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Thiazides and thiazide-type diuretics are recommended as first-line agents for the treatment of hypertension, but contemporary information on their use in clinical practice is lacking. We examined patterns and correlates of thiazide prescription in a cross-sectional analysis of baseline data from participants enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). We examined baseline prescription of thiazides in 7582 participants receiving at least 1 antihypertensive medication by subgroup, and used log-binomial regression to calculate adjusted prevalence ratios for thiazide prescription (versus no thiazide). Forty-three percent of all participants were prescribed a thiazide at baseline, but among participants prescribed a single agent, the proportion was only 16%. The prevalence of thiazide prescription differed significantly by demographic factors, with younger participants, women, and blacks all having higher adjusted prevalence of thiazide prescription than other corresponding subgroups. Participants in the lowest category of kidney function (estimated glomerular filtration rate <30 mL/min per 1.73 m2) were half as likely to be prescribed a thiazide as participants with preserved kidney function. In conclusion, among persons with hypertension and heightened cardiovascular risk, we found that thiazide prescription varied significantly by demographics and kidney disease status, despite limited evidence about relative differences in effectiveness. [ABSTRACT FROM AUTHOR]

Background: Ferric citrate (FC) is a new phosphorus binder shown to increase serum iron stores while reducing intravenous iron and erythropoiesis-stimulating agent usage. Such reductions could lower hospitalization rates and associated costs. Methods: Hospitalizations during a Phase III trial were compared between FC and active control (AC). Hospitalization costs were estimated using the 2013 US Renal Data System Annual Data Report. Results: 34.6% of FC patients were hospitalized at least once versus 45.6% of the AC group (risk reduction 24.2%; p = 0.02). There were 181 unique hospitalizations in the FC group versus 239 in the AC group, for a difference of 58 hospitalizations. Total potential savings was US$ 867,622 in hospitalization costs in the FC group. If the hospitalization reduction in our study was applied to the general end-stage renal disease population, this could translate into a savings of US$ 3002/patient/year. Conclusions: Patients receiving FC experienced fewer hospitalizations with the potential for significant savings. [ABSTRACT FROM AUTHOR]

From 88 subjects with labile high blood pressure (LHBP), we collected blood pressure variability (BPV) and assessed relationships with age, medications, and nocturnal pattern via ambulatory blood pressure monitoring. The average age of the subjects was 64 ± 13 years and they were on 1.5 ± 1.3 antihypertensives. BPV did not differ diurnally and was not influenced by medication. Aging associates with increasing daytime systolic but not diastolic BPV, with increasing nighttime systolic BP, and decreasing diastolic BP diurnally. Subjects had widened pulse pressure and abnormal diurnal pattern with age. Further studies are needed to stratify an individual's risk associated with LHBP. [ABSTRACT FROM AUTHOR]

We describe a 61-year-old woman with acute kidney injury, nephrotic range proteinuria and hematuria. Kidney biopsy showed membranous glomerulopathy (MG) with superimposed pauci-immune necrotizing crescentic glomerulonephritis (PNCGN). Coexistent MG and PNCGN is a rare occurrence. The diagnosis of such an exceptionally rare combination relies on the combination of renal biopsy findings and serologic testing. We also review previous reported cases and discuss possible pathogenesis of this rare dual glomerulopathy. [ABSTRACT FROM AUTHOR]

Type 2 diabetic nephropathy (type 2 DN) patients traditionally develop significant proteinuria prior to the development of renal impairment. However, this clinical paradigm, based on observations prior to the widespread usage of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), has recently been questioned. 2,303 patients enrolled in the Sulodexide Overt Nephropathy Study (OVERT) were analyzed. Prior therapy with ACEi and/or ARB at the time of screening was recorded in 951 patients. 22% of patients had significant renal impairment with a PCR at screening of <500 mg/g. Therapy with ACEi and/or ARB at the time of screening was recorded in 94%, where prior medication data was available. In patients with type 2 DN and advanced renal impairment, levels of proteinuria below that which traditionally defines overt diabetic nephropathy, are found in more than one fifth of patients. We suggest that the high prevalence of ACEi and ARB usage in patients with type 2 DN may be effecting the traditional clinical paradigm of type 2 DN. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Summary: The aim of this study was to assess the validity of the RT3 accelerometer, and its inbuilt algorithm, in measuring inactivity, walking and running in children. Twenty children, aged 7–12 years, participated in the study. The RT3 was compared to physiological energy expenditure obtained via a wireless portable ergospirometric system. Data analysis was performed using Bland and Altman plots and Pearson product moment correlation coefficients. There were no significant differences between the methods for each activity. Bland and Altman 95% limits of agreement between the two measures in kcalmin−1 for each of the activities were as follows: inactivity (−0.058, 0.47), walking at 3kmh−1 (−1.22, 0.83) brisk walking at 6kmh−1 (−2.74, 0.54), brisk walking at 6kmh−1 on an incline of a 10% gradient (−1.69, 2.11), and jogging at 9kmh−1 (−3.67, 1.24). Energy expenditure via the RT3 correlated significantly with that obtained by indirect calorimetry for each activity independently (r =0.56–0.84, all P <0.01). The RT3 provided a valid estimate of inactivity, walking and running and would thus appear appropriate for the objective measurement of physical activity levels. [Copyright &y& Elsevier]

Background Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are part of the standard of care for patients with chronic kidney disease (CKD), both with and without type 2 diabetes. Endothelin A (ETA) receptor antagonists have also been shown to slow progression of CKD. Differing mechanisms of action of SGLT2 and ETA receptor antagonists may enhance efficacy. We outline a study to evaluate the effect of combination zibotentan/dapagliflozin versus dapagliflozin alone on albuminuria and estimated glomerular filtration rate (eGFR). Methods We are conducting a double-blind, active-controlled, Phase 2b study to evaluate the efficacy and safety of ETA receptor antagonist zibotentan and SGLT2i dapagliflozin in a planned 415 adults with CKD (Zibotentan and Dapagliflozin for the Treatment of CKD; ZENITH-CKD). Participants are being randomized (1:2:2) to zibotentan 0.25 mg/dapagliflozin 10 mg once daily (QD), zibotentan 1.5 mg/dapagliflozin 10 mg QD and dapagliflozin 10 mg QD alone, for 12 weeks followed by a 2-week off-treatment wash-out period. The primary endpoint is the change in log-transformed urinary albumin-to-creatinine ratio (UACR) from baseline to Week 12. Other outcomes include change in blood pressure from baseline to Week 12 and change in eGFR the study. The incidence of adverse events will be monitored. Study protocol–defined events of special interest include changes in fluid-related measures (weight gain or B-type natriuretic peptide). Results A total of 447 patients were randomized and received treatment in placebo/dapagliflozin (n  = 177), zibotentan 0.25 mg/dapagliflozin (n  = 91) and zibotentan 1.5 mg/dapagliflozin (n  =  179). The mean age was 62.8 years, 30.9% were female and 68.2% were white. At baseline, the mean eGFR of the enrolled population was 46.7 mL/min/1.73 m2 and the geometric mean UACR was 538.3 mg/g. Conclusion This study evaluates the UACR-lowering efficacy and safety of zibotentan with dapagliflozin as a potential new treatment for CKD. The study will provide information about an effective and safe zibotentan dose to be further investigated in a Phase 3 clinical outcome trial. Clinical Trial Registration Number NCT04724837 [ABSTRACT FROM AUTHOR]

Clinical trial monitoring is evolving from labor-intensive to targeted approaches. The traditional 100% Source Data Monitoring (SDM) approach fails to prioritize data by significance, diverting attention from critical elements. Despite regulatory guidance on Risk-Based Monitoring (RBM), its widespread implementation has been slow. Our study teams assess the study's overall risk, document heightened and critical risks, and create a study-specific risk-based monitoring plan, integrating SDM and Central Data Monitoring (CDM). SDM combines a fixed list of pre-identified variables and a list of randomly identified variables to monitor. Identifying variables follows a two-step approach: first, a random sample of participants is selected, second, a random set of variables for each participant selected is identified. Sampling weights prioritize critical variables. Regular team meetings are held to discuss and compile significant findings into a Study Monitoring Report. We present a random SDM sample and a Study Monitoring Report. The random SDM output includes a look-up table for selected database elements. The report provides a holistic view of the study issues and overall health. The proposed random sampling method is used to monitor a representative set of critical variables, while the Study Monitoring Report is written to summarize significant monitoring findings and data trends. The report allows the sponsor to assess the current status of the study and data effectively. Communicating and sharing emerging insights facilitates timely adjustments of future monitoring activities, optimizing efficiencies, and study outcomes. [ABSTRACT FROM AUTHOR]

Randomized trials are the gold standard for generating clinical practice evidence, but follow-up and outcome ascertainment are resource-intensive. Electronic health record (EHR) data from routine care can be a cost-effective means of follow-up, but concordance with trial-ascertained outcomes is less well-studied. We linked EHR and trial data for participants of the Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial comparing intensive and standard blood pressure targets. Among participants with available EHR data concurrent to trial-ascertained outcomes, we calculated sensitivity, specificity, positive predictive value, and negative predictive value for EHR-recorded cardiovascular disease (CVD) events, using the gold standard of SPRINT-adjudicated outcomes (myocardial infarction (MI)/acute coronary syndrome (ACS), heart failure, stroke, and composite CVD events). We additionally compared the incidence of non-CVD adverse events (hyponatremia, hypernatremia, hypokalemia, hyperkalemia, bradycardia, and hypotension) in trial versus EHR data. 2468 SPRINT participants were included (mean age 68 (SD 9) years; 26% female). EHR data demonstrated ≥80% sensitivity and specificity, and ≥ 99% negative predictive value for MI/ACS, heart failure, stroke, and composite CVD events. Positive predictive value ranged from 26% (95% CI; 16%, 38%) for heart failure to 52% (95% CI; 37%, 67%) for MI/ACS. EHR data uniformly identified more non-CVD adverse events and higher incidence rates compared with trial ascertainment. These results support a role for EHR data collection in clinical trials, particularly for capturing laboratory-based adverse events. EHR data may be an efficient source for CVD outcome ascertainment, though there is clear benefit from adjudication to avoid false positives. [ABSTRACT FROM AUTHOR]

Introduction: Despite the provision of renin-angiotensin-aldosterone-system inhibitors and immunosuppressive therapies, membranous nephropathy often progresses to end-stage kidney disease (ESKD). The objective of this prespecified analysis was to assess the safety and efficacy of dapagliflozin in patients with membranous nephropathy enrolled in the DAPA-CKD trial., Methods: Patients with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m 2 and urinary albumin-to-creatinine ratio (UACR) 200-5,000 mg/g were randomized to dapagliflozin 10 mg once daily or placebo, along with standard-of-care and followed for median 2.4 years. The primary endpoint was a composite of ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Exploratory efficacy endpoints included eGFR slope and UACR., Results: Among DAPA-CKD participants with membranous nephropathy, 19 were randomized to dapagliflozin and 24 to placebo. The mean (SD) age was 59.9 ± 12.1 years, the mean eGFR was 45.7 ± 12.1 mL/min/1.73 m 2 , and the median UACR was 1,694.5 (25%, 75% range 891-2,582.5) mg/g. Two of 19 (11%) patients randomized to dapagliflozin and five of 24 (21%) randomized to placebo experienced the primary composite endpoint. Total and chronic mean eGFR slopes for dapagliflozin and placebo were -3.87 and -4.29 and -2.66 and -4.22 mL/min/1.73 m 2 /year, respectively; corresponding between-group mean differences were 0.42 and 1.57 mL/min/1.73 m 2 /year. Dapagliflozin reduced geometric mean (SEM) UACR relative to placebo (-29.3% ± 1.2% vs. -3.6% ± 1.1%; between-group mean difference [95% CI] -26.7 [-50.4, 8.3]). Four (21%) patients randomized to dapagliflozin and seven (29%) randomized to placebo experienced a serious adverse event., Conclusion: In membranous nephropathy, the effects of dapagliflozin on kidney disease progression and albuminuria were generally favorable; there was insufficient power to justify formal inference testing., Competing Interests: G.M.C. served on the Executive Committee of the DAPA-CKD trial. He has served on the Board of Directors of Satellite Healthcare, a non-profit dialysis provider. He has served as Chair or Co-Chair of Trial Steering Committees with Akebia, CSL Behring, Sanifit, and Vertex. He has served as an Advisor to Applaud, Ardelyx, Calico, CloudCath, Durect, Eliaz Therapeutics, Miromatrix, Outset, Renibus, and Unicycive. He has served on Data Safety Monitoring Boards with Bayer, Mineralys, and ReCor. H.J.L.H. reported receiving research support from and serving as a consultant for AstraZeneca during the conduct of the study; serving as a consultant for Bayer, Chinook Tx, CSL Behring, Dimerix, Eli Lilly, Fresenius, Gilead, Novartis, and Travere Therapeutics outside the submitted work; receiving grants and research support from Boehringer Ingelheim and Janssen outside the submitted work; and receiving grants and clinical trial study medication from, and serving as a consultant for Novo Nordisk outside the submitted work. P.B.M. reported receiving lecture fees and travel to meetings support from Vifor, AstraZeneca, Pharmacosmos, Napp, Astellas, lecture fees from Novartis, Astellas, GSK and grants from Boehringer Ingelheim outside the submitted work. J.P.D. reported receiving fees from AstraZeneca for the conduct of this study; fees from Sanofi-Aventis and CSL Behring as part of a steering committee; fees from Novo Nordisk for outcome adjudication for a trial; fees from Goldfinch Bio, Birdrock Bio, and Boehringer Ingelheim for study design; personal fees from Bayer. M.N. reported receiving honoraria from Boehringer Ingelheim, Swixx Biopharma, Roche, Sanofi Genzyme and Omeros. D.C.W. reported receiving personal fees from AstraZeneca during the conduct of the study; personal fees from Astellas, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Gilead, Merck Sharp and Dohme, George Clinical, Intas, ProKidney, Tricida, Vifor, and Zydus outside the submitted work; and performing guideline development for KDIGO. R.C.-R. reported receiving personal fees from AstraZeneca, during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from Amgen, personal fees from Janssen, grants from GlaxoSmithKline, grants and personal fees from Novo Nordisk, personal fees from Medtronic, outside the submitted work. P.R. reported receiving grants and other from AstraZeneca, during the conduct of the study; from Novo Nordisk, Gilead, Bayer, Sanofi-Aventis, and Eli Lilly, outside the submitted work. R.D.T.’s contribution to this manuscript was supported in part by endowments from the Mary M. Conroy Professorship in Kidney Diseases and the Houston J and Florence A Dosswell Center for Development of New Approaches for the Treatment of Hypertension. He also reported receiving personal fees from AstraZeneca, during the conduct of the study; personal fees from AstraZeneca, Bayer Pharma, Calliditas, Boehringer Ingelheim, Relypsa, Amgen, and Novartis, outside the submitted work. A.M.L. reported being a full-time employee and shareholder of AstraZeneca during the conduct of the study. N.J. reports travel grants from AstraZeneca., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: The REVOLUTIONIZE I study aimed to characterize the relationships between medical nutrition therapy (MNT) and hyperkalemia recurrence in patients with stage 3-4 chronic kidney disease (CKD) and hyperkalemia who received MNT in real-world clinical practice., Methods: This observational cohort study used de-identified electronic health record data from patients aged ≥ 18 years with stage 3-4 CKD who received MNT between January 2019 and October 2022 and had hyperkalemia (serum potassium > 5.0 mmol/L) within 30 days before MNT. Patients were followed for 6 months or until the first censoring event (death, prescription of outpatient potassium binder, or study end). The primary outcome was the percentage of patients with ≥ 1 hyperkalemia recurrence during follow-up. Secondary outcomes included the number of hyperkalemia recurrences per patient, time to each recurrence, and hyperkalemia-related healthcare resource utilization. Exploratory outcomes included all-cause healthcare resource utilization and mortality., Results: The final cohort comprised 2048 patients; 1503 (73.4%) patients remained uncensored after 6 months. During the 6-month follow-up period, 56.0% of patients had ≥ 1 hyperkalemia recurrence and 37.4% had ≥ 1 recurrence within the first month. Patients with ≥ 1 hyperkalemia recurrence during follow-up had a mean ± standard deviation (SD) of 2.6 ± 2.2 recurrences. The mean ± SD time to first hyperkalemia recurrence was 45 ± 46 days; the time between recurrences decreased with subsequent episodes. Hyperkalemia-related hospitalizations and emergency department visits were recorded for 13.7% and 1.5% of patients, respectively. Sensitivity analyses showed that results were consistent across patient subgroups, including those with comorbid heart failure and patients receiving renin-angiotensin-aldosterone system inhibitor therapy at baseline., Conclusion: Most patients with stage 3-4 CKD had hyperkalemia recurrence, and MNT alone was inadequate to prevent recurrence. These patients may require additional long-term treatment, such as novel potassium binders, to maintain normokalemia and prevent hyperkalemia recurrence following MNT. Infographic available for this article. INFOGRAPHIC., (© 2024. The Author(s).)

Background: Intensive BP lowering in the Systolic Blood Pressure Intervention Trial (SPRINT) produced acute decreases in kidney function and higher risk for AKI. We evaluated the effect of intensive BP lowering on long-term changes in kidney function using trial and outpatient electronic health record (EHR) creatinine values., Methods: SPRINT data were linked with EHR data from 49 (of 102) study sites. The primary outcome was the total slope of decline in eGFR for the intervention phase and the post-trial slope of decline during the observation phase using trial and outpatient EHR values. Secondary outcomes included a ≥30% decline in eGFR to <60 ml/min per 1.73 m 2 and a ≥50% decline in eGFR or kidney failure among participants with baseline eGFR ≥60 and <60 ml/min per 1.73 m 2 , respectively., Results: EHR creatinine values were available for a median of 8.3 years for 3041 participants. The total slope of decline in eGFR during the intervention phase was -0.67 ml/min per 1.73 m 2 per year (95% confidence interval [CI], -0.79 to -0.56) in the standard treatment group and -0.96 ml/min per 1.73 m 2 per year (95% CI, -1.08 to -0.85) in the intensive treatment group ( P < 0.001). The slopes were not significantly different during the observation phase: -1.02 ml/min per 1.73 m 2 per year (95% CI, -1.24 to -0.81) in the standard group and -0.85 ml/min per 1.73 m 2 per year (95% CI, -1.07 to -0.64) in the intensive group. Among participants without CKD at baseline, intensive treatment was associated with higher risk of a ≥30% decline in eGFR during the intervention (hazard ratio, 3.27; 95% CI, 2.43 to 4.40), but not during the postintervention observation phase. In those with CKD at baseline, intensive treatment was associated with a higher hazard of eGFR decline only during the intervention phase (hazard ratio, 1.95; 95% CI, 1.03 to 3.70)., Conclusions: Intensive BP lowering was associated with a steeper total slope of decline in eGFR and higher risk for kidney events during the intervention phase of the trial, but not during the postintervention observation phase., (Copyright © 2023 by the American Society of Nephrology.)

Introduction: During the COVID-19 pandemic, research organizations accelerated adoption of technologies that enable remote participation. Now, there's a pressing need to evaluate current decentralization practices and develop appropriate research, education, and operations infrastructure. The purpose of this study was to examine current adoption of decentralization technologies in a sample of clinical research studies conducted by academic research organizations (AROs)., Methods: The setting was three data coordinating centers in the U.S. These centers initiated coordination of 44 clinical research studies during or after 2020, with national recruitment and enrollment, and entailing coordination between one and one hundred sites. We determined the decentralization technologies used in these studies., Results: We obtained data for 44/44 (100%) trials coordinated by the three centers. Three technologies have been adopted across nearly all studies (98-100%): eIRB, eSource, and Clinical Trial Management Systems. Commonly used technologies included e-Signature (32/44, 73%), Online Payments Portals (26/44, 59%), ePROs (23/44, 53%), Interactive Response Technology (22/44, 50%), Telemedicine (19/44, 43%), and eConsent (18/44, 41%). Wearables (7/44,16%) and Online Recruitment Portals (5/44,11%) were less common. Rarely utilized technologies included Direct-to-Patient Portals (1/44, 2%) and Home Health Nurse Portals (1/44, 2%)., Conclusions: All studies incorporated some type of decentralization technology, with more extensive adoption than found in previous research. However, adoption may be strongly influenced by institution-specific IT and informatics infrastructure and support. There are inherent needs, responsibilities, and challenges when incorporating decentralization technology into a research study, and AROs must ensure that infrastructure and informatics staff are adequate., Competing Interests: MC and BB are employees of Doxy.me, LLC, a commercial telemedicine company. The other authors have no relevant competing interests., (© The Author(s) 2023.)

Introduction: Patients receiving cardiorenal-protective renin-angiotensin-aldosterone system inhibitors (RAASis) are at increased risk of developing hyperkalemia, which is associated with increased medical costs. The aim of this study was to evaluate the impact of adding sodium zirconium cyclosilicate (SZC) therapy on 3-month medical costs in patients who experienced hyperkalemia while receiving RAASi therapy., Methods: The retrospective OPTIMIZE II study used medical and pharmacy claims data from IQVIA PharMetrics ® Plus. Patients aged ≥ 18 years who received SZC (≥ 60 day supply over 3 months' follow-up) and continued RAASi between July 2019 and December 2021 (Continue RAASi + SZC cohort) were 1:1 exact and propensity score matched with patients who discontinued RAASi after hyperkalemia diagnosis and did not receive SZC (Discontinue RAASi + no SZC cohort). The primary outcome was hyperkalemia-related medical costs to payers over 3 months; all-cause medical and pharmacy costs were also analyzed., Results: In the Continue RAASi + SZC (n = 467) versus Discontinue RAASi + no SZC (n = 467) cohort, there were significant reductions in mean per-patient hyperkalemia-related medical costs (reduction of $2216.07; p = 0.01) and all-cause medical costs (reduction of $6102.43; p < 0.001); mean hyperkalemia-related inpatient medical costs and all-cause inpatient and emergency department medical costs were significantly reduced. The reduction in all-cause medical cost in the Continue RAASi + SZC cohort offset an increase in the mean per-patient all-cause pharmacy cost (increase of $3117.71; p < 0.001)., Conclusion: RAASi therapy has well-established cardiorenal benefits. In OPTIMIZE II, management of RAASi-induced hyperkalemia with SZC was associated with lower hyperkalemia-related and all-cause medical costs than RAASi discontinuation without SZC, demonstrating medical cost savings with maintaining RAASi therapy with SZC., (© 2023. The Author(s).)

Purpose: Hyperkalemia, defined as abnormally high serum potassium levels of ≥5.1 mmol/L, is associated with increased medical costs. This real-world study evaluated the impact of long-term sodium zirconium cyclosilicate (SZC) therapy on medical costs in patients with hyperkalemia., Patients and Methods: This retrospective, comparative study used claims data from IQVIA PharMetrics ® Plus. Patients aged ≥18 years with hyperkalemia who had outpatient SZC fills (>3-month supply over 6 months) between July 2019 and December 2021 and continuous insurance coverage 6 months before and 6 months after the first SZC fill were included. These patients (SZC cohort) were 1:1 exact- and propensity score-matched on baseline variables with patients with hyperkalemia who did not receive SZC (non-SZC cohort). The primary endpoint was hyperkalemia-related medical costs to payers over 6 months., Results: Each cohort included 661 matched patients. Mean per-patient hyperkalemia-related medical costs were reduced by 49.5% ($3728.47) for the SZC versus non-SZC cohort ($3798.04 vs $7526.51; P <0.001), whereas mean all-cause medical costs were reduced by 21.0% ($5492.20; $20,722.23 vs $26,214.43; P <0.01). A 39.8% ($3621.03) increase in all-cause pharmacy costs ($12,727.20 vs $9106.17; P <0.01) was offset by the medical cost savings., Conclusion: This study demonstrated that long-term (>3 months) outpatient treatment with SZC was associated with medical cost savings compared with no SZC therapy., Competing Interests: Jamie P. Dwyer has acted as a scientific consultant for AstraZeneca and received fees from AstraZeneca for the conduct of this study; has received fees from Sanofi and CSL Behring as part of a steering committee; has received fees from Novo Nordisk for outcome adjudication for a clinical trial; has received fees from Boehringer Ingelheim and Lilly for study design; and has received personal fees from Bayer, CinCor, Caladrius Biosciences, Inversago, GlaxoSmithKline LLC, and ProKidney. Abiy Agiro and Pooja Desai are employees and stockholders of AstraZeneca. Yemisi Oluwatosin was an employee and stockholder of AstraZeneca at the time of the study., (© 2023 Agiro et al.)

Current phosphate management strategies in end-stage renal disease (dietary phosphate restriction, dialysis, and phosphate binders) are inadequate to maintain target phosphate levels in most patients. Dietary phosphate restriction is challenging due to "hidden phosphates" in processed foods, and dialysis and phosphate binders are insufficient to match average dietary phosphate intake. As phosphate binders must be taken with each meal, patients need to ingest many, large pills several times a day, negatively impacting quality of life. Recent advances in our understanding of phosphate absorption pathways have led to the development of new nonbinder therapies that block phosphate absorption. This review describes the limitations of current phosphate management strategies and discusses new therapies in development that inhibit phosphate absorption pathways. These new therapies present an opportunity to rethink phosphate management, potentially by prescribing phosphate absorption inhibitors as a primary therapy and adding phosphate binders if needed., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Adjudication of inpatient AKI in the Systolic Blood Pressure Intervention Trial (SPRINT) was based on billing codes and admission and discharge notes. The purpose of this study was to evaluate the effect of intensive versus standard BP control on creatinine-based inpatient and outpatient AKI, and whether AKI was associated with cardiovascular disease (CVD) and mortality., Methods: We linked electronic health record (EHR) data from 47 clinic sites with trial data to enable creatinine-based adjudication of AKI. Cox regression was used to evaluate the effect of intensive BP control on the incidence of AKI, and the relationship between incident AKI and CVD and all-cause mortality., Results: A total of 3644 participants had linked EHR data. A greater number of inpatient AKI events were identified using EHR data (187 on intensive versus 155 on standard treatment) as compared with serious adverse event (SAE) adjudication in the trial (95 on intensive versus 61 on standard treatment). Intensive treatment increased risk for SPRINT-adjudicated inpatient AKI (HR, 1.51; 95% CI, 1.09 to 2.08) and for creatinine-based outpatient AKI (HR, 1.40; 95% CI, 1.15 to 1.70), but not for creatinine-based inpatient AKI (HR, 1.20; 95% CI, 0.97 to 1.48). Irrespective of the definition (SAE or creatinine based), AKI was associated with increased risk for all-cause mortality, but only creatinine-based inpatient AKI was associated with increased risk for CVD., Conclusions: Creatinine-based ascertainment of AKI, enabled by EHR data, may be more sensitive and less biased than traditional SAE adjudication. Identifying ways to prevent AKI may reduce mortality further in the setting of intensive BP control., Competing Interests: A.K. Agarwal reports serving in an advisory or leadership role for American Society of Diagnostic and Interventional Nephrology (ASDIN), Clinical Nephrology, International Journal of Nephrology, International Society of Nephrology (ISN), Journal of Vascular Access, Kidney Self-Assessment Program, National Kidney Foundation (NKF), and The Open Urology and Nephrology Journal; having other interests in, or relationships with, the American Society of Nephrology, ASDIN, ISN, and NKF; serving on a speakers bureau for AstraZeneca; having consultancy agreements with, and receiving honoraria from, AstraZeneca and Otsuka Pharmaceuticals. S. Beddhu reports receiving research funding from Bayer, Boehringer Ingelheim, and Novartis; having consultancy agreements with Bayer and Reata; and serving in an advisory or leadership role for CJASN and Kidney Reports. M. Dobre reports receiving honoraria from Relypsa and Tricida; and serving in an advisory or leadership role for Relypsa (Resistant Hypertension Working Group) and Tricida (Metabolic Acidosis Working Group). J.P. Dwyer reports having consultancy agreements with Acuta Capital, Akcea, Aleon, Ardelyx, AstraZeneca, Aurinia, Axsome, Bayer, BioRasi, BioVie, Boeringher Ingelheim, Botanix, Caladrius, Cincor, Contrafect, Cumberland, Eli Lilly, ES, Fibrogen, Genentech, Hope Pharma, Icon, Ionis, Innovative Renal Care, Keros, LifeSci Venture, Medpace, MicuRx, PSI, Rarestone, Reata, RenalytixAI, Sanofi, Spero, Tricida, ValenzaBio, and Worldwide Clinical Trials; having ownership interest in BioRasi, Innovative Renal Care, PathEx, ValenzaBio, and Venostent; serving in an advisory or leadership role for Collaborative Study Group (board of directors and president) and The Bolles School (high school in Jacksonville, FL; board of directors); and having other interests in, or relationships with, The Bolles School Board of Visitors. E. Horwitz reports having other interests in, or relationships with, MetroHealth Medical Center, contracted with Fresenius Kidney Care (serving as medical director for inpatient dialysis services). J. Lash reports serving in an advisory or leadership role for Kidney360. A. McWilliams reports having ownership interest in iEnroll. S. Oparil reports receiving research funding from Bayer (site principal investigator [PI] in diabetic kidney disease), CinCor Pharma (site PI for primary aldosterone study), George Clinical (site PI for GMRx2 treatment of hypertension), and Higi (site PI for BP validation study); having ownership interest in CinCor Pharma; serving in an advisory or leadership role for CinCor Pharma (scientific advisory board for primary aldosteronism and hypertension) and Preventric Diagnostics (chair medical and technology committee; from March 2019 to present); and serving as editor-in-chief of Current Hypertension Reports (journal published by Springer Science Business Media LLC; annual stipend of $5000; editor-in-chief term until December 2022). N.M. Pajewski reports having ownership interest in Eyenovia and Ocuphire Pharma. M.A. Parkulo reports having ownership interest in Apple, Blackberry, Carnival, JPMorgan Chase, Marriott, StitchFix, and Zoom. J. Powell reports receiving research funding from Idorsia (for acting as site PI). F.F. Rahbari-Oskoui reports having consultancy agreements with Astute, Kadmon, Keryx, Phoenix (client Otsuka), Sanofi, and UpToDate; serving in an advisory or leadership role for BMC Nephrology (as associate editor), Journal of Cardiology and Vascular Medicine (as editorial board member), and PKD Foundation; receiving research funding from Duke University, Kadmon, NIH, Otsuka, Reata, and Sanofi/Genzyme; serving on a speakers bureau for Otsuka (unbranded speakers bureau; only raising disease awareness in autosomal dominant polycystic kidney disease without any reference to commercial products); receiving honoraria from Otsuka and Sanofi; and having other interests in, or relationships with, PKD Foundation (scientific advisory board member) and UpToDate (as author, receiving authorship royalties). M. Rahman reports serving as an editorial board member of American Journal of Nephrology and as an associate editor of CJASN; having consultancy agreements with Barologics; receiving research funding from Bayer Pharmaceuticals and Duke Clinical Research Institute; and receiving honoraria from Bayer, Reata, and Relypsa. D.S. Raj reports having other interests in, or relationships with, the American Association of Kidney Patients; serving in an advisory or leadership role for National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Novo Nordisk; receiving research funding from the NIH; having consultancy agreements with, and receiving honoraria from, Novo Nordisk. M.V. Rocco reports having consultancy agreements with Bayer, Baxter, and George Clinical; receiving research funding from Bayer, Boehringer Ingelheim, and GlaxoSmithKline; serving as cochair of the ISN Kidney Care Network Project and as chair of NKF Kidney Disease Outcomes Quality Initiative; and serving in an advisory or leadership role for NKF. S. Soman reports serving in an advisory or leadership role for the American Medical Informatics Association, NKF, and NKF of Michigan; having other interests in, or relationships with, American Medical Informatics Association, Cardiorenal Society of America (CRSA), NKF (education committee), and NKF of Michigan (scientific advisory board); being employed by Henry Ford Hospital; and having ownership interest in Nephroceuticals and Pfizer. G. Thomas reports receiving honoraria from UpToDate. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Background: The concept of multinephron segment diuretic therapy (MSDT) has been recommended in severe diuretic resistance with only expert opinion and case-level evidence. The purpose of this study was to investigate the safety and efficacy of MSDT, combining 4 diuretic classes, in acute heart failure (AHF) complicated by diuretic resistance., Methods and Results: A retrospective analysis was conducted in patients hospitalized with AHF at a single medical center who received MSDT, including concomitant carbonic anhydrase inhibitor, loop, thiazide, and mineralocorticoid receptor antagonist diuretics. Subjects served as their own controls with efficacy evaluated as urine output and weight change before and after MSDT. Serum chemistries, renal replacement therapies, and in-hospital mortality were evaluated for safety. Patients with severe diuretic resistance before MSDT were analyzed as a subcohort. A total of 167 patients with AHF and diuretic resistance received MSDT. MSDT was associated with increased median 24-hour urine output in the first day of therapy compared with the previous day (2.16 L [0.95-4.14 L] to 3.08 L [1.74-4.86 L], P = .003) in the total cohort and in the Severe diuretic resistance cohort (0.91 L [0.43-1.43 L] to 2.08 L [1.13-3.96 L], P < .001). The median cumulative weight loss at day 7 or discharge was -7.4 kg (-15.3 to -3.4 kg) (P = .02). Neither serum sodium, chloride, potassium, bicarbonate, or creatinine changed significantly relative to baseline (P > .05 for all)., Conclusions: In an AHF cohort with diuretic resistance, MSDT was associated with increased diuresis without changes in serum chemistries or kidney function. Prospective studies of MSDT in AHF and diuretic resistance are warranted., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200-5000 mg/g and estimated glomerular filtration rate 25-75 mL/min/1.73m 2 ) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury-related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury-related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE-TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function., Methods: In DECLARE-TIMI 58, patients with type 2 diabetes, HbA 1c 6·5-12·0% (47·5-113·1 mmol/mol), with either established atherosclerotic cardiovascular disease or multiple risk factors, and creatinine clearance of at least 60 mL/min were randomly assigned (1:1) to 10 mg dapagliflozin or placebo once daily. A prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in estimated glomerular filtration rate [eGFR] to less than 60 mL/min per 1·73m 2 , end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR <15mL/min per 1·73 m 2 ), or death from renal or cardiovascular causes; a prespecified renal-specific composite outcome was the same but excluding death from cardiovascular causes. In this renal analysis, we report findings for the components of these composite outcomes, subgroup analysis of these composite outcomes, and changes in eGFR at different timepoints. DECLARE-TIMI 58 is registered with ClinicalTrials.gov, number NCT01730534., Findings: The trial took place between April 25, 2013, and Sept 18, 2018; median follow-up was 4·2 years (IQR 3·9-4·4). Of the 17 160 participants who were randomly assigned, 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m 2 , 7732 (45·1%) had an eGFR of 60 to less than 90 mL/min per 1·73 m 2 , and 1265 (7·4%) had an eGFR of less than 60 mL/min per 1·73 m 2 at baseline (one participant had missing data for eGFR); 6974 (40·6%) had established atherosclerotic cardiovascular disease and 10 186 (59·4%) had multiple risk factors. As previously reported, the cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus placebo (hazard ratio [HR] 0·76, 95% CI 0·67-0.87; p<0·0001); excluding death from cardiovascular causes, the HR for the renal-specific outcome was 0·53 (0·43-0·66; p<0·0001). We identified a 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1·73 m 2 (120 [1·4% vs 221 [2·6%]; HR 0·54 [95% CI 0·43-0·67]; p<0·0001). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (11 [0·1%] vs 27 [0·3%]; HR 0·41 [95% CI 0·20-0·82]; p=0·012). Both the cardiorenal and renal-specific composite outcomes were improved with dapagliflozin versus placebo across various prespecified subgroups, including those defined by baseline eGFR (cardiorenal outcome p interaction =0·97; renal-specific outcome p interaction =0·87) and the presence or absence of established atherosclerotic cardiovascular disease (cardiorenal outcome p interaction =0·67; renal-specific outcome p interaction =0·72). 6 months after randomisation, the mean decrease in eGFR was larger in the dapagliflozin group than in the placebo group. The mean change equalised by 2 years, and at 3 and 4 years the mean decrease in eGFR was less with dapagliflozin than with placebo., Interpretation: Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in this large and diverse population of patients with type 2 diabetes with and without established atherosclerotic cardiovascular disease, most of whom had preserved renal function., Funding: AstraZeneca., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hypertension is a global health problem and without adequate diagnosis and treatment is a risk factor for morbidity and mortality. Proper assessment of blood pressure is key to diagnosis and management of hypertension. Different methods of measurement are available for use and varying techniques are applied to patient care. Understanding the proper methods of blood pressure measurement both in and out of the physician's office is crucial for providing appropriate care to an individual patient. In addition, understanding the techniques used in research, on which current guidelines are based, is critical for proper application to daily practice. In this article, we review the types of blood pressure measurement techniques, discuss the benefits and limitations to each, explore future technological advances in measurement devices, and provide insight into research techniques, which ultimately guide our practice., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Iron stores assuring optimal efficacy/safety for erythropoiesis are unknown in the dialysis population. Using multicenter trial data, we related safety profiles, erythropoiesis-stimulating agent (ESA), and intravenous iron dosing to achieved iron stores in 441 subjects randomized 2 : 1 to ferric citrate or active control as their phosphate binder over 52 weeks. Intravenous iron was given at each site's discretion if ferritin ≤ 1,000 ng/mL and transferrin saturation ≤ 30%. Multivariable time-dependent Cox regression jointly related the primary safety outcome (composite of cardiac, infection, gastrointestinal, and hepatobiliary serious adverse events) to moving averages of ferritin and transferrin saturation over the preceding 90 days with covariate adjustment. Multivariable generalized estimating equations related elevated ESA and intravenous iron doses to trailing 90-day averages of ferritin and transferrin saturation with covariate adjustment. The adjusted hazard ratio for the safety composite per 10% increase in transferrin saturation was 0.84 (95% confidence interval 0.68 - 1.02, p = 0.08) and 1.09 (0.86 - 1.35, p = 0.48) per 400 ng/mL increase in ferritin. The adjusted hazard ratio for the safety composite was 0.50 (0.29 - 0.88, p = 0.016) for the highest transferrin saturation tertile vs. the lowest. Adjusted odds ratios for higher intravenous iron dose were lower in the highest (0.23 [0.16 - 0.35], p < 0.001) and middle transferrin saturation tertile (0.42 [0.31 - 0.57], p < 0.001) vs. lowest. Incidence of elevated ESA dose was lower in the highest transferrin saturation tertile (p = 0.01). Ferritin did not predict clinical events or ESA dose. Transferrin saturation may be a better marker than serum ferritin to judge optimal iron stores in dialysis patients. Transferrin saturations > 34% are safe and provide maximal efficacy.
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Objective: The purpose of our study was to evaluate the prevalence of nephrogenic systemic fibrosis (NSF) and nephrotoxicity among patients with differing degrees of renal dysfunction who are exposed to high doses of gadodiamide., Materials and Methods: A search of medical records identified patients who received high-dose IV gadodiamide for catheter angiography or CT between January 2002 and December 2005. The cohort was limited to patients who had received a dose of at least 40 mL of gadodiamide during a single imaging session, who underwent at least 1 year of clinical follow-up, and who had moderate to end-stage renal disease (estimated glomerular filtration rate [GFR] < 60 mL/min/1.73 m(2)) established within the previous 48 hours. Any observation suggestive of NSF was recorded, as were all estimated GFR values obtained during the 2 weeks before and the 5 days after gadodiamide administration., Results: Sixty-one patients met the inclusion criteria. The median estimated GFR was 30 mL/min/1.73 m(2) (range, 3-57 mL/min/1.73 m(2)). The median gadodiamide exposure was 80 mL (range, 40-200 mL). NSF eventually developed in one of the 61 patients, yielding a prevalence of 1.6%. Among the 33 patients not undergoing dialysis with estimated GFR documented within 5 days after contrast injection, the change in estimated GFR ranged from -8.8 to 42.9 mL/min/1.73 m(2), with a statistically significant median improvement of 2.4 mL/min/1.73 m(2) (p = 0.007)., Conclusion: Although gadolinium exposure appears to be a necessary precondition for NSF, gadolinium-based contrast agents alone are not sufficient to cause the disorder, even in very high doses. Clinically relevant nephrotoxicity of gadolinium-based contrast agents was not found.