Search

BACKGROUND: Secondary hyperparathyroidism is observed in patients with early chronic kidney disease (CKD). This study investigated the safety and efficacy of cinacalcet for secondary hyperparathyroidism in participants with CKD not receiving dialysis. STUDY DESIGN: Double-blind, randomized, 32-week, phase 3 study. SETTING & PARTICIPANTS: 404 participants with stage 3 or 4 CKD from 73 centers in 9 countries. INTERVENTIONS: Cinacalcet:placebo (3:1 ratio). OUTCOMES & MEASUREMENTS: Proportion of participants with a mean decrease of 30% or greater in intact parathyroid hormone (iPTH) level, proportion with iPTH level of 70 or less or 110 or less pg/mL (stage 3 and 4 CKD, respectively), and mean percentage of iPTH change from baseline, all during the efficacy-assessment phase. RESULTS: A greater proportion of cinacalcet than placebo participants achieved a 30% or greater decrease in iPTH level (74% versus 28%; P < 0.001), corresponding to a 43.1% decrease in iPTH level from baseline (cinacalcet) compared with a 1.1% increase (placebo). At week 32, serum calcium levels were 8.9 +/- 0.8 mg/dL (-8.9%; cinacalcet) and 9.9 +/- 0.6 mg/dL (+0.8%; placebo), phosphorus levels were 4.5 +/- 1.0 mg/dL (+21.4%) and 4.0 +/- 0.7 mg/dL (+6.8%), and calcium-phosphorus product values were 40.1 +/- 8.3 mg(2)/dL(2) (+18.9%) and 38.9 +/- 6.9 mg(2)/dL(2) (+17.1%), respectively. During the study course, 62% (cinacalcet) and 1% (placebo) of participants experienced 2 consecutive serum calcium concentrations less than 8.4 mg/dL. They generally were asymptomatic and without significant clinical consequences. Treatment generally was well tolerated, and most adverse events were mild to moderate in severity. LIMITATIONS: The study was not designed to assess the effects of cinacalcet on vascular calcification, bone histomorphometric parameters, or other clinical outcomes. It is not known whether the observed differences in changes in iPTH levels are clinically more important than observed differences in changes in serum calcium or phosphorus levels or dosages of vitamin D sterols and phosphate binders. CONCLUSIONS: These data show that cinacalcet treatment in patients with CKD not receiving dialysis can decrease plasma iPTH levels, but with frequent (albeit generally asymptomatic) serum calcium levels less than 8.4 mg/dL and increases in serum phosphorus levels. Copyright © 2009 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Importance: Integrating routine SARS-CoV-2 testing in dialysis facilities may benefit patients receiving dialysis by mitigating risks of serious illness and reducing transmission. Patient acceptance of nonmandatory testing is unknown., Objective: To evaluate the acceptance of 2 SARS-CoV-2 testing strategies among patients in hemodialysis facilities nationwide., Design, Setting, and Participants: This nationwide cluster (dialysis facility-level) randomized trial investigated the acceptance of SARS-CoV-2 testing among patients receiving maintenance hemodialysis at facilities located in 22 states., Intervention: Anterior nares real-time reverse transcriptase-polymerase chain reaction tests offered once every 2 weeks (static testing facilities) vs offered once a week, once every 2 weeks, or once a month depending on county COVID-19 infection prevalence (dynamic testing facilities). Facilities were randomized by county, and tests were offered for 3 months between February 4 and July 24, 2023., Main Outcomes and Measures: The primary outcome was test acceptance. Secondary outcomes included the proportion of patients who accepted at least 1 test., Results: In total, 62 hemodialysis facilities were randomized and 57 participated. Among 2389 participating patients, the median age was 64 (IQR, 54-74) years, 1341 (56%) were male, 138 (6%) were categorized as American Indian, 60 (3%) Asian, 885 (37%) Black, 75 (3%) Native Hawaiian or Pacific Islander, 338 (14%) Hispanic, and 876 (37%) White; and 1603 (67%) had diabetes. A median of 6 (IQR, 6-6) tests were offered per patient in the static arm and 4 (3-6) tests in the dynamic arm. Test acceptance was low: 8% of offered tests were accepted in each of the test arms. Among 503 patients who accepted at least 1 test, the median percentage of offered tests that were accepted was 16% (IQR, 17%-42%) using the static testing strategy and 50% (IQR, 33%-75%) using the dynamic testing strategy (P < .001). Older patients (odds ratio [OR], 1.08 [95% CI, 1.01-1.16] per 5-year age increment), patients with (vs without) diabetes (OR, 1.59 [95% CI, 1.18-2.16]), and women compared with men (OR, 1.30 [95% CI, 0.98-1.73]) were more likely to accept multiple tests. Patients designated in the electronic health record as Hispanic were more likely than patients designated as White (OR, 1.78 [95% CI, 1.15-2.76]) to accept at least 1 test, whereas patients living in zip codes electing Republican representatives to Congress were less likely than patients living in zip codes electing Democratic representatives (OR, 0.34 [95% CI, 0.17-0.69]) to accept multiple tests., Conclusions and Relevance: In this cluster randomized trial evaluating 2 SARS-CoV-2 testing strategies in dialysis facilities, test acceptance was low, and a dynamic testing strategy anchored to COVID-19 infection prevalence did not outperform a static testing strategy of every 2 weeks., Trial Registration: ClinicalTrials.gov Identifier: NCT05225298.

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., (© 2024 S. Karger AG, Basel.)

Importance: Widespread use of at-home COVID-19 tests hampers determination of community COVID-19 incidence., Objective: To examine the association of county-level wastewater metrics with high case and hospitalization rates nationwide both before and after widespread use of at-home tests., Design, Setting, and Participants: This observational cohort study with a time series analysis was conducted from January to September 2022 in 268 US counties in 22 states participating in the US Centers for Disease Control and Prevention's National Wastewater Surveillance System. Participants included the populations of those US counties., Exposures: County level of circulating SARS-CoV-2 as determined by metrics based on viral wastewater concentration relative to the county maximum (ie, wastewater percentile) and 15-day percentage change in SARS-CoV-2 (ie, percentage change)., Main Outcomes and Measures: High county incidence of COVID-19 as evidenced by dichotomized reported cases (current cases ≥200 per 100 000 population) and hospitalization (≥10 per 100 000 population lagged by 2 weeks) rates, stratified by calendar quarter., Results: In the first quarter of 2022, use of the wastewater percentile detected high reported case (area under the curve [AUC], 0.95; 95% CI, 0.94-0.96) and hospitalization (AUC, 0.86; 95% CI, 0.84-0.88) rates. The percentage change metric performed poorly, with AUCs ranging from 0.51 (95% CI, 0.50-0.53) to 0.57 (95% CI, 0.55-0.59) for reported new cases, and from 0.50 (95% CI, 0.48-0.52) to 0.55 (95% CI, 0.53-0.57) for hospitalizations across the first 3 quarters of 2022. The Youden index for detecting high case rates was wastewater percentile of 51% (sensitivity, 0.82; 95% CI, 0.80-0.84; specificity, 0.93; 95% CI, 0.92-0.95). A model inclusive of both metrics performed no better than using wastewater percentile alone. The performance of wastewater percentile declined over time for cases in the second quarter (AUC, 0.84; 95% CI, 0.82-0.86) and third quarter (AUC, 0.72; 95% CI, 0.70-0.75) of 2022., Conclusions and Relevance: In this study, nationwide, county wastewater levels relative to the county maximum were associated with high COVID-19 case and hospitalization rates in the first quarter of 2022, but there was increasing dissociation between wastewater and clinical metrics in subsequent quarters, which may reflect increasing underreporting of cases, reduced testing, and possibly lower virulence of infection due to vaccines and treatments. This study offers a strategy to operationalize county wastewater percentile to improve the accurate assessment of community SARS-CoV-2 infection prevalence when reliability of conventional surveillance data is declining.

Background and Objectives: Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome., Design, Setting, Participants, & Measurements: We randomly assigned patients with Alport syndrome, ages 12-70 years and eGFR 30-90 ml/min per 1.73 m 2 , to bardoxolone methyl ( n =77) or placebo ( n =80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight., Results: Patients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4; P <0.001] and 7.4 [95% confidence interval, 3.1 to 11.7; P =0.0008] ml/min per 1.73 m 2 , respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1; P <0.001) and 4.4 (95% confidence interval, 0.7 to 8.1; P =0.02) ml/min per 1.73 m 2 at 52 and 104 weeks, respectively. In a post hoc analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 [95% confidence interval, -1.9 to 4.9] ml/min per 1.73 m 2 ). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure., Conclusions: In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different., Clinical Trial Registry Name and Registration Number: A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185., (Copyright © 2022 by the American Society of Nephrology.)

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., (Copyright © 2022 by the American Society of Nephrology.)

Background: Despite increasing recognition that CKD may have underlyi ng genetic causes, genetic testing remains limited. This study evaluated the diagnostic yield and phenotypic spectrum of CKD in individuals tested through the KIDNEYCODE sponsored genetic testing program., Methods: Unrelated individuals who received panel testing (17 genes) through the KIDNEYCODE sponsored genetic testing program were included. Individuals had to meet at least one of the following eligibility criteria: eGFR ≤90 ml/min per 1.73m 2 and hematuria or a family history of kidney disease; or suspected/biopsy-confirmed Alport syndrome or FSGS in tested individuals or relatives., Results: Among 859 individuals, 234 (27%) had molecular diagnoses in genes associated with Alport syndrome ( n =209), FSGS ( n =12), polycystic kidney disease ( n =6), and other disorders ( n =8). Among those with positive findings in a COL4A gene, the majority were in COL4A5 ( n =157, 72 hemizygous male and 85 heterozygous female individuals). A positive family history of CKD, regardless of whether clinical features were reported, was more predictive of a positive finding than was the presence of clinical features alone. For the 248 individuals who had kidney biopsies, a molecular diagnosis was returned for 49 individuals (20%). Most ( n =41) individuals had a molecular diagnosis in a COL4A gene, 25 of whom had a previous Alport syndrome clinical diagnosis, and the remaining 16 had previous clinical diagnoses including FSGS ( n =2), thin basement membrane disease ( n =9), and hematuria ( n =1). In total, 491 individuals had a previous clinical diagnosis, 148 (30%) of whom received a molecular diagnosis, the majority (89%, n =131) of which were concordant., Conclusions: Although skewed to identify individuals with Alport syndrome, these findings support the need to improve access to genetic testing for patients with CKD-particularly in the context of family history of kidney disease, hematuria, and hearing loss., Competing Interests: A.R. Chang reports being a scientific advisor to, and receiving an honorarium from, Reata Pharmaceuticals, Inc. A. Mitchell, A. Morales, B.A. Johnson, K. Robinson, S.L. Bristow, and S. Aradhya report being employed by and being shareholders in Invitae. B.A. Warady reports being an advisor to, and receiving honoraria from, Reata Pharmaceuticals, Inc. G.A. Block reports being a former employee of Reata Pharmaceuticals, Inc., and reports being employed by US Renal Care. J.A. McKay and S. McCalley report being employees of Reata Pharmaceuticals, Inc. K. Gibson reports serving as a consultant for and receiving research support from Aurinia and Travere, Inc. (formerly Retrophin, Inc.); and reports serving as a consultant for Reata Pharmaceuticals, Inc. K.V. Lieberman reports receiving honoraria from Reata Pharmaceuticals, Inc. P. Devrajan reports being an advisor to Alnylam Pharmaceuticals, Inc., BioPorto Diagnostics, Inc., Dicerna Pharmaceuticals, Inc., Natera, Inc., Reata Pharmaceuticals, Inc., and UpToDate, Inc.; and reports receiving research support from the National Institutes of Health (P50DK096418). KIDNEYCODE was offered through a sponsored genetic program by Reata Pharmaceuticals and Invitae., (Copyright © 2022 by the American Society of Nephrology.)

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.

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., (Copyright © 2022 by the American Society of Nephrology.)

Background: Individuals with CKD have a high burden of cardiovascular disease (CVD). Abnormalities in cardiac structure and function represent subclinical CVD and can be assessed by cardiac magnetic resonance imaging (cMRI)., Methods: We investigated differences in cMRI parameters in 140 individuals with CKD stages 3b-4 who participated in the CKD Optimal Management with BInders and NicotinamidE (COMBINE) trial and in 24 age- and sex-matched healthy volunteers. Among COMBINE participants, we examined the associations of eGFR, urine albumin-creatinine ratio (UACR), phosphate, fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH) with baseline ( N =140) and 12-month change ( N =112) in cMRI parameters., Results: Mean (SD) ages of the COMBINE participants and healthy volunteers were 64.9 (11.9) and 60.4 (7.3) years, respectively. The mean (SD) baseline eGFR values in COMBINE participants were 32.1 (8.0) and 85.9 (16.0) ml/min per 1.73 m 2 in healthy volunteers. The median (interquartile range [IQR]) UACR in COMBINE participants was 154 (20.3-540.0) mg/g. Individuals with CKD had lower mitral valve E/A ratio compared with healthy volunteers (for CKD versus non-CKD, β estimate, -0.13; 95% CI, -0.24 to -0.012). Among COMBINE participants, multivariable linear regression analyses showed that higher UACR was significantly associated with lower mitral valve E/A ratio ( β estimate per 1 unit increase in natural-log UACR, -0.06; 95% CI, -0.09 to -0.03). This finding was preserved among individuals without baseline CVD. UACR was not associated with 12-month change in any cMRI parameter. eGFR, phosphate, FGF23, and PTH were not associated with any cMRI parameter in cross-sectional or change analyses., Conclusions: Individuals with CKD stages 3b-4 have evidence of cMRI abnormalities. Albuminuria was independently associated with diastolic dysfunction, as assessed by mitral valve E/A ratio, in individuals with CKD with and without clinical CVD. Albuminuria was not associated with change in any cMRI parameter., Competing Interests: G.A. Block reports receiving research funding from Akebia, Ardelyx, and GlaxoSmithKline; having consultancy agreements with Akebia, Keryx, Kirin, and Reata; receiving honoraria from Amgen and Kirin; serving as a scientific advisor for or member of Ardelyx, CJASN, Kirin, and Reata; having ownership interest in Ardelyx and Reata; and having other interests in/relationships with DaVita (previously medical director), Kidney Disease Improving Global Outcomes (previously on Executive Commitee), and Reata (previous employment). J. Carr reports serving on a speakers bureau for Bayer; receiving honoraria from Bayer, Bracco, and Guerbet; having consultancy agreements with Bayer, Bracco, and Siemens; receiving research funding from Bayer, Guerbet, and Siemens; and serving as a scientific advisor for or member of the Society for Cardiovascular MRI. A.K. Cheung reports having consultancy agreements with, and receiving honoraria from, Boehringer Ingelheim, Calliditas, and UptoDate; serving as a scientific advisor for or member of Hong Kong Journal of Nephrology, JASN, and Kidney Diseases; having other interests in/relationships with KDIGO; and having ownership interest in Merck. M. Chonchol reports having consultancy agreements with Amgen, Corvidia, Otsuka, Reata, Tricidia, and Vifor; receiving honoraria from Amgen, Corvidia, Reata, Tricidia, and Vifor; serving as a scientific advisor for or member of the CJASN editorial board; and receiving research funding from the Corvidia, National Institutes of Health (NIH), Otsuka, Reata, and Sanofi. L.F. Fried reports having consultancy agreements with Bayer, and serving on data safety monitoring boards for CSL Behring and Novo Nordisk. J.J. Gassman reports having consultancy agreements with, and receiving honoraria from, the Baim Institute (Harvard Clinical Research Institute). T. Isakova reports having consultancy agreements with, and receiving honoraria from, Akebia Therapeutics Inc.; and serving as an associate editor of American Journal of Kidney Diseases. J.H. Ix reports serving as a scientific advisor for or member of AlphaYoung; having consultancy agreements with Ardelyx, AstraZeneca, Bayer, Jnana, and Sanifit; and receiving research funding from Baxter International. R. Mehta reports having ownership interest in AbbVie Inc.; having consultancy agreements with, and receiving honoraria from, Akebia/Otsuka and AstraZeneca; and serving on the editorial board of the Journal of Cardiac Failure. J.P. Middleton reports serving on the editorial board for Advances in Chronic Kidney Disease and on a data safety monitoring board for the NIDDK; having consultancy agreements with AstraZeneca and Vifor/Relypsa; receiving research funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Vifor/Relypsa; having other interests in/relationships with Raleigh Radiology (via spouse); and receiving honoraria from Relypsa/Vifor. D.S. Raj reports having other interests in/relationships with the American Association of Kidney Patients; serving as a scientific advisor for or member of the National Heart, Lung, and Blood Institute (NHLBI), NIDDK, and Novo Nordisk; receiving research funding from NIH; and having consultancy agreements with, and receiving honoraria from, Novo Nordisk. K.L. Raphael reports having consultancy agreements with AstraZeneca. S.M. Sprague reports serving as a scientific advisor for or member of the American Association of Endocrine Surgeons American Journal of Nephrology, International Federation of Clinical Chemistry and Laboratory Medicine Work Group for Parathyroid Hormone, and National Kidney Foundation of Illinois; having consultancy agreements with Amgen, Ardelyx, Fresenius, Horizon, Litholink Corp., OPKO, Shire, and Vifor; receiving research funding from Amgen, Ardelyx, OPKO, and Reata; receiving honoraria from Amgen, Ardelyx, Fresenius, Horizon, OPKO, and Vifor; serving on speakers bureaus for Amgen, Fresenius, Horizon, and OPKO; and having ownership interest via individually owned stocks in Apple, Bristol Myers, Coca Cola, First Australia Fund, IBM, Paycheck, US Concrete, and Walgreens. A. Srivastava reports serving on a speaker’s bureau for AstraZeneca; receiving honoraria from AstraZeneca, Bayer, and Horizon Therapeutics PLC; and having consultancy agreements with CVS Caremark and Tate & Latham (medicolegal consulting). M. Wolf reports having consultancy agreements with, and receiving honoraria from, Akebia, Amgen, Ardelyx, AstraZeneca, Bayer, Pharmacosmos, Unicycive, and Walden; and having ownership interest in, and serving as a scientific advisor for or member of, Akebia, Unicycive, and Walden. All remaining authors have nothing to disclose.All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Background: Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia., Methods: In this 52-week phase 3 study (NCT03427125), participants receiving maintenance dialysis with both hyperphosphatemia (serum phosphate 6.0-10.0 mg/dl) and a 1.5 mg/dl increase after phosphate binder washout were randomized (3:1) to tenapanor 30 mg twice daily for 26 weeks (randomized treatment period) or sevelamer carbonate (52-week safety control). Participants completing 26 weeks of treatment with tenapanor were rerandomized (1:1) to tenapanor or placebo for 12 weeks (randomized withdrawal period), and were eligible to enter the 14-week safety extension period. With input from the US Food and Drug Administration, the primary efficacy end point was the difference in the change in serum phosphate from the end of the randomized treatment period to the end of the randomized withdrawal period, among participants who achieved ≥1.2 mg/dl decrease in serum phosphate during the randomized treatment period (efficacy analysis set). Efficacy was also evaluated in the intention-to-treat (ITT) analysis set., Results: Of 564 eligible participants randomized to receive tenapanor ( n =423) or sevelamer carbonate ( n =141) during the randomized treatment period, 255 (60%) in the tenapanor group subsequently were rerandomized to tenapanor ( n =128) or placebo ( n =127) during the randomized withdrawal period. In the efficacy analysis set ( n =131), the difference in estimated mean change in serum phosphate level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was -1.4 mg/dl ( P <0.0001); in the ITT analysis set ( n =243), the estimated mean difference was -0.7 mg/dl ( P =0.002). Loosened stools were the most frequently reported adverse event (53% during the randomized treatment period). Serious adverse events were reported more frequently for participants treated with sevelamer carbonate (16%-23% across the three study periods) compared with tenapanor (11%-17%)., Conclusions: Tenapanor reduced serum phosphate concentrations and maintained control of serum phosphate in participants receiving maintenance dialysis, with an acceptable safety and tolerability profile., Competing Interests: A.J. Bleyer reports no affiliation with Ardelyx, Inc. aside from his role as Principal Investigator in the PHREEDOM study. A.L. Silva reports receiving research funding from Ardelyx, Inc. D.E. Weiner reports being the Medical Director of Clinical Research for Dialysis Clinic, Inc., with support paid to his institution by Dialysis Clinic, Inc.; he reports consulting for Akebia, Cara Therapeutics, Janssen Biopharmaceuticals, and Tricida, and has no affiliation with or received funding from Ardelyx, Inc., aside from his role as site Principal Investigator in several tenapanor trials. D.P. Rosenbaum reports being an employee of, and having an ownership interest in, Ardelyx, Inc. G.A. Block reports being a Director for Ardelyx, Inc. and is the Associate Chief Medical Officer for US Renal Care, Inc. G.M. Chertow reports being a consultant to, and has equity ownership interest in, Ardelyx, Inc. R.I. Lynn has no affiliation with Ardelyx, Inc. aside from his role as Principal Investigator in the PHREEDOM and NORMALIZE studies. Y. Yang reports being an employee of Ardelyx, Inc., (Copyright © 2021 by the American Society of Nephrology.)

Importance: Seroprevalence studies complement data on detected cases and attributed deaths in assessing the cumulative spread of the SARS-CoV-2 virus., Objective: To estimate seroprevalence of SARS-CoV-2 antibodies in patients receiving dialysis and adults in the US in January 2021 before the widespread introduction of COVID-19 vaccines., Design, Setting, and Participants: This cross-sectional study used data from the third largest US dialysis organization (US Renal Care), which has facilities located nationwide, to estimate SARS-CoV-2 seroprevalence among US patients receiving dialysis. Remainder plasma (ie, plasma that would have otherwise been discarded) of all patients receiving dialysis at US Renal Care facilities from January 1 to 31, 2021, was tested for SARS-CoV-2 antibodies. Patients were excluded if they had a documented dose of SARS-CoV-2 vaccination or if a residence zip code was missing from electronic medical records. Crude seroprevalence estimates from this sample (January 2021) were standardized to the US adult population using the 2018 American Community Survey 1-year estimates and stratified by age group, sex, self-reported race/ethnicity, neighborhood race/ethnicity composition, neighborhood income level, and urban or rural status. These data and case detection rates were then compared with data from a July 2020 subsample of patients who received dialysis at the same facilities., Exposures: Age, sex, race/ethnicity, and region of residence as well as neighborhood race/ethnicity composition, poverty, population density, and urban or rural status., Main Outcomes and Measures: The spike protein receptor-binding domain total antibody assay (Siemens Healthineers; manufacturer-reported sensitivity of 100% and specificity of 99.8%) was used to estimate crude SARS-CoV-2 seroprevalence in the unweighted sample, and then the estimated seroprevalence rates for the US dialysis and adult populations were calculated, adjusting for age, sex, and region., Results: A total of 21 464 patients (mean [SD] age, 63.1 [14.2] years; 12 265 men [57%]) were included in the unweighted sample from January 2021. The patients were disproportionately older (aged 65-79 years, 7847 [37%]; aged ≥80 years, 2668 [12%]) and members of racial/ethnic minority groups (Hispanic patients, 2945 [18%]; non-Hispanic Black patients, 4875 [29%]). Seroprevalence of SARS-CoV-2 antibodies was 18.9% (95% CI, 18.3%-19.5%) in the sample, with a seroprevalence of 18.7% (95% CI, 18.1%-19.2%) standardized to the US dialysis population, and 21.3% (95% CI, 20.3%-22.3%) standardized to the US adult population. In the unweighted sample, younger persons (aged 18-44 years, 25.9%; 95% CI, 24.1%-27.8%), those who self-identified as Hispanic or living in Hispanic neighborhoods (25.1%; 95% CI, 23.6%-26.4%), and those living in the lowest-income neighborhoods (24.8%; 95% CI, 23.2%-26.5%) were among the subgroups with the highest seroprevalence. Little variability was observed in seroprevalence by geographic region, population density, and urban or rural status in the January 2021 sample (largest regional difference, 1.2 [95% CI, 1.1-1.3] higher odds of seroprevalence in residents of the Northeast vs West)., Conclusions and Relevance: In this cross-sectional study of patients receiving dialysis in the US, fewer than 1 in 4 patients had evidence of SARS-CoV-2 antibodies 1 year after the first case of SARS-CoV-2 infection was detected in the US. Results standardized to the US population indicate similar prevalence of antibodies among US adults. Vaccine introduction to younger individuals, those living in neighborhoods with a large population of racial/ethnic minority residents, and those living in low-income neighborhoods may be critical to disrupting the spread of infection.

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&#95;07&#95;07&#95;JASN2021010104.mp3., (Copyright © 2021 by the American Society of Nephrology.)

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 PRO 2 TECT 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., Competing Interests: Disclosures GMC reports grants from NIDDK and Amgen and personal fees from Akebia Therapeutics, Inc., Satellite Healthcare, Ardelyx, AstraZeneca, Baxter, Cricket, DiaMedica, Gilead, Reata, Sanifit, Vertex, Angion, Bayer, and ReCor. PEP reports personal fees from Akebia Therapeutics, Inc., Astra-Zeneca, Bayer, Reata, Gilead, Corvidia, FibroGen, Tricida, and Ardelyx. PEP's institution, Renal Associates (PA), has received support from multiple pharmaceutical companies, including Akebia Therapeutics, Inc. RA reports personal fees from Akebia Therapeutics, Inc., Relypsa Inc., a Vifor Pharma Group Company, AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Sandoz, ZS Pharma, Takeda, Sanofi, Reata, Ironwood Pharmaceuticals, Otsuka, OPKO Health, and Bird Rock Bio. RA has also served as associate editor of the American Journal of Nephrology and Nephrology, Dialysis, Transplantation and has received research grants from the US Veterans Administration and the National Institutes of Health. GAB reports grants, personal fees, and nonfinancial support from Akebia Therapeutics, Inc., Keryx Biopharmaceuticals, Inc., Astra-Zeneca, Kirin, and Ardelyx, Inc., as well as personal fees from U.S. Renal Care. YMKF reports personal fees and other from Akebia Therapeutics, Inc. AGJ has nothing to disclose. MJK reports personal fees from Akebia Therapeutics, Inc., FibroGen, Inc., and Micelle BioPharma, Inc. WL was an employee of Akebia Therapeutics, Inc., during the conduct of this study. ZK was an employee of Akebia Therapeutics, Inc., during the conduct of this study. EFL reports grants from Akebia Therapeutics, Inc. KM reports grants from NIH and personal fees from Akebia Therapeutics, Inc.; KM also reports grants and personal fees from Kyowa Kirin and Fukuda Denshi. PAM reports personal fees from Akebia Therapeutics, Inc. PSP reports personal fees from Akebia Therapeutics, Inc.; PSP was also a member of an advisory committee for Vifor Pharma and was a member of the data monitoring committee for the CREDANCE trial for Janssen. JW and KAW are employees of Statistics Collaborative, Inc., which received fees from Akebia Therapeutics, Inc. for conduction of study analyses. CT and TL are employees of Firma Clinical Research, which received fees from Akebia Therapeutics, Inc. for data analyses. MJS was a member of the steering committee for Akebia Therapeutics, Inc.; MJS also reports personal fees from Bayer and Carurian. DLV is an employee of Akebia Therapeutics, Inc. WCW reports personal fees from Akebia Therapeutics, Inc., Amgen, and Relypsa. and personal fees and nonfinancial support from AstraZeneca, Bayer, Daiichi-Sankyo, Janssen, Merck, and Vifor Fresenius Medical Care Renal Pharma. KUE reports grants from Amgen, Astra Zeneca, Bayer, Fresenius, Genzyme, and Vifor and personal fees from Akebia Therapeutics, Inc., Bayer, and Boehringer Ingelheim., (Copyright © 2020. Published by Elsevier Inc.)

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; PRO 2 TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.)., (Copyright © 2021 Massachusetts Medical Society.)

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; INNO 2 VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.)., (Copyright © 2021 Massachusetts Medical Society.)

Introduction: High mortality rates in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) receiving maintenance hemodialysis are largely due to cardiovascular (CV) events., Methods: We evaluated associations between MBD parameters, fibroblast growth factor 23 (FGF23) concentrations, and clinically adjudicated CV events from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. Patients enrolled in EVOLVE, who had not experienced any study endpoints between randomization and week 20 with evaluable baseline and week 20 values for key laboratory parameters (parathyroid hormone, calcium, phosphate, and FGF23), were assessed. We used adjusted Cox proportional hazards regression models to estimate relative risk of outcomes (primary composite, all-cause mortality, and CV events) based on FGF23 and MBD parameters. Laboratory values were modeled with linear terms and using natural cubic splines with two degrees of freedom., Findings: For the primary endpoint, patients assessed (N = 2309) were followed up over a mean duration of 3.1 years, during which 1037 CV events (497 deaths, 540 nonfatal events) occurred. Adjusted models showed an association between FGF23 and the risk of CV events. Hazard ratio per log unit of FGF23 at week 20 was 1.09 [95% CI: 1.03-1.16], and the hazard ratio per log unit change in FGF23 from week 0 to week 20 was 1.09 [95% CI: 1.00-1.17]., Discussion: Our data highlight FGF23 as an independent CV risk factor and potential biomarker and therapeutic target for patients with CKD-MBD receiving maintenance hemodialysis., (© 2020 International Society for Hemodialysis.)

In a multinational placebo-controlled phase III clinical trial in 2,185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, treatment with the Nrf2 activator bardoxolone methyl increased estimated glomerular filtration rate, a measure of kidney function, but also resulted in increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase. These increases in liver enzyme level(s) were maximal after 4 weeks of treatment and reversible, trending back toward baseline through week 48. Total bilirubin concentrations did not increase, and no cases met Hy's Law criteria, although two subjects had ALT concentrations that exceeded 10 × the upper limit of the population reference range leading to discontinuation of treatment. Animal and cell culture experiments suggested that the increases in ALT and AST induced by bardoxolone methyl may be related to its pharmacological activity. Bardoxolone methyl significantly induced the mRNA expression of ALT and AST isoforms in cultured cells. Expression of ALT and AST isoforms in liver and kidney also positively correlated with Nrf2 status in mice. Overall, these data suggest that the increases in ALT and AST observed clinically were, at least in part, related to the pharmacological induction of aminotransferases via Nrf2 activation, rather than to any intrinsic form of hepatotoxicity., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

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., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

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 m 2 ; 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., (Copyright © 2020 by the American Society of Nephrology.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

Background and Objectives: Kidney functional magnetic resonance imaging (MRI) requires further investigation to enhance the noninvasive identification of patients at high risk of CKD progression., Design, Setting, Participants, & Measurements: In this exploratory study, we obtained baseline diffusion-weighted and blood oxygen level-dependent MRI in 122 participants of the CKD Optimal Management with Binders and Nicotinamide trial, which was a multicenter, randomized, double-blinded, 12-month, four-group parallel trial of nicotinamide and lanthanum carbonate versus placebo conducted in individuals with eGFR 20-45 ml/min per 1.73 m 2 . Lower values of apparent diffusion coefficient (ADC) on diffusion-weighted MRI may indicate increased fibrosis, and higher values of relaxation rate (R2*) on blood oxygen level-dependent MRI may represent decreased oxygenation. Because there was no effect of active treatment on eGFR over 12 months, we tested whether baseline kidney functional MRI biomarkers were associated with eGFR decline in all 122 participants. In a subset of 87 participants with 12-month follow-up MRI data, we evaluated whether kidney functional MRI biomarkers change over time., Results: Mean baseline eGFR was 32±9 ml/min per 1.73 m 2 , and mean annual eGFR slope was -2.3 (95% confidence interval [95% CI], -3.4 to -1.1) ml/min per 1.73 m 2 per year. After adjustment for baseline covariates, baseline ADC was associated with change in eGFR over time (difference in annual eGFR slope per 1 SD increase in ADC: 1.3 [95% CI, 0.1 to 2.5] ml/min per 1.73 m 2 per year, ADC×time interaction P =0.04). This association was no longer significant after further adjustment for albuminuria (difference in annual eGFR slope per 1 SD increase in ADC: 1.0 (95% CI, -0.1 to 2.2) ml/min per 1.73 m 2 per year, ADC×time interaction P =0.08). There was no significant association between baseline R2* and change in eGFR over time. In 87 participants with follow-up functional MRI, ADC and R2* values remained stable over 12 months (intraclass correlation: 0.71 and 0.68, respectively)., Conclusions: Baseline cortical ADC was associated with change in eGFR over time, but this association was not independent of albuminuria. Kidney functional MRI biomarkers remained stable over 1 year., Clinical Trial Registry Name and Registration Number: CKD Optimal Management with Binders and Nicotinamide (COMBINE), NCT02258074., (Copyright © 2020 by the American Society of Nephrology.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Oral sodium bicarbonate (NaHCO 3 ) 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 NaHCO 3 over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m 2 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-NaHCO 3 ; 0.8 meq/kg of lean body wt per day; n =90) or lower-dose (LD-NaHCO 3 ; 0.5 meq/kg of lean body wt per day; n =52) NaHCO 3 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 m 2 , 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-NaHCO 3 , 96% in LD-NaHCO 3 , and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO 3 , 98% in LD-NaHCO 3 , 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-NaHCO 3 compared with LD-NaHCO 3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group., Conclusions: Both NaHCO 3 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 NaHCO 3 may be a reasonable choice for future trials., (Copyright © 2020 by the American Society of Nephrology.)

Background: High serum phosphate (Pi) levels strongly associate with cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients with vascular calcification playing a major role in the pathogenesis of related cardiovascular disease. High-Pi challenged vascular smooth muscle cells (VSMCs) undergo simil-osteoblastic transformation and actively deposit calcium-phosphate crystals. Iron-based Pi-binders are used to treat hyperphosphatemia in CKD patients., Methods: In this study, we investigated the direct effect of iron citrate on extracellular matrix (ECM) modification induced by high-Pi, following either prophylactic or therapeutic approach., Results: Iron prophylactically prevents and therapeutically blocks high-Pi induced calcification. Masson's staining highlights the changes of muscular ECM that after high-Pi stimulation becomes fibrotic and which modifications are prevented or partially reverted by iron. Interestingly, iron preserves glycogen granules and either prevents or partially reverts the formation of non-glycogen granules induced by high-Pi. In parallel, iron addition is able to either prevent or block the high-Pi induced acid mucin deposition. Iron inhibited calcification also by preventing exosome osteo-chondrogenic shift by reducing phosphate load (0,61 ± 0.04vs0,45 ± 0.05, PivsPi + Fe, p < 0,05, nmol Pi/mg protein) and inducing miRNA 30c (0.62 ± 0.05vs3.07 ± 0.62; PivsPi + Fe, p < 0.01, relative expression). Studying aortic rings, we found that iron significantly either prevents or reverts the high-Pi induced collagen deposition and the elastin decrease, preserving elastin structure (0.7 ± 0.1 vs 1.2 ± 0.1; Pi vs Pi + Fe, p < 0.05, elastin mRNA relative expression)., Conclusions: Iron directly either prevents or partially reverts the high-Pi induced osteo-chondrocytic shift of ECM. The protection of muscular nature of VSMC ECM may be one of the mechanisms elucidating the anti-calcific effect of iron., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In chronic kidney disease (CKD), the first cause of mortality is cardiovascular disease induced mainly by vascular calcification (VC). Recently, iron-based phosphate binders have been proposed in advanced CKD to treat hyperphosphatemia. We studied the effect of iron citrate (iron) on the progression of calcification in high-phosphate (Pi) calcified VSMC. Iron arrested further calcification when added on days 7-15 in the presence of high Pi (1.30 ± 0.03 vs 0.61 ± 0.02; OD/mg protein; day 15; Pi vs Pi + Fe, p < 0.01). We next investigated apoptosis and autophagy. Adding iron to high-Pi-treated VSMC, on days 7-11, decreased apoptotic cell number (17.3 ± 2.6 vs 11.6 ± 1.6; Annexin V; % positive cells; day 11; Pi vs Pi + Fe; p < 0.05). The result was confirmed thorough analysis of apoptotic nuclei both in VSMCs and aortic rings treated on days 7-15 (3.8 ± 0.2 vs 2.3 ± 0.3 and 4.0 ± 0.3 vs 2.2 ± 0.2; apoptotic nuclei; arbitrary score; day 15; Pi vs Pi + Fe; VSMCs and aortic rings; p < 0.05). Studying the prosurvival axis GAS6/AXL, we found that iron treatment on days 9-14 counteracted protein high-Pi-stimulated down-regulation and induced its de novo synthesis. Moreover, iron added on days 9-15 potentiated autophagy, as detected by an increased number of autophagosomes with damaged mitochondria and an increase in autophagic flux. Highlighting the effect of iron on apoptosis, we demonstrated its action in blocking the H 2 O 2 -induced increase in calcification added both before high Pi treatment and when the calcification was already exacerbated. In conclusion, we demonstrate that iron arrests further high Pi-induced calcium deposition through an anti-apoptotic action and the induction of autophagy on established calcified VSMC.

Background and Objectives: Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2-4., Design, Setting, Participants, & Measurements: Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T 50 ) from primary to secondary calciprotein particles, with lower T 50 corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T 50 with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality., Results: The mean T 50 was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T 50 was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T 50 , 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T 50 , 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T 50 , 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T 50 , 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T 50 was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality., Conclusions: Among patients with CKD stages 2-4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019&#95;10&#95;28&#95;CJN04710419.mp3., (Copyright © 2019 by the American Society of Nephrology.)

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., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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 m 2 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., (Copyright © 2019 by the American Society of Nephrology.)

Background: Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), ferric citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation., Methods: We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with ferric citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT)., Results: We analyzed a total of 117 and 115 ferric citrate-treated and placebo-treated patients, respectively. At 16 weeks, ferric citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms., Conclusions: Ferric citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.)

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 (T 50 ) from primary to secondary calciprotein particles, with lower T 50 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, T 50 was not associated with CAC prevalence but was significantly associated with greater CAC severity among participants with prevalent CAC: 1-SD lower T 50 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, T 50 was not associated with incident CAC but was significantly associated with CAC progression: 1-SD lower T 50 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., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)