline characteristics.

Current clinical practice guidelines for anemia management in non-dialysis-dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PRO2TECT program comprises 2 global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (N = 1751) had hemoglobin <10 g/dL and had not received an ESA within 8 weeks prior to inclusion in the study. Patients recruited into the ESA-treated NDD-CKD trial (N = 1725) had hemoglobin between 8 and 11 g/dL (US) or 9 and 12 g/dL (non-US) and were actively treated with an ESA for anemia associated with CKD. Trial periods in both trials include (1) correction/conversion (weeks 0-23); (2) maintenance (weeks 24-52); (3) long-term treatment (week 53 to end of treatment); and (4) safety follow-up (end-of-treatment to 4 weeks later). The primary safety endpoint is time to first adjudicated major adverse cardiovascular event, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke, pooled across both trials. The primary efficacy endpoint in each trial is change in hemoglobin from baseline to primary evaluation period (weeks 24-36), comparing vadadustat vs darbepoetin alfa treatment groups. Demographics and baseline characteristics are similar among patients in both trials and broadly representative of the NDD-CKD population. These trials will help to evaluate the safety and efficacy of vadadustat for management of anemia associated with NDD-CKD.

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome.

INTRODUCTION: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. METHODS: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. RESULTS: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/CONCLUSION: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

A Randomized Trial Comparing the Safety, Adherence, and Pharmacodynamics Profiles of Two Doses of Sodium Bicarbonate in CKD: the BASE Pilot Trial.

BACKGROUND: Oral sodium bicarbonate (NaHCO3) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown. METHODS: This multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO3 over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m2 with urinary albumin/creatinine (ACR) ≥50 mg/g and serum bicarbonate 20-28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO3; 0.8 meq/kg of lean body wt per day; n=90) or lower-dose (LD-NaHCO3; 0.5 meq/kg of lean body wt per day; n=52) NaHCO3 or matching placebo (n=52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if ≥67% of participants were on full-dose and ≥80% were on ≥25% of the per-protocol dose. RESULTS: Mean±SD baseline eGFR was 36±9 ml/min per 1.73 m2, serum bicarbonate was 24±2 meq/L, and median (IQR) ACR was 181 (25-745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO3, 96% in LD-NaHCO3, and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO3, 98% in LD-NaHCO3, and 92% in placebo were on ≥25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO3 compared with LD-NaHCO3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group. CONCLUSIONS: Both NaHCO3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO3 may be a reasonable choice for future trials.

A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD).

BACKGROUND: Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain. METHODS: To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism. RESULTS: A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings. CONCLUSIONS: In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Australian Clinical Trials Registry, ACTRN12610000650099.

Understanding the role of the cytoprotective transcription factor nuclear factor erythroid 2-related factor 2-lessons from evolution, the animal kingdom and rare progeroid syndromes.

The cytoprotective transcriptor factor nuclear factor erythroid 2- related factor 2 (NRF2) is part of a complex regulatory network that responds to environmental cues. To better understand its role in a cluster of inflammatory and pro-oxidative burden of lifestyle diseases that accumulate with age, lessons can be learned from evolution, the animal kingdom and progeroid syndromes. When levels of oxygen increased in the atmosphere, mammals required ways to protect themselves from the metabolic toxicity that arose from the production of reactive oxygen species. The evolutionary origin of the NRF2-Kelch-like ECH-associated protein 1 (KEAP1) signalling pathway from primitive origins has been a prerequisite for a successful life on earth, with checkpoints in antioxidant gene expression, inflammation, detoxification and protein homoeostasis. Examples from the animal kingdom suggest that superior antioxidant defense mechanisms with enhanced NRF2 expression have been developed during evolution to protect animals during extreme environmental conditions, such as deep sea diving, hibernation and habitual hypoxia. The NRF2-KEAP1 signalling pathway is repressed in progeroid (accelerated ageing) syndromes and a cluster of burden of lifestyle disorders that accumulate with age. Compelling links exist between tissue hypoxia, senescence and a repressed NRF2 system. Effects of interventions that activate NRF2, including nutrients, and more potent (semi)synthetic NRF2 agonists on clinical outcomes are of major interest. Given the broad-ranging actions of NRF2, we need to better understand the mechanisms of activation, biological function and regulation of NRF2 and its inhibitor, KEAP1, in different clinical conditions to ensure that modulation of this thiol-based system will not result in major adverse effects. Lessons from evolution, the animal kingdom and conditions of accelerated ageing clarify a major role of a controlled NRF2-KEAP1 system in healthy ageing and well-being.

Differential effects of phosphate binders on vitamin D metabolism in chronic kidney disease.

BACKGROUND: Phosphate binders are commonly used in the treatment of patients with hyperphosphatemia. While phosphate binders are used to lower phosphate, the effects of specific phosphate binder types on vitamin D metabolism are unknown. METHODS: We performed a secondary analysis of the Phosphate Normalization Trial in which patients with moderate to advanced chronic kidney disease were randomized to receive either placebo, sevelamer carbonate, lanthanum carbonate or calcium acetate for 9 months. We evaluated changes in serum concentrations of vitamin D metabolites including 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the ratio of 24,25(OH)2D3 to 25-hydroxyvitamin D [the vitamin D metabolite ratio (VMR)] and the ratio of serum 1,25(OH)2D to 25-hydroxyvitamin D. RESULTS: Compared with placebo, randomization to the calcium acetate arm was associated with a 0.6 ng/mL (95% CI 0.2, 1) and 13.5 pg/ng (95% CI 5.5, 21.5) increase in 24,25(OH)2D and VMR, respectively, and a 5.2 pg/mL (95% CI 1.1, 9.4) reduction in 1,25(OH)2D. Randomization to sevelamer carbonate was associated with a 0.5 ng/mL (95% CI -0.9, -0.1) and 11.8 pg/ng (95% CI -20, -3.5) reduction in 24,25(OH)2D3 and VMR, respectively. There was no association of the sevelamer arm with the change in 1,25(OH)2D3, and randomization to lanthanum carbonate was not associated with a change in any of the vitamin D metabolites. CONCLUSION: Administration of different phosphate binders to patients with moderate to severe CKD results in unique changes in vitamin D metabolism.

One-year safety and efficacy of intravenous etelcalcetide in patients on hemodialysis with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (sHPT), a common complication of chronic kidney disease, is characterized by elevated serum parathyroid hormone (PTH). Etelcalcetide is an intravenous calcimimetic that increases sensitivity of the calcium-sensing receptor to calcium and decreases PTH secretion. This open-label extension (OLE) trial evaluated the long-term effects of etelcalcetide for sHPT treatment in patients receiving hemodialysis. METHODS: This 52-week, multicenter, single-arm OLE enrolled patients from three parent trials: two randomized, double-blind, placebo-controlled trials and one open-label, single-arm, 'switch' study from cinacalcet to etelcalcetide. The primary endpoint was to investigate the nature, frequency, severity and relation to treatment of all adverse events (AEs) reported throughout the trial. Secondary endpoints included the proportion of patients with >30% reduction from baseline in PTH and the percentage change from baseline in PTH, albumin-corrected calcium (Ca), phosphate (P) and the calcium-phosphate product (Ca × P).ClinicalTrials.gov identifier: NCT01785875; Amgen study: 20120231. RESULTS: Overall, 89.8% of the patients experienced one or more treatment-emergent AE. The most common were decreased blood Ca (43.3%), diarrhea (10.8%), vomiting (10.4%) and nausea (9.6%); symptomatic hypocalcemia occurred in 3.7% of the patients. Approximately 68% of patients achieved >30% reduction in PTH, and ∼56% achieved PTH ≤300 pg/mL. Mean percent changes from baseline ranged from -25.4% to -26.1% for PTH, -8.3% to -9.1% for Ca, -3.6% to -4.1% for P and -12.0% to -12.6% for Ca × P. CONCLUSIONS: Etelcalcetide effectively lowered PTH and its effect was sustained, while no new safety concerns emerged over a 1-year treatment period.

Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial.

BACKGROUND: Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport. METHODS: In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group. RESULTS: Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action. CONCLUSIONS: Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.

A Pilot Randomized Trial of Ferric Citrate Coordination Complex for the Treatment of Advanced CKD.

BACKGROUND: Researchers have yet to determine the optimal care of patients with advanced CKD. Evidence suggests that anemia and CKD-related disordered mineral metabolism (including abnormalities in phosphate and fibroblast growth factor 23 [FGF23]) contribute to adverse outcomes in this population. METHODS: To investigate whether fixed-dose ferric citrate coordination complex favorably affects multiple biochemical parameters in patients with advanced CKD, we randomly assigned 203 patients with eGFR≤20 ml/min per 1.73 m2 2:1 to receive a fixed dose of ferric citrate coordination complex (two tablets per meal, 210 mg ferric iron per tablet) or usual care for 9 months or until 3 months after starting dialysis. No single biochemical end point was designated as primary; sample size was determined empirically. RESULTS: The two groups had generally similar baseline characteristics, although diabetes and peripheral vascular disease were more common in the usual-care group. Ferric citrate coordination complex significantly increased hemoglobin, transferrin saturation, and serum ferritin, and it significantly reduced serum phosphate and intact FGF23 (P<0.001 for all). Of the 133 patients randomized to ferric citrate coordination complex, 31 (23%) initiated dialysis during the study period, as did 32 of 66 (48%) patients randomized to usual care (P=0.001). Compared with usual care, ferric citrate coordination complex treatment resulted in significantly fewer annualized hospital admissions, fewer days in hospital, and a lower incidence of the composite end point of death, provision of dialysis, or transplantation (P=0.002). CONCLUSIONS: The beneficial effects of fixed-dose ferric citrate coordination complex on biochemical parameters, as well as the exploratory results regarding the composite end point and hospitalization, suggest that fixed-dose ferric citrate coordination complex has an excellent safety profile in an unselected population with advanced CKD and merits further study.

Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial.

BACKGROUND: Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. METHODS: To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. RESULTS: Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. CONCLUSIONS: LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.

Effect of bardoxolone methyl on the urine albumin-to-creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease.

Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor κB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: -0.035 [95% confidence interval -0.031 to -0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

Serum Calcification Propensity and Coronary Artery Calcification Among Patients With CKD: The CRIC (Chronic Renal Insufficiency Cohort) Study.

RATIONALE & OBJECTIVE: Coronary artery calcification (CAC) is prevalent among patients with chronic kidney disease (CKD) and increases risks for cardiovascular disease events and mortality. We hypothesized that a novel serum measure of calcification propensity is associated with CAC among patients with CKD stages 2 to 4. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Participants from the Chronic Renal Insufficiency Cohort (CRIC) Study with baseline (n=1,274) and follow-up (n=780) CAC measurements. PREDICTORS: Calcification propensity, quantified as transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. Covariates included age, sex, race/ethnicity, clinical site, estimated glomerular filtration rate, proteinuria, diabetes, systolic blood pressure, number of antihypertensive medications, current smoking, history of cardiovascular disease, total cholesterol level, and use of statin medications. OUTCOMES: CAC prevalence, severity, incidence, and progression. ANALYTICAL APPROACH: Multivariable-adjusted generalized linear models. RESULTS: At baseline, 824 (65%) participants had prevalent CAC. After multivariable adjustment, T50 was not associated with CAC prevalence but was significantly associated with greater CAC severity among participants with prevalent CAC: 1-SD lower T50 was associated with 21% (95% CI, 6%-38%) greater CAC severity. Among 780 participants followed up an average of 3 years later, 65 (20%) without baseline CAC developed incident CAC, while 89 (19%) with baseline CAC had progression, defined as annual increase≥100 Agatston units. After multivariable adjustment, T50 was not associated with incident CAC but was significantly associated with CAC progression: 1-SD lower T50 was associated with 28% (95% CI, 7%-53%) higher risk for CAC progression. LIMITATIONS: Potential selection bias in follow-up analyses; inability to distinguish intimal from medial calcification. CONCLUSIONS: Among patients with CKD stages 2 to 4, higher serum calcification propensity is associated with more severe CAC and CAC progression.

The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia.

Background: Elevated serum fibroblast growth factor 23 (FGF23) is strongly associated with cardiovascular risk and mortality. Tenapanor, an inhibitor of gastrointestinal sodium/hydrogen exchanger isoform 3, decreased serum phosphate in a randomized, double-blind, placebo-controlled Phase 2 trial (ClinicalTrials.gov identifier NCT02081534) of patients receiving hemodialysis with hyperphosphatemia. Here, we report a secondary analysis of effects on serum FGF23 during that study. Methods: After 1-3 weeks of washout of phosphate binders, 162 patients were randomized to receive 4 weeks of treatment with placebo or one of six tenapanor regimens (3 or 30 mg once daily, or 1, 3, 10 or 30 mg twice daily). Intact FGF23 concentrations were determined from serum samples collected at screening, post-washout and end of treatment, assayed in duplicate in a single batch at the end of the study. Results: After phosphate-binder washout, serum FGF23 concentrations increased in all groups [range of geometric means: 1430-2605 pg/mL before, to 2601-6294 pg/mL after washout (P < 0.001 for all patients analyzed as a single group)]. Serum FGF23 concentrations subsequently decreased in tenapanor-treated patients (2030-3563 pg/mL), whereas they increased further in placebo-treated patients (6930 pg/mL). In an analysis of covariance, FGF23 decreased by 9.1-27.9% in tenapanor-treated patients and increased by 21.9% in placebo-treated patients (P ≤ 0.001-0.04). Conclusions: Following a marked increase in serum FGF23 in response to withdrawal of phosphate binders, tenapanor significantly decreased serum FGF23 in patients receiving hemodialysis with hyperphosphatemia. Further studies are required to explore the long-term effects of controlling FGF23 with tenapanor.