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Background: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear., Purpose: To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death., Data Sources: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023., Study Selection: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 ., Data Extraction: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m 2 ), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes., Data Synthesis: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m 2 , of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes ( P for interaction > 0.05 for all)., Limitation: Individual participant-level data for hyperkalemia or acute kidney injury were not available., Conclusion: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD., Primary Funding Source: National Institutes of Health. (PROSPERO: CRD42022307589)., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-3236.

Background: Despite the availability of effective therapies for patients with chronic kidney disease, type 2 diabetes, and hypertension (the kidney-dysfunction triad), the results of large-scale trials examining the implementation of guideline-directed therapy to reduce the risk of death and complications in this population are lacking., Methods: In this open-label, cluster-randomized trial, we assigned 11,182 patients with the kidney-dysfunction triad who were being treated at 141 primary care clinics either to receive an intervention that used a personalized algorithm (based on the patient's electronic health record [EHR]) to identify patients and practice facilitators to assist providers in delivering guideline-based interventions or to receive usual care. The primary outcome was hospitalization for any cause at 1 year. Secondary outcomes included emergency department visits, readmissions, cardiovascular events, dialysis, and death., Results: We assigned 71 practices (enrolling 5690 patients) to the intervention group and 70 practices (enrolling 5492 patients) to the usual-care group. The hospitalization rate at 1 year was 20.7% (95% confidence interval [CI], 19.7 to 21.8) in the intervention group and 21.1% (95% CI, 20.1 to 22.2) in the usual-care group (between-group difference, 0.4 percentage points; P = 0.58). The risks of emergency department visits, readmissions, cardiovascular events, dialysis, or death from any cause were similar in the two groups. The risk of adverse events was also similar in the trial groups, except for acute kidney injury, which was observed in more patients in the intervention group (12.7% vs. 11.3%)., Conclusions: In this pragmatic trial involving patients with the triad of chronic kidney disease, type 2 diabetes, and hypertension, the use of an EHR-based algorithm and practice facilitators embedded in primary care clinics did not translate into reduced hospitalization at 1 year. (Funded by the National Institutes of Health and others; ICD-Pieces ClinicalTrials.gov number, NCT02587936.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Higher temperatures are associated with higher rates of hospital admissions for nephrolithiasis and acute kidney injury. Occupational heat stress is also a risk factor for kidney dysfunction in resource-poor settings. It is unclear whether ambient heat exposure is associated with loss of kidney function in patients with established chronic kidney disease. We assessed the association between heat index and change in estimated glomerular filtration rate (eGFR) in participants from the DAPA-CKD trial in a post-hoc analysis., Methods: DAPA-CKD was a randomised controlled trial of oral dapagliflozin 10 mg once daily or placebo that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73 m 2 . In this post-hoc analysis, we explored the association between time-varying daily centre-level heat index (ERA5 dataset) and individual-level change in eGFR in trial participants using linear mixed effect models and case-time series. The DAPA-CKD trial is registered with ClinicalTrials.gov, NCT03036150., Findings: Climate and eGFR data were available for 4017 (93·3%) of 4304 participants in 21 countries (mean age: 61·9 years; mean eGFR: 43·3 mL per 1·73 m 2 ; median 28 months follow-up). Across centres, a heat index of more than 30°C occurred on a median of 0·6% of days. In adjusted linear mixed effect models, within each 120-day window, each 30 days' heat index of more than 30°C was associated with a -0·6% (95% CI -0·9% to -0·3%) change in eGFR. Similar estimates were obtained using case-time series. Additional analyses over longer time-windows showed associations consistent with haemodynamic or seasonal variability, or both, but overall estimates corresponded to an additional 3·7 mL per 1·73 m 2 (95% CI 0·1 to 7·0) loss of eGFR per year in a patient with an eGFR of 45 mL per 1·73 m 2 located in a very hot versus a temperate environment., Interpretation: Higher ambient heat exposure is associated with more rapid eGFR decline in those with established chronic kidney disease. Efforts to mitigate heat exposure should be tested as part of strategies to attenuate chronic kidney disease progression., Funding: None., Competing Interests: Declaration of interests HJLH has received honoraria, paid to his institution (University Medical Center Groningen), for participation in steering committees from AstraZeneca, Janssen, Gilead, Bayer, Chinook, and CSL Pharma; honoraria for participation in advisory boards from Merck, Mitsubishi Tanabe, Janssen, and Mundipharma; fees for consultancy from AstraZeneca, AbbVie, Retrophin, Boehringer Ingelheim, and Novo Nordisk; and research grant support from AstraZeneca, AbbVie, Janssen, and Boehringer Ingelheim. GMC has received fees from AstraZeneca for the DAPA-CKD trial steering committee; serves on the Board of Directors for Satellite Healthcare, a non-profit dialysis provider; has received research grants from the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Institute of Allergy and Infectious Diseases, US National Heart, Lung, and Blood Institute, and CSL Behring; has served on trial steering committees with Akebia, AstraZeneca, Gilead, Sanifit, and Vertex; has served as an adviser to Ardelyx, CloudCath, Durect, Miromatrix, Outset, Renibus, Reata, Sanifit, Unicycive, and Vertex; and has served on data and safety monitoring boards for the National Institute of Diabetes and Digestive and Kidney Diseases, Bayer, Mineralys, and ReCor. RC-R has received honoraria as a consultant from AstraZeneca (DAPA-CKD Steering Committee), Boehringer Ingelheim, Bayer, Chinook, and Novo Nordisk; and research support and speaker fees from AstraZeneca, GSK, and Novo Nordisk. AML is an employee and stockholder of AstraZeneca. NJ has received support from AstaZeneca to attend conferences. JJVM has received payments for his work on clinical trials paid to his employer, Glasgow University; has received payments for consulting; is on the advisory board of Alnylam, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cardurion, Cytokinetics, DAICor, GSK, Ionis Pharmaceuticals, KBP Biosciences, Novartis, and Theracos; and has received personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus. PR has received honoraria to Steno Diabetes Center Copenhagen for lecture fees, steering group participation, and advisory board participation from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Novo Nordisk, Sanofi, and Eli Lilly, and research support from AstraZeneca. RDT has received consulting fees from Boehringer Ingelheim, Reata Pharma, and Chinook Pharma; received speakers fees from Medscape; participated in advisory boards for Bayer and Viofor; and participated in data monitoring committees for Akebia and Otsuka. DN reports unrelated work funded by GSK involving studies of kidney function in sub-Saharan Africa. DCW provides ongoing consultancy services to AstraZeneca and has received honoraria for participation in advisory boards and other activities, consultancy fees, or both from Amgen, AstraZeneca, Boehringer Ingelheim, Bayer, KSk, Janssen, Napp, Mundipharma, Medscape, Merck Sharp & Dohme, Pharmacosmos, Reata, Takeda, and Vifor Fresenius. BC has received research grant funding, paid to his employers (University College London and Royal Free London NHS Foundation Trust), from the UK Medical Research Council, the Colt Foundation, and AstraZeneca along with consultancy fees (also paid to his employer) from LifeArc. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Significance Statement: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy for CKD but are underused, in part because they are frequently withheld and not restarted due to hyperkalemia, AKI, or hospitalization. Consequently, ensuring persistent use of ACE inhibitors and ARBs in CKD has long been a major clinical priority. In this joint analysis of the CREDENCE and DAPA-CKD trials, the relative risk of discontinuation of ACE inhibitors and ARBs was reduced by 15% in patients randomized to sodium-glucose cotransporter 2 (SGLT2) inhibitors. This effect was more pronounced in patients with urine albumin:creatinine ratio ≥1000 mg/g, for whom the absolute benefits of these medications are the greatest. These findings indicate that SGLT2 inhibitors may enable better use of ACE inhibitors and ARBs in patients with CKD., Background: Strategies to enable persistent use of renin-angiotensin system (RAS) blockade to improve outcomes in CKD have long been sought. The effect of SGLT2 inhibitors on discontinuation of RAS blockade has yet to be evaluated., Methods: We conducted a joint analysis of canagliflozin and renal events in diabetes with established nephropathy clinical evaluation (CREDENCE) and dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD), two randomized, double-blind, placebo-controlled, event-driven trials of SGLT2 inhibitors in patients with albuminuric CKD. The main outcome was time to incident temporary or permanent discontinuation of RAS blockade, defined as interruption of an ACE inhibitor or ARB for at least 4 weeks or complete cessation during the double-blind on-treatment period. Cox regression analyses were used to estimate the treatment effects from each trial. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled with fixed effects meta-analysis to obtain summary treatment effects, overall and across key subgroups., Results: During median follow-up of 2.2 years across both trials, 740 of 8483 (8.7%) patients discontinued RAS blockade. The relative risk for discontinuation of RAS blockade was 15% lower in patients randomized to receiving SGLT2 inhibitors (HR, 0.85; 95% CI, 0.74 to 0.99), with consistent effects across trials ( P -heterogeneity = 0.92). The relative effect on RAS blockade discontinuation was more pronounced among patients with baseline urinary albumin:creatinine ratio ≥1000 mg/g (pooled HR, 0.77; 95% CI, 0.63 to 0.94; P -heterogeneity = 0.009)., Conclusions: In patients with albuminuric CKD with and without type 2 diabetes, SGLT2 inhibitors facilitate the use of RAS blockade., Clinical Trial Registry Name and Registration Number: ClinicalTrials.gov, NCT02065791 and NCT03036150 ., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023&#95;11&#95;21&#95;JASN0000000000000248.mp3., (Copyright © 2023 by the American Society of Nephrology.)

BACKGROUND: In the DAPA-CKD (Dapagliflozin in Patients with Chronic Kidney Disease) trial, dapagliflozin improved kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) with or without type 2 diabetes (T2D). In this post hoc analysis of DAPA-CKD, we assessed the effects of dapagliflozin on the correction and prevention of anemia. METHODS: The DAPA-CKD trial randomized patients (1:1) with an estimated glomerular filtration rate of 25 to 75 ml/min/1.73 m2 and a urinary albumin-to-creatinine ratio of 200 to 5000 mg/g to receive dapagliflozin 10 mg or placebo daily. Hematocrit was measured at baseline, 2 weeks, 2 and 4 months, and every 4 months thereafter. Anemia was defined as hematocrit less than 39% in men and less than 36% in women. Correction and incidence of anemia were defined as two consecutive measurements above or below these thresholds relative to baseline, respectively, during follow-up. We classified anemia-related adverse events using data from site investigator reports. RESULTS: Mean age of the 4304 participants was 61.8 years, and 67.5% had T2D. Among the 4292 (99.7%) participants with baseline hematocrit data, 1716 (40.0%) had anemia. Over the 2.4-year median follow-up, patients assigned to dapagliflozin had an increase in hematocrit of 2.3 percentage points (95% confidence interval [CI], 2.1 to 2.5) greater than those assigned to placebo. Among patients with anemia at baseline, anemia was corrected in 443 (53.3%) patients randomized to receive dapagliflozin and 247 (29.4%) patients randomized to receive placebo (hazard ratio, 2.29; 95% CI, 1.96 to 2.68). Among patients without anemia at baseline, 10.4% of patients assigned to dapagliflozin developed incident anemia compared with 23.7% in the placebo group (hazard ratio, 0.39; 95% CI, 0.31 to 0.48). Anemia-related adverse events occurred in 2.2% of patients assigned to dapagliflozin compared with 3.8% assigned to placebo. Effects of dapagliflozin on the correction and prevention of anemia were consistent in patients with and without T2D. The adverse event profile was similar to that known for dapagliflozin. CONCLUSIONS: This exploratory analysis suggests that dapagliflozin is associated with the prevention or correction of anemia in patients with CKD with and without T2D. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03036150.)

Background The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial (NCT03036150) demonstrated that dapagliflozin reduced the risk of kidney and cardiovascular events in patients with chronic kidney disease and albuminuria with and without type 2 diabetes. We aimed to determine whether baseline cardiovascular medication use modified the dapagliflozin treatment effect. Methods and Results We randomized 4304 adults with baseline estimated glomerular filtration rate 25 to 75 mL/min per 1.73 m 2 and urinary albumin:creatinine ratio 200 to 5000 mg/g to dapagliflozin 10 mg or placebo once daily. The primary end point was a composite of ≥50% estimated glomerular filtration rate decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. We categorized patients according to baseline cardiovascular medication use/nonuse. Patients were required by protocol to receive a stable (and maximally tolerated) dose of a renin-angiotensin-aldosterone system inhibitor. We observed consistent benefits of dapagliflozin relative to placebo, irrespective of baseline use/nonuse of renin-angiotensin-aldosterone system inhibitors (98.1%), calcium channel blockers (50.7%), β-adrenergic antagonists (39.0%), diuretics (43.7%), and antithrombotic (47.4%), and lipid-lowering (15.0%) agents. Use of these drugs in combination with dapagliflozin did not increase the number of serious adverse events. Conclusions The safety profile and efficacy of dapagliflozin on kidney and cardiovascular end points in patients with chronic kidney disease were consistent among patients treated and not treated at baseline with a range of cardiovascular medications. Registration Information clinicaltrials.gov. Identifier: NCT03036150.

Objective: To determine whether the benefits of dapagliflozin in patients with type 2 diabetes and chronic kidney disease (CKD) in the Dapagliflozin And Prevention of Adverse Outcomes in CKD trial (DAPA-CKD) varied by background glucose-lowering therapy (GLT)., Research Design and Methods: We randomized 4,304 adults (including 2,906 with type 2 diabetes) with a baseline estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio of 200-5,000 mg/g to dapagliflozin 10 mg or placebo once daily (NCT03036150). The primary end point was a composite of ≥50% eGFR decline, end-stage kidney disease, and kidney or cardiovascular cause of death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. In this prespecified analysis, we investigated the effects of dapagliflozin on these and other outcomes according to baseline GLT class or number of GLTs., Results: The effects of dapagliflozin on the primary composite outcome were consistent across GLT classes and according to the number of GLTs (all interaction P > 0.08). Similarly, we found consistent benefit of dapagliflozin compared with placebo on the secondary end points regardless of background GLT class or number of GLTs. The same applied to the rate of decline in the eGFR rate and safety end points. Dapagliflozin reduced the initiation of insulin therapy during follow-up compared with placebo (hazard ratio 0.72; 95% CI 0.54-0.96; P = 0.025)., Conclusions: Dapagliflozin reduced kidney and cardiovascular events in patients with type 2 diabetes and CKD across baseline GLT class or classes in combination., (© 2023 by the American Diabetes Association.)

Background: Acute hospitalizations are common in patients with chronic kidney disease (CKD) and often lead to decreases in health-related quality of life and increased care costs., Objective: To determine the effects of dapagliflozin on first hospitalizations and all (first and subsequent) hospitalizations and to explore effects on cause-specific hospitalizations., Design: Post hoc analysis of a randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT03036150)., Setting: 386 ambulatory practice sites in 21 countries from 2 February 2017 through 12 June 2020., Participants: Adults with an estimated glomerular filtration rate of 25 to 75 mL/min/1.73 m 2 and a urinary albumin-creatinine ratio of 200 to 5000 mg/g, with and without type 2 diabetes., Intervention: Dapagliflozin, 10 mg once daily, or matching placebo (1:1 ratio)., Measurements: The effects of dapagliflozin on first hospitalizations for any cause, all hospitalizations, and cause-specific (first and recurrent) hospitalizations were determined. The reported system organ class was used to evaluate reasons for admission. Hospitalizations were analyzed using Cox proportional hazards regression models (first hospitalization), the Lin-Wei-Yang-Ying method (all hospitalizations or death), and negative binomial models (cause-specific hospitalizations)., Results: The study included 4304 patients (mean age, 61.8 years; 33.1% women). During a median follow-up of 2.4 years, 2072 hospitalizations were reported among 1224 (28.4%) participants. Compared with placebo, dapagliflozin reduced risk for a first hospitalization (hazard ratio, 0.84 [95% CI, 0.75 to 0.94]) and all hospitalizations or death (rate ratio, 0.79 [CI, 0.70 to 0.89]). There was no evidence that the effects of dapagliflozin on first and all hospitalizations varied by baseline presence of type 2 diabetes ( P for interaction = 0.60 for each). Compared with placebo, dapagliflozin reduced the rate of admissions due to cardiac disorders, renal and urinary disorders, metabolism and nutrition disorders, and neoplasms., Limitations: This was a post hoc analysis and should be viewed as hypothesis-generating. Hospitalizations and causes were reported by site investigators and were not centrally adjudicated., Conclusion: Dapagliflozin reduced the risk for hospitalization for any cause in patients with CKD with and without type 2 diabetes., Primary Funding Source: AstraZeneca.

Background: Dapagliflozin reduces kidney failure risk in patients with CKD but can result in a reversible acute reduction in eGFR upon treatment initiation. Determinants of this eGFR reduction and its associations with efficacy and safety outcomes are unknown., Methods: The DAPA-CKD trial randomized 4304 adults with CKD and albuminuria to once-daily dapagliflozin 10 mg or placebo, added to standard care. We prespecified an analysis comparing the effects of dapagliflozin among patients who experienced relative reductions in eGFR (>10% or >0%-10%) or an increase in eGFR from baseline to 2 weeks and assessed long-term efficacy and safety thereafter., Results: A total of 4157 (96.6%) patients had eGFR data available at baseline and at 2 weeks. In the dapagliflozin and placebo groups, 1026 (49.4%) and 494 (23.7%), respectively, experienced an acute reduction in eGFR >10%. Among patients receiving dapagliflozin, those with an acute reduction in eGFR >10% experienced a long-term eGFR decline of -1.58 ml/min per 1.73 m 2 per year compared with -2.44 and -2.48 ml/min per 1.73 m 2 per year among those experiencing a less pronounced reduction or increase in eGFR, respectively ( P -interaction=0.05). In the placebo group, long-term eGFR decline was -3.27, -3.84, and -3.77 ml/min per 1.73 m 2 per year for acute eGFR reduction subgroups of >10%, >0%-10%, or increase in eGFR ( P -interaction=0.48). Rates of serious adverse events and adverse events of special interest in patients randomized to dapagliflozin were unrelated to the acute eGFR change., Conclusions: Among patients with CKD and albuminuria treated with dapagliflozin, an acute reduction in eGFR (from baseline to 2 weeks) is not associated with higher rates of CKD progression. Clinical Trial registration number: A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD) NCT03036150., (Copyright © 2022 by the American Society of Nephrology.)

Background: Despite renin-angiotensin-aldosterone system blockade and immunosuppressive treatment, focal segmental glomerulosclerosis (FSGS) often progresses to kidney failure. The objective of this prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease trial (DAPA-CKD) was to assess efficacy and safety of dapagliflozin in a small subgroup of participants with FSGS confirmed by kidney biopsy., Methods: In DAPA-CKD, patients with an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2 and urinary albumin:creatinine ratio (UACR) 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10 mg once daily or placebo as an adjunct to standard care and followed for median 2.4 years. The primary composite endpoint was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The endpoint of interest for this analysis was eGFR slope (acute effects from baseline to Week 2 and chronic effects from Week 2 to end of treatment)., Results: Of 104 participants with biopsy-confirmed FSGS, 45 were randomized to dapagliflozin and 59 to placebo. Mean (standard deviation) age was 54.0 (14.3) years, mean eGFR 41.9 (11.5) mL/min/1.73 m2 and median (interquartile range) UACR 1248 (749-2211) mg/g. The primary outcome occurred in 4 (8.9%) and 7 (11.9%) participants randomized to dapagliflozin and placebo, respectively [hazard ratio 0.62, 95% confidence interval (95% CI) 0.17, 2.17]. Dapagliflozin led to a larger acute reduction (standard error) in eGFR compared with placebo (-4.5, 95% CI -5.9 to -3.1 versus -0.9, -2.1 to 0.4 mL/min/1.73 m2/2 weeks). Thereafter, mean rates of chronic eGFR decline with dapagliflozin and placebo were -1.9 (-3.0, -0.9) and -4.0 (-4.9, -3.0) mL/min/1.73 m2/year, respectively (difference 2.0, 95% CI 0.6 to 3.5, mL/min/1.73 m2/year). Adverse events leading to study drug discontinuation were similar in both groups; there were fewer serious adverse events with dapagliflozin., Conclusions: Among DAPA-CKD participants with FSGS, dapagliflozin reduced the rate of chronic decline of eGFR compared with placebo, although this difference was not statistically significant., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Aims/hypothesis: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risks of progressive kidney disease, hospitalised heart failure or cardiovascular death, and death from all causes in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Patients with more severe CKD are at higher risk of kidney failure, cardiovascular events and all-cause mortality. In this post hoc analysis, we assessed the efficacy and safety of dapagliflozin according to baseline Kidney Disease Improving Global Outcomes (KDIGO) risk categories., Methods: DAPA-CKD was a double-blind, placebo-controlled trial that randomised patients with an eGFR of 25-75 ml min -1 [1.73 m] -2 and urinary albumin/creatinine ratio (UACR) of ≥22.6 and <565.0 mg/mmol (200-5000 mg/g) to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of ≥50% reduction in eGFR, end-stage kidney disease (ESKD), and death from a kidney or cardiovascular cause. Secondary endpoints included a kidney composite (≥50% reduction in eGFR, ESKD and death from a kidney cause), a cardiovascular composite (heart failure hospitalisation or cardiovascular death), and death from all causes. We used Cox proportional hazards regression analyses to assess relative and absolute effects of dapagliflozin across KDIGO risk categories., Results: Of the 4304 participants in the DAPA-CKD study, 619 (14.4%) were moderately high risk, 1349 (31.3%) were high risk and 2336 (54.3%) were very high risk when categorised by KDIGO risk categories at baseline. Dapagliflozin reduced the hazard of the primary composite (HR 0.61; 95% CI 0.51, 0.72) and secondary endpoints consistently across KDIGO risk categories (all p for interaction >0.09). Absolute risk reductions for the primary outcome were also consistent irrespective of KDIGO risk category (p for interaction 0.26). Analysing patients with and without type 2 diabetes separately, the relative risk reduction with dapagliflozin in terms of the primary outcome was consistent across subgroups of KDIGO risk categories. The relative frequencies of adverse events and serious adverse events were also similar across KDIGO risk categories., Conclusion/interpretations: The consistent benefits of dapagliflozin on kidney and cardiovascular outcomes across KDIGO risk categories indicate that dapagliflozin is efficacious and safe across a wide spectrum of kidney disease severity., Trial Registration: ClinicalTrials.gov NCT03036150., Funding: The study was funded by AstraZeneca., (© 2022. The Author(s).)

Aim: To assess the effects of dapagliflozin in patients with chronic kidney disease (CKD) and albuminuria, with and without type 2 diabetes, stratified by the Quételet (body mass) index (BMI)., Methods: We randomized 4304 adult patients with an estimated glomerular filtration rate (eGFR) of 25-75 ml/min/1.73m 2 and urinary albumin-to-creatinine ratio of 200-5000 mg/g to dapagliflozin 10 mg/day or placebo. The primary outcome was a composite of sustained decline in eGFR of 50% or more, kidney failure, or death from kidney or cardiovascular causes. Secondary outcomes included kidney composite endpoint (primary composite endpoint without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure/ cardiovascular death), and all-cause mortality. We categorized participants according to World Health Organization BMI criteria: lean/ideal (<25 kg/m 2 ), overweight (25-< 30 kg/m 2 ), grade 1 obesity (30-<35 kg/m 2 ), and grade 2/3 obesity (≥35 kg/m 2 )., Results: Of 4296 (99.8%) randomized participants, 888 (20.7%), 1491 (34.7%), 1136 (26.4%), and 781 (18.2%) were categorized as lean/ideal, overweight, grade 1 obesity, and grade 2/3 obesity, respectively. Median follow-up was 2.4 years. Benefits of dapagliflozin were observed independent of baseline BMI for primary and secondary endpoints. Hazard ratios (95% CI) for dapagliflozin versus placebo for the primary composite endpoint were 0.60 (0.43, 0.85), 0.55 (0.40, 0.75), 0.71 (0.49, 1.04), and 0.57 (0.37, 0.87) among participants in the lean/ideal, overweight, grade 1 obesity, and grade 2/3 obesity groups (interaction P = .72)., Conclusion: Among participants with CKD and albuminuria, with or without type 2 diabetes, kidney and cardiovascular benefits of dapagliflozin were evident and consistent across the BMI spectrum., (© 2022 John Wiley & Sons Ltd.)

The Kidney Precision Medicine Project (KPMP) seeks to establish a molecular atlas of the kidney in health and disease and improve our understanding of the molecular drivers of CKD and AKI. Herein, we describe the case of a 66-year-old woman with CKD who underwent a protocol KPMP kidney biopsy. Her clinical history included well-controlled diabetes mellitus, hypertension, and proteinuria. The patient's histopathology was consistent with modest hypertension-related kidney injury, without overt diabetic kidney disease. Transcriptomic signatures of the glomerulus, interstitium, and tubular subsegments were obtained from laser microdissected tissue. The molecular signatures that were uncovered revealed evidence of early diabetic kidney disease adaptation and ongoing active tubular injury with enriched pathways related to mesangial cell hypertrophy, glycosaminoglycan biosynthesis, and apoptosis. Molecular evidence of diabetic kidney disease was found across the nephron. Novel molecular assays can supplement and enrich the histopathologic diagnosis obtained from a kidney biopsy., (Copyright © 2022 by the American Society of Nephrology.)

Background: Chronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials., Methods: This study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials. Participants with no history of diabetes and HbA 1c less than 6·5% (48 mmol/mol) at baseline were included in this pooled analysis. New-onset type 2 diabetes was a prespecified exploratory endpoint in both DAPA-CKD and DAPA-HF trials and is the focus of this analysis. New-onset type 2 diabetes was identified by serial trial measurements of HbA 1c (two consecutive values ≥6·5% [≥48 mmol/mol]) or following a clinical diagnosis of diabetes between trial visits. Time to new-onset type 2 diabetes was analysed in a Cox proportional Hazards model from random assignment to end of treatment., Findings: 4003 participants (1398 [34·9%] from the DADA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) were included in our analysis: 1995 (49·8%) had received dapagliflozin and 2008 (50·2%) had received placebo. Over a median follow-up of 21·2 months (IQR 16·0 to 25·4), 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed type 2 diabetes (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). There was no heterogeneity between studies (p interaction 0·77) and there was no clear evidence that the effect of dapagliflozin varied in prespecified subgroups including sex, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use. More than 90% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA 1c 5·7% to 6·4% [39 to 46 mmol/mol]). Mean HbA 1c remained unchanged (placebo-adjusted change in the dapagliflozin group of -0·01% [95% CI -0·03 to 0·01], -0·1 mmol/mol [95% CI -0·3 to 0·1] at 12 months)., Interpretation: Treatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes in participants with chronic kidney disease and HF without a reduction in HbA 1c ., Funding: AstraZeneca., Competing Interests: Declaration of interests PR reports funding to his institution from AstraZeneca for participating in the steering committee for DAPA-CKD; has received funding to his institution for advisory boards from Sanofi Avensis and Boehringer Ingelheim; from Bayer, Gilead and Novo Nordisk for steering committees; from Novo Nordisk, Bayer and Eli Lilly for lectures; has received grants from Novo Nordisk; and has held stock in Novo Nordisk in the past 3 years. SEI received funding from AstraZeneca for participating in the steering committee for DAPA-HF; has received consultancy fees from Abbott, VTV Therapeutics, Esperion, Pfizer, and Merck; reports fees for clinical trial committee participation, advisory roles, and travel costs from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk; and honoraria for lectures from Merck, and AstraZeneca. KFD received funding to the University of Glasgow, Glasgow, UK, from AstraZeneca for DAPA-HF; and has received honoraria for lectures from AstraZeneca and Eli Lilly. PSJ reports payment to the University of Glasgow by AstraZeneca for his time working on the DAPA-HF and DELIVER trials, from Novartis for work on the PARADIGM-HF and PARAGON-HF trials, and Novo Nordisk; reports Speakers and advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and reports Research funding from Boehringer Ingelheim and Analog Devices. LK reports speakers honoriaria from Novo Nordisk, Novartis, AstraZeneca and Boehringer Ingleheim; support from AstraZeneca; and personal fees from Novartis and Bristol Myers Squibb as a speaker. MNK reports payment to his institution for participation in DAPA-HF; has received grant payment to his institution from Boehringer Ingelheim; has received personal fees or fees to his institution, or both, for consultancy from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck, Novo Nordisk, Sanofi, and Vifor Pharma; has received personal honoraria and honoraria to his institution for lectures from AstraZeneca, Boeringer Ingelheim, and Novo Nordisk; has received personal honoraria and honoraria to his institution from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Vifor Pharma for participation on DSMB for advisory boards; and has received study drug for a clinical trial from AstraZeneca and Boehringer Ingelheim. FAM reports personal fees from AstraZeneca. PP reports personal fees for consultancy and speakers bureau from AstraZeneca, Boehringer Ingelheim, Vifor Pharma, Servier, Bayer, Bristol Myers Squibb, Respocardia, Berlin-Chemie, Cibiem, Novartis and RenalGuard; other support for participation in clinical trials from Boehringer Ingelheim, Amgen, Vifor Pharma, Bayer, Bristol Myers Squibb, Cibiem, Novartis and RenalGuard; and research grants to his institution from Vifor Pharma. MSS reports grants from Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; grants and personal fees from Amgen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; and personal fees from Anthos Therapeutics, Bristol Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, and Ionis. MSS received an institutional research grant from AstraZeneca for DAPA-HF; received institutional research grants from Abbott, Amgen, Anthos Therapeutics, Bayer, Daiichi-Sankyo, Eisai, Intarcia, IONIS, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; received consulting fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy's Laboratories, Fibrogen, IFM Therapeutics, Intarcia, MedImmune, Merck, Moderna, and Novo Nordisk; MSS is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Regeneron, Roche, and Zora Biosciences. SDS received payment to his institution for participation in DAPA-HF; received grants to his institution from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, IONIS, Lilly, Mesoblast, MyoKardia, National Institutes of Health National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; received fees for consultancy from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta; and received honoraria for lectures from Novartis and AstraZeneca. DLD received funding from AstraZeneca for participating in the steering committee for DAPA-HF; reports consulting fees from AstraZeneca, Frontier Science − Madison Office, and 3D Communication; receives royalties or licenses for Fundamentals of Clinical Trials, Data Monitoring Committees: Practical Perspective, Data Monitoring Committees: A Case Studies Approach, and Statistical Methods for Clinical Trials; has received honoraria for lectures from Vanderbilt University, Nashville, TN, USA, and Harvard University, Cambridge, MA, USA: CME Course on Clinical Trials; and honoraria for participation on data safety monitoring board or advisory boards for Patient Centered Outcome Research Institute, Bristol Meiers Squibb, Sanifit, Tricidia, Boston Scientific, Actelion, Medtronic, Duke University, Lisa Nova, Mesoblast, GlaxoSmithKline, DalCor, and Cardiovascular Research Foundation. OB, ML, AML, MS, BVS, and CK are employees and stockholders of AstraZeneca. GMC received funding from AstraZeneca for participating in the steering committee for DAPA-CKD; has received research support from Amgen; data safety monitoring board participation for Bayer and ReCor; is on the board of directors for Satellite Healthcare; has participated on trial steering committees for Akebia, Gilead, Sanifit, Vertex; and holds stock in Ardelyx, loudCath, Durect, DxNow, Micromatrix, Outset, and Unicycive. FFH is a member of the DAPA-CKD study executive committee and is a study investigator and reports personal fees from Abbvie. RC-R received funding from AstraZeneca for participating in the steering committee for DAPA-CKD; received research grants from GlaxoSmithKline, and Novo Nordisk; has received consulting fees from Boehringer Ingleheim and Chinook; and honoraria for advisory boards or lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk. RDT received funding from AstraZeneca for participating in the steering committee for DAPA-CKD; has received fees for consultancy from Boehringer Ingelheim, Reata Pharma, and Chinook Pharma. received honoraria for lectures from Medscape and Medical Education Resources; and participated in data safety monitoring boards or advisory boards for Bayer, Viofor, Akebia, and Otsuka. DCW provides ongoing consultancy services to AstraZeneca; has received fees for data safety monitoring board or advisory board activity from Zydus and Gilead; and received personal fees from Bayer, Boehringer Ingelheim, Astellas, GSK, Janssen, Napp, Mundipharma, Vifor, TRicida, Zydus, and Amgen. JJVM reports payment to Glasgow University by AstraZeneca for time spent as principal investigator of DAPA-HF and co-principal Investigator of DELIVER and DETERMINE in heart failure and meetings and other activities related to these trials; AstraZeneca has also paid travel and accommodation for these meetings. These payments were made through a consultancy with Glasgow University and he did not receive personal payments in relation to this trial or drug; has received personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus; and reports steering committee and travel fees from Cytokinetics, advisor and travel fees from KBP Biosciences; steering committee and travel fees from Amgen, steering committee fees from Bayer, investigator and travel fees from Theracos, consultantcy and travel fees from IONIS, steering committee fees from DalCor, investigator, steering committee, and travel fees from Novartis, investigator, steering committee, and travel fees from GlaxoSmithKline, steering committee fees from Bristol Myers Squibb, consultantcy fees from Boehringer Ingelheim, advisory board fees from Cardurion, and advisory board fees from Alnylam all paid to the University of Glasgow. HJLH reports grant funding and honoraria for consultancy as a member of the steering committee of the DAPA-CKD trial paid to their institution from AstraZeneca; research grants paid to his employer from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk for clinical trials; consulting fees, paid to his employer from Abbvie, Boehringer Ingelheim, Travere Pharmaceuticals, and Novo Nordisk; fees for steering committee membership paid to his employer from Bayer, Chinook, CSL Pharma, Janssen, and Gilead; honoraria for lectures from AstraZeneca and Mitsubishi Tanabe; and has received honoraria for advisory board participation for Merck (paid to his employer), Mitsubishi Tanabe, and Mundipharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. 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: Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial., Methods: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m 2 and 75 mL/min per 1·73 m 2 and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150., Findings: Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI -33·1 to -25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of -35·1% (95% CI -39·4 to -30·6; p<0·0001) in patients with type 2 diabetes and -14·8% (-22·9 to -5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (p interaction <0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change -3·06, 95% CI -5·20 to -0·90; p=0·0056)., Interpretation: In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria., Funding: AstraZeneca., Competing Interests: Declaration of interests TG has received grants for statistical consulting from AstraZeneca, CSL Pharma, and Boehringer-Ingelheim, and has received personal fees from Janssen Pharmaceuticals, DURECT Corporation and Pfizer for statistical consulting. GMC has received fees from AstraZeneca for the DAPA-CKD trial steering committee, research grants from the US National Institute of Diabetes and Digestive and Kidney Diseases, and Amgen, is on the board of directors for Satellite Healthcare, has received fees for advisory boards from Baxter, Cricket, DiaMedica, and Reata, holds stock options for Ardelyx, CloudCath, Durect, DxNow, and Outset, has received fees from Akebia, Sanifit and Vertex for trial steering committees, and has received fees for data safety and monitoring board service from Angion, Bayer, and ReCor. JJVM's employer, Glasgow University, has received payments for his work on clinical trials, consulting, and is on the advisory board of Alnylam, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cardurion, Cytokinetics, DAICor, GSK, Ionis Pharmaceuticals, KBP Biosciences, Novartis, and Theracos; and had received personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus. AML, CDS, and BVS are employees and stockholders of AstraZeneca. RC-R has received consulting fees from Boehringer Ingelheim and Chinook; lecture fees from Amgen, Boehringer Ingelheim, and Janssen; honoraria for advisory boards from Boehringer Ingelheim and Novo Nordisk; and research support from GSK, Novo Nordisk, and AstraZeneca. PR has received honoraria to Steno Diabetes Center Copenhagen for lecture fees, steering group participation, and advisory board participation from AstraZeneca, Bayer, Boehringer Ingelheim,Gilead, Novo Nordisk, Sanofi,and Eli Lilly, and research support from AstraZeneca. RDT is a consultant for AstraZeneca, Amgen, Bayer, Boehringer-Ingelheim, Medscape, Otsuka, Reata, and Relypsa. DCW provides ongoing consultancy services to AstraZeneca and has received honoraria or consultancy fees from Amgen, AstraZeneca, Astellas, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Napp, Mundipharma, Tricida, and Vifor Fresenius. HJLH is consultant for AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Gilead, Janssen, Merck, Mundi Pharma, Mitsubishi Tanabe, Novo Nordisk, and Travere, and has received research support from Abbvie, AstraZeneca, Boehringer Ingelheim, and Janssen. NJ declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF)., Background: Patients with CKD, with and without type 2 diabetes, were enrolled in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial. Some patients had HF at baseline., Methods: A total of 4,304 participants were randomized to dapagliflozin 10 mg daily or placebo. The primary composite endpoint was ≥50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/cardiovascular death. Secondary endpoints were a kidney composite (primary endpoint minus cardiovascular death), the composite of cardiovascular death/HF hospitalization, and all-cause death. Analysis of outcomes according to HF history was prespecified., Results: HF patients (n = 468; 11%) were older and had more coronary disease, atrial fibrillation, and type 2 diabetes. Mean estimated glomerular filtration rate was similar in patients with and without HF. Rates of HF hospitalization/cardiovascular death and death from any cause were higher in HF patients, but the secondary kidney failure outcome occurred at the same rate in people with and without HF. Dapagliflozin reduced the risk of the primary outcome equally in patients with HF (HR: 0.58 [95% CI: 0.37-0.91]) and without HF (HR: 0.62 [95% CI: 0.51-0.75]) (P interaction = 0.59). The proportional risk-reductions were similar in patients with and without HF for the cardiovascular death/HF hospitalization composite (HR: 0.68 [95% CI: 0.44-1.05] vs HR: 0.70 [95% CI: 0.51-0.97], respectively; P interaction = 0.90), and all-cause death (HR: 0.56 [95% CI: 0.34-0.93] vs HR: 0.73 [95% CI: 0.54-0.97], respectively; P interaction = 0.39), although absolute risk reductions were larger in HF patients. Adverse event rates were low and did not differ among patients with or without HF., Conclusions: Dapagliflozin reduced the risk of kidney failure and cardiovascular death/HF hospitalization and prolonged survival in CKD patients with or without type 2 diabetes, independently of history of HF. (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD]; NCT03036150)., Competing Interests: Funding Support and Author Disclosures The DAPA-CKD trial was funded by AstraZeneca. Prof McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; his employer, Glasgow University, has received payment for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, Theracos; and he has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca. Dr Wheeler has received honoraria and/or consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Napp, Mundipharma, Medscape, Merck Sharp and Dohme, Pharmacosmos, Reata, Takeda, and Vifor Fresenius. Drs Stefánsson, Sjöström, and Langkilde are employees and stockholders of AstraZeneca. Dr Correa-Rotter has received honoraria from AbbVie, AstraZeneca, GlaxoSmithKline, Medtronic, and Boehringer Ingelheim; has lectured for Amgen, Janssen, Takeda, AstraZeneca, and Boehringer Ingelheim; and has received research support from GlaxoSmithKline, Novo Nordisk, and AstraZeneca. Dr Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee; has received research grants from NIDDK and Amgen; is on the board of directors for Satellite Healthcare; has received fees for advisory boards for Baxter, Cricket, DiaMedica, and Reata; holds stock options for Ardelyx, CloudCath, Durect, DxNow, and Outset; has received fees from Akebia, Sanifit, and Vertex for trial steering committees; and has received fees for DSMB service from Angion, Bayer, and ReCor. Dr Hou has received honoraria from AbbVie and AstraZeneca. Dr Rossing has received honoraria to Steno Diabetes Center Copenhagen for consultancy from AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Vifor; and has received research support from AstraZeneca, and Novo Nordisk. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, and Theracos, and has consulted for Abbott, Action Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Lilly, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent. Dr Toto has served as a consultant for AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Medscape, Otsuka, Reata, and Relypsa. Dr Heerspink has served as a consultant for AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Gilead, Janssen, Merck, Mundi Pharma, Mitsubishi Tanabe, Novo Nordisk, and Retrophin; and has received research support from Abbvie, AstraZeneca, Boehringer Ingelheim, and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Dapagliflozin reduced the risk of kidney failure in patients with chronic kidney disease with and without type 2 diabetes in the DAPA-CKD trial. In this pre-specified analysis, we assessed the effect of dapagliflozin on the rate of change in estimated glomerular filtration rate (eGFR)-ie, the eGFR slope., Methods: DAPA-CKD was a randomised controlled trial that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio (UACR) of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73m 2 . Participants were randomly assigned (1:1) to oral dapagliflozin 10 mg once daily or placebo, added to standard care. In this pre-specified analysis, we analysed eGFR slope using mixed-effect models with different slopes from baseline to week 2 (acute eGFR decline), week 2 to end of treatment (chronic eGFR slope), and baseline to end of treatment (total eGFR slope). DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150, and is now complete., Findings: Between Feb 2, 2017, and April 3, 2020, 4304 participants were recruited, of whom 2152 (50%) were assigned to dapagliflozin and 2152 (50%) were assigned to placebo. At baseline, the mean age was 62 years (SD 12), 1425 (33·1%) participants were women, 2906 (67·5%) participants had type 2 diabetes. The median on-treatment follow-up was 2·3 years (IQR 1·8-2·6). From baseline to the end of treatment, dapagliflozin compared with placebo slowed eGFR decline by 0·95 mL/min per 1·73 m 2 per year (95% CI 0·63 to 1·27) in the overall cohort. Between baseline and week 2, dapagliflozin compared with placebo resulted in an acute eGFR decline of 2·61 mL/min per 1·73 m 2 (2·16 to 3·06) in patients with type 2 diabetes and 2·01 mL/min per 1·73 m 2 (1·36 to 2·66) in those without type 2 diabetes. Between week 2 and end of treatment, dapagliflozin compared with placebo reduced the mean rate of eGFR decline by a greater amount in patients with type 2 diabetes (mean difference in chronic eGFR slope 2·26 mL/min per 1·73 m 2 per year [1·88 to 2·64]) than in those without type 2 diabetes (1·29 mL/min per 1·73 m 2 per year [0·73 to 1·85]; p interaction =0·0049). Between baseline and end of treatment, the effect of dapagliflozin compared with placebo on the decline of total eGFR slope in patients with type 2 diabetes was 1·18 mL/min per 1·73 m 2 per year (0·79 to 1·56) and without type 2 diabetes was 0·46 mL/min per 1·73 m 2 per year (-0·10 to 1·03; p interaction =0·040). The total eGFR slope was steeper in patients with higher baseline HbA 1c and UACR; the effect of dapagliflozin on eGFR slope was also more pronounced in patients with higher baseline HbA 1c and UACR., Interpretation: Dapagliflozin significantly slowed long-term eGFR decline in patients with chronic kidney disease compared with placebo. The mean difference in eGFR slope between patients treated with dapagliflozin versus placebo was greater in patients with type 2 diabetes, higher HbA 1c , and higher UACR., Funding: AstraZeneca., Competing Interests: Declaration of interests HJLH is consultant for AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Gilead, Janssen, Merck, Mundi Pharma, Mitsubishi Tanabe, Novo Nordisk, and Travere, and has received research support from Abbvie, AstraZeneca, Boehringer Ingelheim, and Janssen. GMC has received fees from AstraZeneca for the DAPA-CKD trial steering committee; has received research grants from the US National Institute of Diabetes and Digestive and Kidney Diseases, and Amgen; is on the board of directors for Satellite Healthcare; has received fees for advisory boards from Baxter, Cricket, DiaMedica, and Reata; holds stock options for Ardelyx, CloudCath, Durect, DxNow, and Outset; has received fees from Akebia, Sanifit, and Vertex for trial steering committees; and has received fees for Data Safety and Monitoring Board service from Angion, Bayer, and ReCor. TG has received grants for statistical consulting from AstraZeneca, CSL-pharma, and Boehringer Ingelheim and has received personal fees from Janssen Pharmaceuticals, DURECT Corporation, and Pfizer for statistical consulting. JJVM's employer, Glasgow University, has received payments for his work on clinical trials, consulting, and is on the advisory board of Alnylam, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cardurion, Cytokinetics, DAICor, GSK, Ionis Pharmaceuticals, KBP Biosciences, Novartis, and Theracos; and had received personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus. RC-R has received consulting fees from Boehringer Ingelheim, and Chinook; lecture fees from Amgen, Boehringer Ingelheim, and Janssen; honoraria for advisory boards from Boehringer Ingelheim and Novo Nordisk; and research support from GSK, Novo Nordisk and AstraZeneca. RDT has received consulting fees from Boehringer Ingelheim, Reata Pharma, and Chinook Pharma; received speakers fees from Medscape; participated in advisory boards for Bayer and Viofor; and participated in data monitoring committees for Akebia and Otsuka. PR has received honoraria to Steno Diabetes Center Copenhagen for lecture fees, steering group participation, and advisory board participation from AstraZeneca, Bayer, Boehringer Ingelheim,Gilead, Novo Nordisk, Sanofi, and Eli Lilly, and research support from AstraZeneca. DCW provides ongoing consultancy services to AstraZeneca and has received honoraria or consultancy fees from Amgen, AstraZeneca, Astellas, Boehringer Ingelheim, Bayer, GSK, Janssen, Napp, Mundipharma, Tricida, and Vifor Fresenius. BVS, CDS, and AML are employees and stockholders of AstraZeneca. NJ declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin significantly reduced risk of kidney failure and prolonged survival in patients with CKD with or without type 2 diabetes., Methods: Adults with eGFR of 25-75 ml/min per 1.73 m 2 and urinary albumin-to-creatinine ratio of 200-5000 mg/g had been randomized to receive dapagliflozin 10 mg/d or placebo. Here, we conducted a prespecified analysis of dapagliflozin's effects in patients with stage 4 CKD (eGFR,30 ml/min per 1.73 m 2 ) at baseline. The primary end point was a composite of time to ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Secondary end points were a kidney composite (same as the primary end point but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death., Results: A total of 293 participants with stage 4 CKD received dapagliflozin and 331 received placebo. Patients with stage 4 CKD randomized to dapagliflozin experienced a 27% (95% confidence interval [95% CI]: -2 to 47%) reduction in the primary composite endpoint, and 29% (-2 to 51%), 17% (-53 to 55%), and 32% (-21 to 61%) reductions in the kidney, cardiovascular and mortality endpoints, respectively, relative to placebo. Interaction P-values were 0.22, 0.13, 0.63, and 0.95, respectively, comparing CKD stages 4 versus 2/3. The eGFR slope declined by 2.15 and 3.38 ml/min per 1.73 m 2 per year in the dapagliflozin and placebo groups, respectively ( P =0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest., Conclusions: Among patients with stage 4 CKD and albuminuria, the effects of dapagliflozin were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks., (Copyright © 2021 by the American Society of Nephrology.)

Objective: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status., Research Design and Methods: We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m 2 , and urinary albumin-to-creatinine ratio 200-5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death., Results: Of 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent ( P for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes., Conclusions: Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status., (© 2021 by the American Diabetes Association.)

Immunoglobulin A (IgA) nephropathy is a common form of glomerulonephritis, which despite use of renin-angiotensin-aldosterone-system blockers and immunosuppressants, often progresses to kidney failure. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in participants with chronic kidney disease with and without type 2 diabetes, including those with IgA nephropathy. Participants with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m 2 and urinary albumin-to-creatinine ratio 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10mg or placebo, as adjunct to standard care. The primary composite endpoint was a sustained decline in eGFR of 50% or more, end-stage kidney disease, or death from a kidney disease-related or cardiovascular cause. Of 270 participants with IgA nephropathy (254 [94%] confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to placebo, and followed for median 2.1 years. Overall, mean age was 51.2 years; mean eGFR, 43.8 mL/min/1.73m 2 ; and median urinary albumin-to-creatinine ratio, 900 mg/g. The primary outcome occurred in six (4%) participants on dapagliflozin and 20 (15%) on placebo (hazard ratio, 0.29; 95% confidence interval, 0.12, 0.73). Mean rates of eGFR decline with dapagliflozin and placebo were -3.5 and -4.7 mL/min/1.73m 2 /year, respectively. Dapagliflozin reduced the urinary albumin-to-creatinine ratio by 26% relative to placebo. Adverse events leading to study drug discontinuation were similar with dapagliflozin and placebo. There were fewer serious adverse events with dapagliflozin, and no new safety findings in this population. Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Aims: Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death., Methods and Results: DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo., Conclusion: In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials., Methods: In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol)., Results: Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR)., Conclusions: Participants with a wide range of underlying kidney diseases receiving renin-angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2-4 and increased albuminuria, with and without T2D., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Rationale & Objective: Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes., Study Design: Post hoc analysis of a randomized controlled trial., Setting & Participants: Participants with type 2 diabetes and chronic kidney disease who progressed to dialysis therapy (n=590) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)., Exposure: Randomized treatment assignment (darbepoetin vs placebo)., Outcomes: All-cause mortality, CV mortality, nonfatal myocardial infarction, heart failure, and stroke within the first 180 days of dialysis therapy initiation., Analytical Approach: Proportional hazards regression., Results: Overall, 590 of 4,038 (14.6%) participants initiated dialysis therapy during the trial (n=298 and 292 in the darbepoetin and placebo groups, respectively). Corresponding hemoglobin levels were 11.3±1.6 and 9.5±1.5g/dL (P<0.001). Death from any cause occurred in 31 (10.4%) participants assigned to darbepoetin and 28 (9.6%) assigned to placebo (HR, 1.16; 95% CI, 0.69-1.93), while death from CV causes occurred in 15 (5.0%) and 13 (4.5%) participants, respectively (HR, 1.21; 95% CI, 0.58-1.93). There were no differences in risk for nonfatal myocardial infarction or heart failure. Stroke occurred in 8 (2.8%) participants assigned to darbepoetin and 1 (0.3%) assigned to placebo (HR, 8.6; 95% CI, 1.1-68.7)., Limitations: Post hoc analyses of a subgroup of study participants., Conclusions: Despite initiating dialysis therapy with a higher hemoglobin level, prior treatment with darbepoetin was not associated with a reduction in mortality, myocardial infarction, or heart failure in the first 180 days, but a higher frequency of stroke was observed. In the absence of more definitive data, this may inform decisions regarding the use of erythropoiesis-stimulating agents to treat mild to moderate anemia in patients with type 2 diabetes and chronic kidney disease nearing dialysis therapy initiation., (Copyright © 2018. Published by Elsevier Inc.)

Sodium-glucose cotransporter 2 inhibitors are antihyperglycaemic medications with an emerging evidence base for cardiovascular and kidney disease risk reduction. Sodium-glucose cotransporter 2 inhibitors medications lower plasma glucose by inhibiting glucose reabsorption in the proximal tubule of the kidney independent of insulin. Furthermore, they reduce intraglomerular pressure by restoring tubuloglomerular feedback. Large cardiovascular outcome trials of both empagliflozin and canagliflozin have consistently shown beneficial kidney effects that go beyond glycaemic control, such as reducing risk for incident nephropathy and progression of chronic kidney disease. The mechanisms by which sodium-glucose cotransporter 2 inhibitors improve kidney outcomes are not clear. Proposed hypotheses underpinning the kidney benefits include kidney-specific effects such as decreased intraglomerular pressure, activation of angiotensin-(1-7) and the Mas receptor leading to decreased inflammation, decrease in overall kidney oxygen consumption, rise in erythropoietin levels, inhibition of the renal sodium-hydrogen exchanger and secondary kidney effects related to improvements in HbA 1c and blood pressure. This review will focus on describing the mechanisms of action of sodium-glucose cotransporter 2 inhibitors in the kidney, clinical efficacy data on their use in patients with chronic kidney disease, postulated physiologic underpinnings of kidney protection observed with sodium-glucose cotransporter 2 inhibitors and the promise and potential pitfalls for their use in patients with chronic kidney disease.

Background: Low serum magnesium (SMg) has been linked to increased mortality and cardiovascular disease (CVD) in the general population. We examined whether this association is similar in participants with versus without prevalent chronic kidney disease (CKD) in the multiethnic Dallas Heart Study (DHS) cohort., Methods: SMg was analyzed as a continuous variable and divided into tertiles. Study outcomes were all-cause death, cardiovascular (CV) death or event, and CVD surrogate markers, evaluated using multivariable Cox regression models adjusted for demographics, comorbidity, anthropometric and biochemical parameters including albumin, phosphorus and parathyroid hormone, and diuretic use. Median follow-up was 12.3 years (11.9-12.8, 25th percentile-75th percentile)., Results: Among 3551 participants, 306 (8.6%) had prevalent CKD. Mean SMg was 2.08 ± 0.19 mg/dL (0.85 ± 0.08 mM, mean ± SD) in the CKD and 2.07 ± 0.18 mg/dL (0.85 ± 0.07 mM) in the non-CKD subgroups. During the follow-up period, 329 all-cause deaths and 306 CV deaths or events occurred. In a fully adjusted model, every 0.2 mg/dL decrease in SMg was associated with ∼20-40% increased hazard for all-cause death in both CKD and non-CKD subgroups. In CKD participants, the lowest SMg tertile was also independently associated with all-cause death (adjusted hazard ratio 2.31; 95% confidence interval 1.23-4.36 versus 1.15; 0.55-2.41; for low versus high tertile, respectively)., Conclusions: Low SMg levels (1.4-1.9 mg/dL; 0.58-0.78 mM) were independently associated with all-cause death in patients with prevalent CKD in the DHS cohort. Randomized clinical trials are important to determine whether Mg supplementation affects survival in CKD patients.

Background: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA ® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk., Methods: CARMELINA ® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA ® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure., Results: Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m 2 , and eGFR 55 ± 25 mL/min/1.73 m 2 . A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m 2 or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common., Conclusions: CARMELINA ® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier-NCT01897532; registered July 9, 2013.

Importance: Major depressive disorder (MDD) is prevalent among patients with chronic kidney disease (CKD) and is associated with morbidity and mortality. The efficacy and adverse events of selective serotonin reuptake inhibitors in these patients are unknown., Objective: To determine whether treatment with sertraline improves depressive symptoms in patients with CKD and MDD., Design, Setting, and Participants: The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) was a randomized, double-blind, placebo-controlled trial involving 201 patients with stage 3, 4, or 5 non-dialysis-dependent CKD, who were enrolled at 3 US medical centers. The Mini Neuropsychiatric Interview was used to establish MDD. The first participant was randomized in March 2010 and the last clinic visit occurred in November 2016., Interventions: After a 1-week placebo run-in, participants were randomized to sertraline (n = 102) for 12 weeks at an initial dose of 50 mg/d (escalated to a maximum dose of 200 mg/d based on tolerability and response) or matching placebo (n = 99)., Main Outcomes and Measures: The primary outcome was improvement in depressive symptom severity from baseline to 12 weeks determined by the 16-item Quick Inventory of Depression Symptomatology-Clinician Rated (QIDS-C16) (score range, 0-27; minimal clinically important difference, 2 points). Secondary outcomes included improvement in quality of life (Kidney Disease Quality of Life Survey-Short Form; score range, 0-100; higher scores indicate more favorable quality of life) and adverse events., Results: There were 201 patients (mean [SD] age, 58.2 [13.2] years; 27% female) randomized. The primary analysis included 193 patients who had at least 1 outcome assessment after randomization. The mean (SD) baseline QIDS-C16 score was 14.0 (2.4) in the sertraline group (n = 97) and 14.1 (2.4) in the placebo group (n = 96). The median participation time was 12.0 weeks and the median achieved dose was 150 mg/d, which was not significantly different between the groups. The QIDS-C16 score changed by -4.1 in the sertraline group and by -4.2 in the placebo group (between-group difference, 0.1 [95% CI, -1.1 to 1.3]; P = .82). There was no significant between-group difference in change in patient-reported overall health on the Kidney Disease Quality of Life Survey (median score, 0 in the sertraline group vs 0 in the placebo group; between-group difference, 0 [95% CI, -10.0 to 0]; P = .61). Nausea or vomiting occurred more frequently in the sertraline vs placebo group (22.7% vs 10.4%, respectively; between-group difference, 12.3% [95% CI, 1.9% to 22.6%], P = .03), as well as diarrhea (13.4% vs 3.1%; between-group difference, 10.3% [95% CI, 2.7% to 17.9%], P = .02)., Conclusions and Relevance: Among patients with non-dialysis-dependent CKD and MDD, treatment with sertraline compared with placebo for 12 weeks did not significantly improve depressive symptoms. These findings do not support the use of sertraline to treat MDD in patients with non-dialysis-dependent CKD., Trial Registration: clinicaltrials.gov Identifier: NCT00946998.

Background: The pathogenesis of chronic kidney disease associated anemia is multifactorial and includes decreased production of erythropoietin (EPO), iron deficiency, inflammation, and EPO resistance. To better understand the trajectory of these parameters, we described temporal trends in hemoglobin (Hb), ferritin, transferrin saturation, C-reactive protein (CRP), and darbepoetin dosing in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT)., Methods: We performed a post hoc analysis of 4,038 participants in TREAT. Mixed effects linear regression models were used to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD). Likelihood ratio tests were used to determine the overall differences in biomarker values and differences in trajectories between those who did and did not develop ESRD., Results: Hb declined precipitously in the year prior to the development of ESRD (irrespective of treatment assignment), and was on average 1.15 g/dL (95% CI -1.26 to -1.04) lower in those who developed ESRD versus those who did not, at the time of ESRD/end of follow-up. Simultaneously, the mean darbepoetin dose and CRP concentration increased, while serum ferritin and transferrin saturations were >140 μg/L and 20%, respectively., Conclusions: Our analyses provide descriptive insights regarding the temporal changes of Hb, darbepoetin dose, and related parameters as ESRD approaches in participants of TREAT. Hb declined as much as 1-2 years prior to the development of ESRD, without biochemical evidence of iron deficiency. The most precipitous decline occurred in the months immediately prior to ESRD, despite administration of escalating doses of darbepoetin and in parallel with an increase in CRP., (© 2017 S. Karger AG, Basel.)

Objective: Incident acute kidney injury and prevalent chronic kidney disease are commonly encountered in septic patients. We examined the differential effect of acute kidney injury and chronic kidney disease on the association between cumulative fluid balance and hospital mortality in critically ill septic patients., Design: Retrospective cohort study., Setting: Urban academic medical center ICU., Patients: ICU adult patients with severe sepsis or septic shock and serum creatinine measured within 3 months prior to and 72 hours of ICU admission. Patients with estimated glomerular filtration rate less than 15 mL/min/1.73 m or receiving chronic dialysis were excluded., Interventions: None., Measurements and Main Results: A total of 2,632 patients, 1,211 with chronic kidney disease, were followed up until hospital death or discharge. Acute kidney injury occurred in 1,525 patients (57.9%), of whom 679 (44.5%) had chronic kidney disease. Hospital mortality occurred in 603 patients (22.9%). Every 1-L increase in cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality in all patients (adjusted odds ratio, 1.06 [95% CI] 1.04-1.08; p < 0.001), and in each acute kidney injury/chronic kidney disease subgroup (adjusted odds ratio, 1.06 [1.03-1.09] for acute kidney injury+/chronic kidney disease+; 1.09 [1.05-1.13] for acute kidney injury-/chronic kidney disease+; 1.05 [1.03-1.08] for acute kidney injury+/chronic kidney disease-; and 1.07 [1.02-1.11] for acute kidney injury-/chronic kidney disease-). There was a significant interaction between acute kidney injury and chronic kidney disease on cumulative fluid balance (p =0.005) such that different cumulative fluid balance cut-offs with the best prognostic accuracy for hospital mortality were identified: 5.9 L for acute kidney injury+/chronic kidney disease+; 3.8 L for acute kidney injury-/chronic kidney disease+; 4.3 L for acute kidney injury+/chronic kidney disease-; and 1.5 L for acute kidney injury-/chronic kidney disease-. The addition of cumulative fluid balance to the admission Sequential Organ Failure Assessment score had increased prognostic utility for hospital mortality when compared with Sequential Organ Failure Assessment alone, particularly in patients with acute kidney injury., Conclusions: Higher cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality regardless of acute kidney injury or chronic kidney disease presence. We characterized cumulative fluid balance cut-offs associated with hospital mortality based on acute kidney injury/chronic kidney disease status, underpinning the heterogeneity of fluid regulation in sepsis and kidney disease.

Thrombotic events while receiving antiplatelet agents (APAs) are more common in subjects with versus without chronic kidney disease (CKD). Data on antiplatelet effects of APA in CKD are scarce and limited by lack of baseline platelet function before APA treatment. We hypothesized subjects with stages 4 to 5 CKD versus no CKD have greater baseline platelet aggregability and respond poorly to aspirin and clopidogrel. In a prospective controlled study, we measured whole blood platelet aggregation (WBPA) in 28 CKD and 16 non-CKD asymptomatic stable outpatients not on APA, frequency-matched for age, gender, obesity, and diabetes mellitus. WBPA was remeasured after 2 weeks of each aspirin and aspirin plus clopidogrel. The primary outcome was percent inhibition of platelet aggregation (IPA) from baseline. The secondary outcome was residual platelet aggregability (RPA; proportion with <50% IPA). Baseline platelet aggregability was similar between groups except adenosine diphosphate-induced WBPA, which was higher in CKD versus non-CKD; median (interquartile range) = 13.5 (9.5 to 16.0) versus 9.0 (6.0 to 12.0) Ω, p = 0.007. CKD versus non-CKD participants had lower clopidogrel-induced IPA, 38% versus 72%, p = 0.04. A greater proportion of CKD versus non-CKD participants had RPA after clopidogrel treatment (56% vs 8.3%, p = 0.01). There were no significant interactions between CKD and the presence of cytochrome P450 2C19 polymorphisms for platelet aggregability in clopidogrel-treated participants. In conclusion, CKD versus non-CKD subjects exhibited similar platelet aggregation at baseline, similar aspirin effects and greater RPA on clopidogrel, which was independent of cytochrome P450 2C19 polymorphisms., (Published by Elsevier Inc.)

In this manuscript, nephrologist-investigators from one of five Clinical Center Networks of the Systolic Blood Pressure Intervention Trial (SPRINT) provide background information and context on the intensity of anti-hypertensive therapy in conjunction with the release of detailed results from SPRINT's primary analysis. The authors highlight published evidence on the safety and efficacy of differing intensities of anti-hypertensive therapy in mild to moderate CKD, where SPRINT will help to inform practice, as well as where gaps in evidence will remain. The authors also challenge the nephrology community to renew its attention and efforts on hypertension clinical care and research., (Copyright © 2016 by the American Society of Nephrology.)

Background: The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified., Study Design: Retrospective analysis of prospective randomized clinical trial., Setting & Participants: We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo., Predictors: Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR)., Outcomes: Cause of death as adjudicated by a blinded committee., Results: Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection-related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles., Limitations: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available., Conclusions: In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown., Methods: We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes., Results: The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group., Conclusions: Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).

Background: Type 2 diabetes mellitus (T2DM) is the most important contributing cause of end-stage renal disease (ESRD) worldwide. Bardoxolone methyl, a nuclear factor-erythroid-2-related factor 2 activator, augments estimated glomerular filtration. The Bardoxolone methyl EvAluation in patients with Chronic kidney disease and type 2 diabetes mellitus: the Occurrence of renal eveNts (BEACON) trial was designed to establish whether bardoxolone methyl slows or prevents progression to ESRD. Herein, we describe baseline characteristics of the BEACON population., Methods: BEACON is a randomized double-blind placebo-controlled clinical trial in 2185 patients with T2DM and chronic kidney disease stage 4 (eGFR between 15 and 30 mL/min/1.73 m(2)) designed to test the hypothesis that bardoxolone methyl added to guideline-recommended treatment including inhibitors of the renin-angiotensin-aldosterone system slows or prevents progression to ESRD or cardiovascular death compared with placebo., Results: Baseline characteristics (mean or percentage) of the population include age 68.5 years, female 43%, Caucasian 78%, eGFR 22.5 mL/min/1.73 m(2) and systolic/diastolic blood pressure 140/70 mmHg. The median urinary albumin:creatinine ratio was 320 mg/g and the frequency of micro- and macroalbuminuria was 30 and 51%, respectively. Anemia, abnormalities in markers of bone metabolism and elevations in cardiovascular biomarkers were frequently observed. A history of cardiovascular disease was present in 56%, neuropathy in 47% and retinopathy in 41% of patients., Conclusions: The BEACON trial enrolled a population heretofore unstudied in an international randomized controlled trial. Enrolled patients suffered with numerous co-morbid conditions and exhibited multiple laboratory abnormalities, highlighting the critical need for new therapies to optimize management of these conditions.

Major Depressive Disorder (MDD) affects one in five patients with Chronic Kidney Disease (CKD) and is an independent risk factor for hospitalization and death before and after dialysis initiation. However, it remains an under-recognized and under-treated problem, in part due to the lack of well-controlled studies that support or refute the efficacy and safety of antidepressant medications in CKD patients. Major trials of antidepressant treatment excluded patients with stages 3-5 CKD, precisely those at higher risk for both depression and increased mortality. The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) is a randomized, double-blinded, placebo-controlled trial of sertraline, a selective serotonin reuptake inhibitor (SSRI). It will enroll 200 adults with stages 3-5 CKD and MDD excluding kidney transplant and chronic dialysis patients. Sertraline will be administered at an initial dose of 50mg once daily or matching placebo followed by a dose escalation strategy consisting of 50mg increments at 2week intervals (as tolerated) to a maximum dose of 200mg. The primary outcome is improvement in depression symptom severity measured by the Quick Inventory of Depressive Symptomatology scale. Secondary outcomes include safety endpoints and improvement in quality of life. Changes in cognitive function, adherence to medications, nutritional status, inflammation, and platelet function will be explored as potential mechanisms by which depression may mediate poor outcomes. We discuss the rationale and design of the CAST study, the largest placebo-controlled trial aimed to establish safety and efficacy of a SSRI in the acute phase treatment of CKD patients with MDD., (Published by Elsevier Inc.)

Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD., Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality., Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events., Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD., (Copyright © 2013 S. Karger AG, Basel.)

Background: Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined., Methods: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m(2) of body-surface area) in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks., Results: Patients receiving bardoxolone methyl had significant increases in the mean (±SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m(2) of 8.2±1.5 ml in the 25-mg group, 11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml in the 150-mg group; P<0.001). The increases were maintained through week 52, with significant differences per minute per 1.73 m(2) of 5.8±1.8 ml, 10.5±1.8 ml, and 9.3±1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl., Conclusions: Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT00811889.).

Background: In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients., Methods: We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years., Results: During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01)., Conclusions: In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)