Search

BACKGROUND Lowering blood pressure (BP) after stroke remains a challenge, even in the context of clinical trials. The Secondary Prevention of Small Subcortical Strokes (SPS3) BP protocol, BP management during the study, and achieved BPs are described here. METHODS Patients with recent symptomatic lacunar stroke were randomized to 1 of 2 levels of systolic BP (SBP) targets: lower: <130mm Hg, or higher: 130–149mm Hg. SBP management over the course of the trial was examined by race/ethnicity and other baseline conditions. RESULTS Mean SBP decreased for both groups from baseline to the last follow-up, from 142.4 to 126.7mm Hg for the lower SBP target group and from 143.6 to 137.4mm Hg for the higher SBP target group. At baseline, participants in both groups used an average of 1.7±1.2 antihypertensive medications, which increased to a mean of 2.4±1.4 (lower group) and 1.8±1.4 (higher group) by the end-study visit. It took an average of 6 months for patients to reach their SBP target, sustained to the last follow-up. Black participants had the highest proportion of SBP ≥150mm Hg at both study entry (40%) and end-study visit (17%), as compared with whites (9%) and Hispanics (11%). CONCLUSIONS These results show that it is possible to safely lower BP even to a SBP goal <130mm Hg in a variety of patients and settings, including private and academic centers in multiple countries. This provides further support for protocol-driven care in lowering BP and consequently reducing the burden of stroke. [ABSTRACT FROM AUTHOR]

BACKGROUND Hypertension is the most powerful risk factor for stroke. The aim of this study was to characterize baseline blood pressure in participants in the Secondary Prevention of Small Subcortical Strokes trial. METHODS For this cross-sectional analysis, participants were categorized by baseline systolic blood pressure (SBP) < 120, 120–139, 140–159, 160–179, and ≥ 180mm Hg and compared on demographic and clinical characteristics. Predictors of SBP < 140mm Hg were examined. RESULTS Mean SBP was 143±19mm Hg while receiving an average of 1.7 antihypertensive medications; SBP ≥ 140mm Hg for 53% and ≥ 160 mm Hg for 18% of the 3,020 participants. Higher SBP was associated with a history of hypertension and hypertension for longer duration (both P < 0.0001). Higher SBPs were associated with more extensive white matter disease on magnetic resonance imaging (P < 0.0001). There were significant differences in entry-level SBP when participants were categorized by race and region (both P < 0.0001). Black participants were more likely to have SBP ≥ 140mm Hg. Multivariable logistic regression showed an independent effect for region with those from Canada more likely (odds ratio = 1.7; 95% confidence interval, 1.29, 2.32) to have SBP < 140mm Hg compared with participants from United States. CONCLUSIONS In this cohort with symptomatic lacunar stroke, more than half had uncontrolled hypertension at approximately 2.5 months after stroke. Regional, racial, and clinical differences should be considered to improve control and prevent recurrent stroke. CLINICAL TRIALS REGISTRATION Trial Number NCT00059306 [ABSTRACT FROM PUBLISHER]

Presents a letter to the editor about the high-dose iron gluconate in chronic kidney disease patients published in the January 2004 of the journal "Nephrology."

Aims: Obesity is associated with progression of chronic kidney disease (CKD). Treatment with bardoxolone methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with bardoxolone methyl.Methods: Eligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to <30 mL/min/1.73 m2) were randomized 1:1 to receive once-daily oral dose of bardoxolone methyl (20 mg) or placebo.Results: BEACON enrolled 2185 patients. Patients randomized to bardoxolone methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (-5.7 kg; 95% CI: -6.0 to -5.3 kg; p < 0.001). In patients randomized to bardoxolone methyl, rate and magnitude of body weight loss were proportional to baseline BMI. Bardoxolone methyl resulted in significant reductions in waist circumference and improved glycemic control.Conclusions: Bardoxolone methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI. [ABSTRACT FROM AUTHOR]

Purpose:We applied cluster analysis to identify discrete patterns of concomitant responses of systolic (SBP), diastolic (DBP) and pulse pressure (PP) during intensive BP lowering; and to evaluate their clinical relevance and association with risk of mortality, major vascular events (MVEs), and stroke. Material and methods:We used an unsupervised cluster procedure to identify distinct patterns of BP change during the first 9 months of anti-hypertensive therapy intensification among 1,331 participants in the Secondary Prevention of Small Subcortical Strokes Trial who were previously randomized to lower BP target (SBP < 130 mm Hg) after lacunar stroke. Results:The cluster procedure partitioned participants into three groups in the lower SBP target arm, persons with: 1) mildly elevated baseline SBP and minimal visit-to-visit BP variability (mild reducers); 2) moderately elevated baseline SBP and moderate visit-to-visit BP variability (moderate reducers); and 3) very elevated baseline SBP with very large visit-to-visit BP variability during intensification (large reducers). In the lower SBP target group, moderate reducers had a higher risk of death (adjusted HR 1.6 [95% CI 1.0–2.7]), MVE (adjusted HR 2.1 [95% CI 1.4–3.2]), and stroke (adjusted HR 2.6[95% CI 1.7–4.1]) compared to mild reducers. Large reducers had the highest risk of death (adjusted HR 2.3 [95% CI 1.2–4.4]), but risk of MVE (HR = 1.7 [95%CI 0.9–3.1]) and stroke (HR = 1.6 [95%CI: 0.8–3.5]) were not statistically significantly different compared to mild reducers. Conclusions:Among persons with prior lacunar stroke, baseline BP levels, and BP variability in the setting of intensive BP lowering can identify discrete groups of persons at higher risk of adverse outcomes. [ABSTRACT FROM PUBLISHER]

Background: Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor that reduces inflammation, fibrosis, and apoptosis. The MOSAIC study evaluated whether selonsertib attenuated kidney function decline in patients with diabetic kidney disease., Methods: We conducted a phase 2b study in adults with type 2 diabetes and eGFR 20 to <60 ml/min/1.73 m2 with UACR 150 to 5000 mg/g on maximum tolerated dose of ACE inhibitor or ARB. To account for an acute selonsertib-related decrease in eGFRcr, patients entered a 4-week selonsertib run-in period to establish treatment-specific baseline eGFRcr. Patients were randomized 1:1 to selonsertib 18 mg or matching placebo once daily. We followed all participants up until the last randomized participant completed 48 weeks follow-up. The primary efficacy outcome was the difference in eGFRcr slopes from treatment-specific baselines to week 84, evaluated at a prespecified two-sided P = 0.30. We also evaluated kidney clinical events (eGFRcr ≥40% decline from pre-run-in baseline, kidney failure, or death due to kidney disease) and adverse events., Results: In total, 310 patients were randomized (selonsertib n=154, placebo n=156; 68% male, mean age 65 years, mean baseline eGFRcr 35 ml/min/1.73 m2). Mean difference between selonsertib and placebo eGFRcr slopes at week 84 was 1.20 ml/min/1.73 m2/year (95% CI, -0.41 to 2.81; P = 0.14). Kidney clinical events occurred in 17% (26/154) of patients randomized to selonsertib and 12% (19/156) of those randomized to placebo (difference 4.7%; 95% CI, -6.3% to 15.9%). The most common investigator-reported adverse event was acute kidney injury (selonsertib 11.0/100 and placebo 5.9/100 patient-years)., Conclusions: Selonsertib attenuated the decline in eGFRcr over up to 84 weeks; however, it resulted in a numerically higher number of patients reaching a kidney clinical event and a numerically higher rate of investigator-reported acute kidney injury., (Copyright © 2024 by the American Society of Nephrology.)

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia in chronic kidney disease (CKD). Single ascending dose (SAD) and multiple ascending dose (MAD) studies assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of vadadustat in healthy volunteers. A single-dose, open-label study was conducted in patients with CKD stages 3 and 4 not on dialysis. In the SAD study, 48 healthy adult men (n = 8/cohort) received single doses of vadadustat (80-1,200 mg) or placebo. In the MAD study, 34 healthy adult men (n = 8-9/cohort) received daily vadadustat (500-900 mg) or placebo for 10 days. In the single-dose CKD study, 22 male and female patients with CKD (stage 3: n = 10; stage 4: n = 12) received single doses of vadadustat (500 mg). PK parameters included plasma vadadustat; PD biomarkers were measured, including erythropoietin (EPO) levels, reticulocytes, and others. Plasma vadadustat peaked 3-4 hours after single or multiple dosing in healthy volunteers, with a mean t 1/2 of approximately 4.5 hours. In patients with CKD, plasma vadadustat peaked at 5-6 hours, with a mean t 1/2 of 7.2 (stage 3) and 8.5 (stage 4) hours. Vadadustat AUC ∞ and C max increased dose proportionally in SAD and MAD trials. In all trials, EPO concentrations increased in a dose-related manner and returned approximately to baseline by 24 hours. Adverse events were mild and considered not study drug related. The PK and PD results of these studies were utilized for further clinical development of vadadustat for treatment of anemia in CKD patients., (© 2024 Akebia Therapeutics, Inc. and The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Significance Statement: Systemic inflammation in CKD can lead to anemia. Ziltivekimab, a fully human monoclonal antibody targeting the IL-6 ligand, has been shown to reduce systemic inflammation in patients with CKD. It has also been shown to increase serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to treatment with erythropoiesis-stimulating agents. This exploratory analysis of the RESCUE clinical trial found that among patients with CKD stage 3-5 and systemic inflammation, ziltivekimab treatment significantly increased hemoglobin (Hb) levels after 12 weeks compared with placebo. Ziltivekimab was also associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation. No major safety concerns were reported. Further clinical trials are warranted to study ziltivekimab's potential for anemia management in patients with CKD., Background: In the phase 2 RESCUE clinical trial, ziltivekimab, a fully human monoclonal antibody against the IL-6 ligand, significantly reduced the biomarkers of inflammation compared with placebo, in patients with CKD and systemic inflammation (high-sensitivity C-reactive protein ≥2 mg/L). The aim of this subanalysis of RESCUE trial data was to assess the effect of ziltivekimab on Hb and iron homeostasis in this patient population., Methods: This was an analysis of exploratory end points from the RESCUE trial ( NCT03926117 ), which included 264 adults with CKD stage 3-5 and high-sensitivity C-reactive protein ≥2 mg/L. Participants received placebo or subcutaneous ziltivekimab (7.5, 15, or 30 mg) (1:1:1:1) once every 4 weeks, up to 24 weeks. End points for this analysis were changes in Hb and biomarkers of iron homeostasis from baseline to week 12., Results: The trial was terminated early due to the coronavirus disease 2019 pandemic, and thus, data up to week 12 are presented. Hb levels significantly increased from baseline to week 12 with ziltivekimab 7.5, 15, and 30 mg (treatment differences versus placebo: +0.57 g/dl [95% confidence interval, 0.27 to 0.86], +1.05 g/dl [0.76 to 1.33], and +0.99 g/dl [0.70 to 1.28], respectively, all P < 0.001). Ziltivekimab was associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation from baseline to week 12 ( P < 0.05 versus placebo for all doses and comparisons). Cases of sustained thrombocytopenia, sustained neutropenia, anemia, and iron deficiency anemia were infrequent and similar across all groups., Conclusions: Anti-inflammatory therapy with ziltivekimab improved the markers of anemia and iron homeostasis in people with stage 3-5 CKD and systemic inflammation, suggesting a possible role in anemia management., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation., (© 2022 Akebia Therapeutics Inc and The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Hyperkalemia (serum K + >5.0 mmol/L) is commonly observed among patients receiving maintenance hemodialysis and associated with increased risk of cardiac arrhythmias. Current international guidelines may not reflect the latest evidence on managing hyperkalemia in patients undergoing hemodialysis, and there is a lack of high-quality published studies in this area. This consensus guideline aims to provide recommendations in relation to clinical practice. Available published evidence was evaluated through a systematic literature review, and the nominal group technique was used to develop consensus recommendations from a panel of experienced nephrologists, covering monitoring, dietary restrictions, prescription of K + binders, and concomitant prescription of renin-angiotensin-aldosterone system inhibitors. Recent studies have shown that K + binders reduce the incidence of hyperkalemia, but further evidence is needed in areas including whether reduced-K + diets or treatment with K + binders improve patient-centered outcomes. Treatment of hyperkalemia in the hemodialysis setting is complex, and decisions need to be tailored for individual patients., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Background: Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation., Methods: This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies., Results: No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin., Conclusions: Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy., Clinical Trial Registry Name and Registration Number: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229., (Copyright © 2021 by the American Society of Nephrology.)

Background: Apoptosis signal-regulating kinase 1 (ASK1) activation in glomerular and tubular cells resulting from oxidative stress may drive kidney disease progression. Findings in animal models identified selonsertib, a selective ASK1 inhibitor, as a potential therapeutic agent., Methods: In a phase 2 trial evaluating selonsertib's safety and efficacy in adults with type 2 diabetes and treatment-refractory moderate-to-advanced diabetic kidney disease, we randomly assigned 333 adults in a 1:1:1:1 allocation to selonsertib (oral daily doses of 2, 6, or 18 mg) or placebo. Primary outcome was change from baseline eGFR at 48 weeks., Results: Selonsertib appeared safe, with no dose-dependent adverse effects over 48 weeks. Although mean eGFR for selonsertib and placebo groups did not differ significantly at 48 weeks, acute effects related to inhibition of creatinine secretion by selonsertib confounded eGFR differences at 48 weeks. Because of this unanticipated effect, we used piecewise linear regression, finding two dose-dependent effects: an acute and more pronounced eGFR decline from 0 to 4 weeks (creatinine secretion effect) and an attenuated eGFR decline between 4 and 48 weeks (therapeutic effect) with higher doses of selonsertib. A post hoc analysis (excluding data for 20 patients from two sites with Good Clinical Practice compliance-related issues) found that between 4 and 48 weeks, rate of eGFR decline was reduced 71% for the 18-mg group relative to placebo (difference 3.11±1.53 ml/min per 1.73 m 2 annualized over 1 year; 95% confidence interval, 0.10-6.13; nominal P =0.043). Effects on urine albumin-to-creatinine ratio did not differ between selonsertib and placebo., Conclusions: Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression., (Copyright © 2019 by the American Society of Nephrology.)

Background and Objectives: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial., Design, Setting, Participants, & Measurements: In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium =3.5-5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5-5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout., Results: Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m 2 , and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0-3.4 mmol/L, respectively., Conclusions: After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months., (Copyright © 2019 by the American Society of Nephrology.)

Background We aimed to determine whether cerebral white matter hyperintensities ( WMHs ) can distinguish stroke survivors susceptible to rapid kidney function decline from intensive blood pressure ( BP ) lowering. Methods and Results The SPS3 (Secondary Prevention of Small Subcortical Strokes) trial randomized participants with recent lacunar stroke to systolic BP targets of 130 to 149 and <130 mm Hg. We included 2454 participants with WMH measured by clinical magnetic resonance imaging at baseline and serum creatinine measured during follow-up. We tested interactions between BP target and WMH burden on the incidence of rapid kidney function decline (≥30% decrease from baseline estimated glomerular filtration rate at 1-year follow-up) and recurrent stroke. Rapid kidney function decline incidence was 11.0% in the lower- BP -target arm and 8.1% in the higher-target arm (odds ratio=1.40; 95% CI=1.07-1.84). Odds ratio for rapid kidney function decline between lower- and higher-target groups ranged from 1.26 in the lowest WMH tertile (95% CI , 0.80-1.98) to 1.71 in the highest tertile (95% CI , 1.05-2.80; P for interaction=0.65). Overall incidence of recurrent stroke was 7.9% in the lower-target arm and 9.6% in the higher-target arm (hazard ratio=0.80; 95% CI , 0.63-1.03). Hazard ratio for recurrent stroke in the lower-target group was 1.13 (95% CI , 0.73-1.75) within the lowest WMH tertile compared with 0.73 (95% CI , 0.49-1.09) within the highest WMH tertile ( P for interaction=0.04). Conclusions Participants with higher WMH burden appeared to experience greater benefit from intensive BP lowering in prevention of recurrent stroke. By contrast, intensive BP lowering increased the odds of kidney function decline, but WMH burden did not significantly distinguish this risk. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00059306.

Background and Objectives: Patiromer is a sodium-free, nonabsorbed, potassium-binding polymer that uses calcium as the counter-exchange ion and is approved for treatment of hyperkalemia. The 4-week TOURMALINE study in patients with hyperkalemia previously demonstrated that patiromer administered once daily reduces serum potassium similarly when given with or without food. We report a prespecified exploratory efficacy analysis as well as a post hoc efficacy and safety analysis of the TOURMALINE study on circulating markers of mineral metabolism., Design, Setting, Participants, & Measurements: Adults with hyperkalemia (potassium >5.0 mEq/L) were randomized to once-daily patiromer 8.4 g without/with food for 4 weeks, with doses adjusted to achieve and maintain serum potassium 3.8-5.0 mEq/L. Baseline and week 4 serum and 24-hour urine markers of mineral metabolism are reported for all patients combined (evaluable for efficacy, n =112; evaluable for safety, n =113). P values were calculated using a paired t test for change from baseline, unless otherwise specified., Results: Mean (SD) baseline eGFR was 41±26 ml/min per 1.73 m 2 . Mean (SD) changes from baseline to week 4 were 0.0±0.5 mg/dl ( P =0.78; n =100) for albumin-corrected serum calcium, -0.2±0.2 mg/dl ( P <0.001; n =100) for serum magnesium, and -0.1±0.7 mg/dl ( P =0.47; n =100) for serum phosphate. Median (quartile 1, quartile 3) changes in 24-hour creatinine-normalized urine calcium and phosphate from baseline to week 4 were 2.5 (-11.5, 23.7) mg/24 h ( P =0.10; n =69) and -43.0 (-162.6, 35.7) mg/24 h ( P =0.004; n =95), respectively. Median (quartile 1, quartile 3) changes in intact parathyroid hormone and 1,25-dihydroxyvitamin D from baseline to week 4 were -13 (-31, 4) pg/ml ( P <0.001; n =97) and -2 (-9, 3) pg/ml ( P =0.05; n =96), respectively. There were no changes in fibroblast growth factor-23 or 25-hydroxyvitamin D. In patients ( n =16) with baseline serum phosphate >4.8 mg/dL, the mean (SD) changes in serum and 24-hour creatinine-normalized urine phosphate from baseline to Week 4 were -0.6±0.8 mg/dl ( n =13) and -149.1±162.6 mg/24hr ( n =9), respectively., Conclusions: Patiromer lowered urine phosphate in all patients, and lowered both serum and urine phosphate in a small subset of patients with hyperphosphatemia. Intact parathyroid hormone and 1,25-dihydroxyvitamin D decreased, with no change in serum calcium., (Copyright © 2019 by the American Society of Nephrology.)

Background: It is unknown whether the physiological impact of a given blood pressure (BP) varies by body size. We explored interactions between higher vs. lower systolic BP (SBP) targets and anthropometric measures (body mass index (BMI), body surface area (BSA), height, weight) and recurrent stroke and death in the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial., Methods: Patients with recent magnetic resonance imaging-proven lacunar infarcts were randomized to 2 BP targets (130-149 mm Hg vs. <130) in a prospective, open-label, blinded end-point design. Time to outcome was evaluated with Cox proportional hazard models and compared between targets. We examined multiplicative interactions between each anthropometric measure and target and mean difference in achieved BP 1 year after randomization between BP groups by quartile. We also computed rates of recurrent stroke and death by quartiles of anthropometrics., Results: Three thousand and twenty patients were followed over a mean of 3.7 (SD 2.0) years. Mean age was 63; 63% were male. Mean height was 167 (SD 11) cm, weight 81 (18) kg, BMI 29 (5.9) kg/m(2), and BSA 1.9 (0.25) m(2). Achieved BP at 1 year was comparable between quartiles for each anthropometric measurement. We found no consistent interactions between BP target and anthropometrics for either outcome, nor were there any significant associations between hazard of stroke or death when assessed by BMI, BSA, height, or weight., Conclusions: We found no interactions between BP target groups and quartiles of anthropometrics for rates of stroke and death in SPS3. There is no evidence at this time supporting body size-based modifications to current BP targets for secondary prevention after lacunar stroke., Clinical Trials Registration: Trial Number NCT00059306., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)