This Special Communication discusses the potential of the Ziltivekimab Cardiovascular Outcomes Trial (ZEUS) to provide a fully novel approach for prevention of myocardial infarction, stroke, cardiovascular death, and kidney function decline among high-risk patients with chronic kidney disease. ImportanceCardiovascular inflammation is a major determinant of atherosclerotic disease, and inhibition of the central signaling cytokine, interleukin 6 (IL-6), is a promising target for intervention. Patients with chronic kidney disease (CKD) commonly have plasma elevations of inflammatory biomarkers, such as high-sensitivity C-reactive protein (hsCRP) and IL-6, and are at high risk for life-threatening atherosclerotic events as well as loss of kidney function and might therefore benefit from IL-6 inhibition.ObservationsThe Ziltivekimab Cardiovascular Outcomes Trial (ZEUS; NCT05021835) will determine the safety and efficacy of IL-6 inhibition with ziltivekimab among patients with atherosclerotic cardiovascular disease (ASCVD), CKD, and systemic inflammation. ZEUS is a multinational, double-blind, placebo-controlled, event-driven, randomized clinical trial inclusive of 6376 participants with ASCVD, CKD, and an hsCRP level greater than or equal to 2 mg/L who were randomized in a 1:1 fashion to receive either ziltivekimab, 15 mg, administered subcutaneously every month or matching placebo. At randomization, mean age was 69.5 years, 27.5% were female, 92.0% had hypertension, 65.7% had diabetes, and 41.3% had heart failure. At baseline, the mean estimated glomerular filtration rate (eGFR) was 44.5 mL/min/1.73 m2, mean low-density lipoprotein cholesterol level was 77.7 mg/dL, median hsCRP level was 4.5 mg/L, and median IL-6 level was 4.9 pg/mL. At enrollment, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists were being used by 36.8% and 11.3% of the cohort, respectively. The primary outcome is 3-point major adverse cardiovascular events. Secondary cardiovascular outcomes include (1) an expanded major adverse cardiovascular event outcome including hospitalization for unstable angina requiring urgent coronary revascularization, (2) hospitalizations for heart failure or urgent heart failure visits or cardiovascular death, and (3) all-cause mortality. The secondary kidney outcome is a composite of greater than 40% decline in eGFR, eGFR less than 15 mL/min/1.73 m2, dialysis, kidney transplant, death from kidney disease, or cardiovascular death.Conclusions and RelevanceThe ZEUS randomized clinical trial will formally test the hypothesis that IL-6 inhibition with ziltivekimab will lower incident cardiovascular event rates and potentially slow kidney decline among participants with known ASCVD, CKD, and elevated hsCRP. If successful, the ZEUS trial would provide a fully novel approach for prevention of myocardial infarction, stroke, cardiovascular death, and kidney function decline among high-risk patients with CKD.

Introduction Deutaleglitazar (AP303) is a novel dual peroxisome proliferator-activated receptor (PPAR) α and γ agonist, which has the potential to offer the combined clinical benefit on diabetic kidney disease (DKD) management by normalizing the elevated glomerular capillary pressure, ameliorating podocyte depletion, as well as correcting diabetic dyslipidemia and hyperglycemia Methods Three single-center, randomized, placebo-controlled single-ascending-dose and/or multiple-ascending-dose studies investigated its pharmacokinetics (PK), pharmacodynamic, safety and tolerability in healthy participants with different ethnicities and in patients with diabetic kidney disease (DKD) and reduced kidney function. Results A total of 80 healthy participants, and 18 patients with DKD and estimated glomerular filtration rate (eGFR) 30-60 mL/min/1.73m2 from Australia and China received either placebo, a single oral dose or multi-dose of deutaleglitazar for 14 days. Deutaleglitazar exposure increased in a dose-dependent manner both after a single dose and at steady state, with no accumulation. Minor differences of PK profiles in Caucasian vs. Asian participants, and in those with normal vs reduced kidney function are considered unlikely to be clinically significant. Reduction in eGFR with reversibility after drug discontinuation was evident. Improvement in diabetic dyslipidemia and hyperglycemia were observed. Few adverse events were reported, only neutropenia was dose related. Conclusion The PPARα and PPARγ related effects occurred over similar dose ranges, indicating that deutaleglitazar is a balanced agonist of the two receptor subtypes targeting on the root cause and multi-pathway of DKD progression.

Importance:Glomerular diseases are a leading cause of chronic kidney disease (CKD) and kidney failure. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces the risk of kidney function loss in CKD, but its effects in individuals with CKD due to glomerular diseases are uncertain. Objectives:To evaluate the efficacy and safety of finerenone in patients with glomerular diseases. Design, Setting, and Participants:Prespecified exploratory subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled trial conducted across 24 countries and regions, focusing on participants with an investigator-reported glomerular disease diagnosis. The overall trial enrolled adults with nondiabetic CKD and an estimated glomerular filtration rate (eGFR) of either (1) at least 25 to less than 60 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 200 mg/g to less than 500 mg/g or (2) an eGFR of at least 25 to less than 90 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 500 mg/g to less than 3500 mg/g. Intervention:Finerenone 10 mg or 20 mg taken orally once daily (n = 446) vs matching placebo (n = 457). Main Outcomes and Measures:Annualized rate of eGFR decline (total eGFR slope) from baseline to month 32 (primary outcome of the main trial); percent change in albuminuria to 12 months; and a composite outcome of kidney failure or sustained 40% or more decline in eGFR (prespecified exploratory outcomes). Results:Of 1584 participants, 903 (57.0%) had investigator-reported glomerular disease, including 416 (46.1%) with immunoglobulin A nephropathy, 215 (23.8%) with focal segmental glomerulosclerosis, and 90 (10.0%) with membranous nephropathy. Participants with glomerular disease (mean [SD] age, 51.1 [13.6] years; 362 female [40.1%]; 558 Asian [61.9%]) had a mean eGFR of 48.8 mL/min/1.73 m2 and median urinary albumin to creatinine ratio of 839.6 mg/g. The total eGFR slope up to 32 months was -3.50 mL/min/1.73 m2 per year with finerenone and -4.23 mL/min/1.73 m2 per year with placebo (0.73 mL/min/1.73 m2 per year difference; 95% CI, 0.22-1.24). Finerenone reduced albuminuria at month 12 by 42% (95% CI, 35%-48%) and lowered the risk of kidney failure or 40% or more eGFR decline (7.42 vs 9.60 events per 100 patient-years; hazard ratio, 0.74; 95% CI, 0.57-0.97). Conclusions and Relevance:In this exploratory analysis, treatment with finerenone slowed kidney function decline, reduced albuminuria, and lowered the risk of kidney failure or substantial loss of kidney function in patients with glomerular diseases. These findings suggest an important role for finerenone in preserving kidney function in this population. Trial Registration:ClinicalTrials.gov Identifier: NCT05047263.

Importance:Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce chronic kidney disease (CKD) progression in individuals with type 2 diabetes, CKD, or heart failure. However, their effects in those with stage 4 CKD or little to no albuminuria remain uncertain. Objective:To assess whether estimated glomerular filtration rate (eGFR) or degree of albuminuria, measured by urinary albumin to creatinine ratio (UACR), modifies the effects of SGLT2 inhibitors on kidney outcomes. Data Sources:SGLT2 inhibitor trials participating in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium (SMART-C). Study Selection:Randomized, double-blind, placebo-controlled trials within SMART-C evaluating an SGLT2 inhibitor with label indications for reducing CKD progression including at least 500 participants in each group with at least 6 months of follow-up. Data Extraction and Synthesis:Treatment effects in individual trials were pooled using inverse variance-weighted meta-analysis. Main Outcomes and Measures:CKD progression, defined as kidney failure, at least 50% reduction in eGFR, or death due to kidney failure. Other outcomes included annual rate of eGFR decline and kidney failure. Results:Among 70 361 participants (mean [SD] age, 64.8 [8.7] years; 24 595 [35.0%] females) in 10 randomized trials, 2314 (3.3%) experienced CKD progression and 988 (1.4%) reached kidney failure. SGLT2 inhibitors reduced the risk of CKD progression (25.4 vs 40.3 events per 1000 patient-years; hazard ratio [HR], 0.62 [95% CI, 0.57-0.68]), irrespective of baseline eGFR (HR of 0.61 [95% CI, 0.52-0.71] for eGFR ≥60 mL/min/1.73 m2; 0.57 [95% CI, 0.47-0.70] for eGFR of 45 to <60 mL/min/1.73 m2; 0.64 [95% CI, 0.54-0.75] for eGFR of 30 to <45 mL/min/1.73 m2; and 0.71 [95% CI, 0.60-0.83] for eGFR <30 mL/min/1.73 m2; P for trend = .16) and baseline albuminuria (HR of 0.58 [95% CI, 0.44-0.76] for albuminuria ≤30 mg/g; 0.74 [95% CI, 0.57-0.96] for >30-300 mg/g; and 0.57 [95% CI, 0.52-0.64] for more than 300 mg/g; P for trend = .49). Although the magnitude of protection varied, SGLT2 inhibitors reduced the annual rate of eGFR decline across all eGFR and UACR subgroups, including when participants with and without diabetes were analyzed separately. SGLT2 inhibitors also reduced the risk of kidney failure alone (HR, 0.66 [95% CI, 0.58-0.75]). Conclusions and Relevance:In this meta-analysis, SGLT2 inhibitors were found to lower the risk of CKD progression regardless of baseline eGFR or albuminuria, including in patients with stage 4 CKD or minimal albuminuria, supporting their routine use to improve kidney outcomes across the full spectrum of kidney function among patients with type 2 diabetes, CKD, or heart failure.

INTRODUCTION:Patients with advanced stages of chronic kidney disease (CKD) and dialysis-dependent kidney failure are at a greater risk of cardiovascular events and mortality than those with early stages of CKD. There are no completed definitive randomized trials on the safety and efficacy of anticoagulant therapy in this patient population. METHODS:Treatment of cardiovascular disease with low-dose Rivaroxaban in Advanced Chronic Kidney disease (TRACK) is a multi-center, randomized, placebo-controlled trial (NCT03969953), designed to enrol 1886 adult participants with CKD stage 4 or 5 (estimated glomerular filtration rate 29 mL/min/1.73 m2) or dialysis-dependent kidney failure and high cardiovascular risk (defined as at least one of the following risk factors; coronary artery disease, non-hemorrhagic non-lacunar stroke, peripheral artery disease [PAD], diabetes mellitus, or age 65 years). Participants are randomized to rivaroxaban 2.5 mg twice daily or matching placebo. The primary efficacy outcome is a composite of cardiovascular death, myocardial infarction, stroke, or PAD event. The primary safety outcome is major bleeding, defined as a composite of fatal bleeding, bleeding leading to hospitalization, or symptomatic bleeding in a critical area or organ. From January 2021 through July 2025, 1458 eligible participants (mean age 63.2 years, 700 [48%] age 65 years, 432 [29.6%] women, 715 [49%] dialysis-dependent kidney failure and 743 [51%] CKD stage 4 or 5, 1125 [77.2%] diabetes mellitus, 674 [46.2%] treated with aspirin at baseline) underwent randomization. CONCLUSION:TRACK will evaluate the effect of low dose rivaroxaban on major adverse cardiovascular events in participants with CKD stages 4 and 5 and dialysis-dependent kidney failure, and elevated cardiovascular risk.

Chronic kidney disease (CKD) is a leading cause of premature death due to the loss of kidney function and development of kidney failure, and because of attendant major adverse cardiovascular events. High-sensitivity C-reactive protein (hsCRP), a biomarker of systemic inflammation, is associated with increased risks of cardiovascular events and CKD progression. CKD is characterized by a pro-inflammatory state with upregulation of inflammatory pathways and disruption of anti-inflammatory mechanisms. The resulting systemic inflammation, along with local tissue-based inflammatory mechanisms, are key contributors to kidney damage, atherosclerosis and cardiac dysfunction. As a result, a series of inflammatory pathways and mediators have emerged as potential therapeutic targets for CKD and its major cardiovascular complications. Investigational treatments that have targeted inflammation include inhibition of apoptosis signal-regulating kinase-1 (ASK1) by selonsertib, Janus kinase (JAK) 1/2 inhibition with baricitinib, protein kinase C-β (PKCβ) inhibition with ruboxistaurin, nuclear factor erythroid 2-related factor 2 (Nrf2) activation with bardoxolone, phosphodiesterase inhibition with pentoxifylline and monoclonal antibodies against IL-1β and IL-6. Furthermore, proven therapies for CKD, including renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid antagonists, possess anti-inflammatory properties that might contribute to their previously established clinical benefits.

The ASPIRED trial aims to determine whether a daily low-dose of aspirin is effective in preventing major cardiovascular events when compared to placebo in patients receiving dialysis. It is designed as a pragmatic trial two-arm double-blind randomised trial conducted within an established Dialysis Registry consisting of at least 80 centres and 30,000 participants. This statistical analysis plan pre-specifies the method of analysis for every outcome and key variables collected in the trial. The primary outcome is time from randomisation to first occurrence of major cardiovascular event including myocardial infarction, ischemic stroke or death from cardiovascular cause. The primary analysis will consist in a Cox proportional hazard model adjusted for stratification variables. The analysis plan also includes planned sensitivity analyses including covariate adjustments and subgroup analyses. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04381143 ### Funding Statement This study is funded by Guangdong Provincial People's Hospital (Grant number: DFJH2020023) and The George Institute for Global Health ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Research Ethics Review Committee of Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences (Ethics number: GDREC 2019327H, Ethics Approval Date: 21 May 2019). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Not relevant

BACKGROUND AND AIMS:Iron deficiency occurs commonly in chronic kidney disease (CKD), but its association with heart failure and other cardiovascular outcomes, independent of anemia, is not well defined. METHODS:We conducted a post-hoc analysis of the Anaemia Studies in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial. We assessed the independent associations of transferrin saturation (TSAT) and ferritin levels with cardiovascular and mortality outcomes using time-updated multivariable Cox regression models. The primary outcome was heart failure hospitalization (HFH) or cardiovascular death. RESULTS:Among 3,872 participants (median age 67 years, 56% women, median estimated glomerular filtration rate 18 mL/min/1.73m2), those with lower TSAT were more likely to be women, have diabetes, atrial fibrillation, and a history of cardiovascular disease. In fully adjusted models (including hemoglobin), compared to TSAT >30-≤40%, time-updated TSAT ≤20% was associated with a 2-fold higher risk of the primary outcome (HR 2.13, 95% CI 1.62-2.80), with similar associations observed for HFH (HR 1.97, 95% CI 1.40-2.79) and for cardiovascular death (HR 2.19, 95% CI 1.45-3.29), as well as all-cause mortality (HR 1.60, 95% CI 1.25-2.03). Ferritin levels ≤100 ng/mL (vs >100 to ≤300 ng/mL) were not associated with a higher risk of any cardiovascular or mortality outcomes. CONCLUSIONS:Iron deficiency defined by low transferrin saturation, but not low ferritin levels, is associated with increased risk of heart failure and cardiovascular death in CKD, independent of hemoglobin.

BACKGROUND:Overactivation of the mineralocorticoid receptor is a common pathway for chronic kidney disease (CKD) progression across multiple disease aetiologies. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has shown kidney and cardiovascular benefits in CKD due to type 2 diabetes, but its efficacy and safety across disease aetiologies, and levels of glycaemia, estimated glomerular filtration rate (eGFR), and albuminuria have not been evaluated. The aim of this study was to evaluate the efficacy and safety of finerenone across the spectrum of CKD. METHODS:We conducted an individual participant data meta-analysis of three randomised, double-blind, placebo-controlled trials of finerenone in patients with CKD: FIDELIO-DKD (NCT02540993; Sept 17, 2015, to April 14, 2020), FIGARO-DKD (NCT02545049; Sept 17, 2015, to Feb 2, 2021), and FIND-CKD (NCT05047263; Sept 21, 2021, to Feb 2, 2026). We used Cox regression models to evaluate relative effects on kidney and cardiovascular outcomes. The main kidney outcome was kidney failure or sustained 57% or more decline in eGFR; the main cardiovascular outcome was hospitalisation for heart failure or cardiovascular death. This study was registered with PROSPERO, CRD420251269149. FINDINGS:Across the three trials enrolling 14 574 participants, the mean age was 63·7 years (SD 10·6), 4467 (30·7%) were female, 10 107 (69·3%) were male, mean eGFR was 56·4 mL/min per 1·73 m2 (SD 21·4), and median urinary albumin-to-creatinine ratio was 567·4 mg/g (IQR 233·6-1164·7). Finerenone reduced the risk of the composite kidney outcome by 24% versus placebo (22·3 vs 28·8 events per 1000 patient-years; hazard ratio 0·76 [95% CI 0·68-0·86]) and kidney failure alone (0·85 [0·74-0·99]). Finerenone reduced the risk of the composite cardiovascular outcome versus placebo (19·1 vs 23·9 events per 1000 patient-years; 0·80 [0·70-0·91]), including heart failure hospitalisation (0·78 [0·66-0·92]) and cardiovascular death (0·82 [0·67-0·999]). Finerenone also reduced the risk of all-cause death (0·88 [0·79-0·99]). Treatment effects on the composite kidney outcome were consistent irrespective of glycaemic status, CKD aetiology, baseline eGFR, albuminuria, and use of sodium-glucose co-transporter-2 inhibitors. Hyperkalaemia occurred more frequently with finerenone than with placebo, but the absolute incidence of hyperkalaemia leading to hospitalisation was low. INTERPRETATION:In the studied populations with CKD, finerenone reduced the risk of CKD progression, including kidney failure alone, and reduced heart failure hospitalisation, cardiovascular death, and all-cause death. These findings support finerenone as a foundational therapy for CKD across a broad range of disease aetiologies and levels of glycaemia, eGFR, and albuminuria. FUNDING:Bayer.

Importance:There is uncertainty about the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in participants with chronic kidney disease, with guidelines offering different strengths of recommendation based on diabetes status and urine albumin to creatinine ratio (UACR). Objective:To assess the relative and absolute effects of SGLT2 inhibitor use across efficacy and serious safety outcomes in participants stratified by diabetes status and UACR (≥200 mg/g or <200 mg/g). Data Sources and Study Selection:Included 8 randomized clinical trials that studied an SGLT2 inhibitor with a label indication for use in kidney disease and recorded longitudinal kidney outcomes and baseline data on albuminuria. Data Extraction and Synthesis:Data were combined using inverse variance-weighted meta-analysis; group-specific absolute effects were estimated by applying relevant relative risks to the event rates of the placebo groups. Main Outcomes and Measures:Assessed the effects of SGLT2 inhibitor use on clinical efficacy and safety outcomes. Heterogeneity by baseline level of UACR was assessed separately by diabetes status. Results:A total of 58 816 participants (mean age, 64 [SD, 10] years; 35% were female; 48 946 with diabetes and 9870 without diabetes) were included from trials comparing an SGLT2 inhibitor vs placebo. Allocation to an SGLT2 inhibitor produced a lower rate of kidney disease progression (33 vs 48 for placebo per 1000 patient-years; hazard ratio [HR], 0.65 [95% CI, 0.60-0.70] in those with diabetes and 32 vs 46 per 1000; HR, 0.74 [95% CI, 0.63-0.85] in those without diabetes), a lower rate of acute kidney injury (14 vs 18 per 1000 [HR, 0.77; 95% CI, 0.69-0.87] with diabetes and 13 vs 18 per 1000 [HR, 0.72; 95% CI, 0.56-0.92] without diabetes), a lower rate of any hospitalization (202 vs 231 per 1000 [HR, 0.90; 95% CI, 0.87-0.92] with diabetes and 203 vs 237 per 1000 [HR, 0.89; 95% CI, 0.83-0.95] without diabetes), and a lower rate of any death (42 vs 47 per 1000 [HR, 0.86; 95% CI, 0.80-0.91] with diabetes and 42 vs 48 per 1000 [HR, 0.91; 95% CI, 0.78-1.05] without diabetes). Diabetes-specific HRs were similar in participants (with a UACR ≥200 mg/g vs with a UACR <200 mg/g) considered separately. Higher absolute risk at a UACR of 200 mg/g or greater meant larger estimated absolute benefits on kidney disease progression were evident in this subgroup. Clear absolute benefits were evident for other efficacy outcomes, and particularly hospitalization, in participants with a UACR less than 200 mg/g. Net absolute benefits remained in the analyses of non-heart failure populations and when estimated glomerular filtration rate was less than 60 mL/min/1.73 m2. Conclusions and Relevance:Within the studied participants, there were clear absolute benefits of SGLT2 inhibitors on kidney, hospitalization, and mortality outcomes irrespective of diabetes status and level of UACR.

Importance:Approximately 10% to 15% of patients with advanced chronic kidney disease (CKD) experience a fatal or nonfatal cardiovascular event annually. The effects of antithrombotic therapies on cardiovascular events in patients with advanced CKD are unknown. Objective:To determine whether low-dose rivaroxaban reduces rates of adverse cardiovascular events compared with placebo in patients with advanced CKD. Design, Setting, and Participants:Randomized, double-blind, placebo-controlled trial conducted at 90 centers in 12 countries. Eligible participants were adults with CKD stage 4 or 5 and patients with dialysis-dependent kidney failure. Participants had a history of either coronary artery disease; nonhemorrhagic, nonlacunar stroke; peripheral artery disease; diabetes; or were 65 years or older. Enrollment occurred between January 2021 and July 2025. The trial was stopped early on August 7, 2025, for lack of efficacy. Final follow-up occurred on October 30, 2025. Statistical analyses were conducted in February and March 2026. Interventions:Patients were randomized 1:1 to receive rivaroxaban 2.5 mg twice daily or placebo. Main Outcomes and Measures:The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, or a peripheral artery disease event. The primary safety outcome was major bleeding. Results:Of 1458 randomized patients (mean [SD] age, 63.2 [11.6] years, 432 [29.6%] female), 1360 (93.3%) completed follow-up. During a median follow-up of 1.7 years, the primary outcome occurred in 164 patients (22.6%) in the low-dose rivaroxaban group and 151 (20.7%) in the placebo group (13.0 vs 11.8 events per 100 person-years; hazard ratio, 1.09 [95% CI, 0.87-1.36]; P = .46). Major bleeding occurred in 64 patients (8.8%) receiving low-dose rivaroxaban and 44 (6.0%) receiving placebo (5.1 vs 3.4 events per 100 person-years; hazard ratio, 1.51 [95% CI, 1.02-2.22]; P = .04). Conclusions and Relevance:In patients with advanced CKD at high cardiovascular risk, low-dose rivaroxaban did not reduce the risk of a composite cardiovascular outcome. Major bleeding rates were significantly higher in the low-dose rivaroxaban group compared with the placebo group. Trial Registration:ClinicalTrials.gov Identifier: NCT03969953.

QuestionWhat is the effect of finerenone in patients with chronic kidney disease due to glomerular diseases?FindingsIn this prespecified exploratory analysis of a randomized clinical trial that enrolled 903 participants with glomerular diseases, finerenone, compared with placebo, slowed kidney function decline (difference in eGFR slope decline, 073 mL/min/1.73 m2 per year), reduced albuminuria, and lowered the risk of kidney failure or sustained loss of kidney function, with consistent effects across glomerular disease subtypes.MeaningFinerenone may have an important role in preserving kidney function in patients with glomerular diseases. ImportanceGlomerular diseases are a leading cause of chronic kidney disease (CKD) and kidney failure. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces the risk of kidney function loss in CKD, but its effects in individuals with CKD due to glomerular diseases are uncertain.ObjectivesTo evaluate the efficacy and safety of finerenone in patients with glomerular diseases.Design, Setting, and ParticipantsPrespecified exploratory subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled trial conducted across 24 countries and regions, focusing on participants with an investigator-reported glomerular disease diagnosis. The overall trial enrolled adults with nondiabetic CKD and an estimated glomerular filtration rate (eGFR) of either (1) at least 25 to less than 60 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 200 mg/g to less than 500 mg/g or (2) an eGFR of at least 25 to less than 90 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 500 mg/g to less than 3500 mg/g.InterventionFinerenone 10 mg or 20 mg taken orally once daily (n = 446) vs matching placebo (n = 457).Main Outcomes and MeasuresAnnualized rate of eGFR decline (total eGFR slope) from baseline to month 32 (primary outcome of the main trial); percent change in albuminuria to 12 months; and a composite outcome of kidney failure or sustained 40% or more decline in eGFR (prespecified exploratory outcomes).ResultsOf 1584 participants, 903 (57.0%) had investigator-reported glomerular disease, including 416 (46.1%) with immunoglobulin A nephropathy, 215 (23.8%) with focal segmental glomerulosclerosis, and 90 (10.0%) with membranous nephropathy. Participants with glomerular disease (mean [SD] age, 51.1 [13.6] years; 362 female [40.1%]; 558 Asian [61.9%]) had a mean eGFR of 48.8 mL/min/1.73 m2 and median urinary albumin to creatinine ratio of 839.6 mg/g. The total eGFR slope up to 32 months was -3.50 mL/min/1.73 m2 per year with finerenone and -4.23 mL/min/1.73 m2 per year with placebo (0.73 mL/min/1.73 m2 per year difference; 95% CI, 0.22-1.24). Finerenone reduced albuminuria at month 12 by 42% (95% CI, 35%-48%) and lowered the risk of kidney failure or 40% or more eGFR decline (7.42 vs 9.60 events per 100 patient-years; hazard ratio, 0.74; 95% CI, 0.57-0.97).Conclusions and RelevanceIn this exploratory analysis, treatment with finerenone slowed kidney function decline, reduced albuminuria, and lowered the risk of kidney failure or substantial loss of kidney function in patients with glomerular diseases. These findings suggest an important role for finerenone in preserving kidney function in this population.Trial RegistrationClinicalTrials.gov Identifier: NCT05047263 This exploratory analysis of a randomized clinical trial evaluates the efficacy and safety of finerenone in reducing chronic kidney disease of participants with glomerular diseases, including disease subtype.

INTRODUCTION:Corticosteroids are effective for treating IgA nephropathy but have important adverse effects. In this secondary analysis of the TESTING cohort, we generated a model to predict, for an individual patient, the probability that they will respond to corticosteroids. METHODS:Time to the primary outcome (40% reduction in eGFR, kidney failure or death due to kidney disease) was evaluated in a Cox proportional hazards model including all potential treatment modifiers as main effects. Selected variables were forced into a model with treatment exposure and interaction terms between treatment and each included variable. The predicted four-year absolute risk of the primary outcome was generated for every patient individually under separate scenarios of being treated with methylprednisolone or placebo. The difference between the two scenarios was the predicted individual treatment effect on absolute risk reduction (ARR). Model performance was assessed using discrimination plots, restricted mean survival time (RMST) and the C-statistic for benefit. RESULTS:During a median of 43 months follow-up, 176 of 483 participants experienced the primary outcome. Selected treatment modifiers were eGFR, age, proteinuria, renin-angiotensin-aldosterone-system blockade dose, ethnicity, time from biopsy to enrollment, systolic blood pressure, sex, body mass index, and MEST-C T-score and C-score. Compared to the average ARR associated with methylprednisolone (16.1%), the predicted individual-level ARR was highly variable (-10% to 40%). Patients with predicted ARR over 10% had greater observed benefit from methylprednisolone (ARR 24%) versus those with predicted ARR 10% or less (observed ARR -5%). A policy of treating only patients with higher anticipated benefit had a longer RMST than using random treatment allocation (1,194 v 1,028 days). The C-statistic for benefit was 0.63 (95% confidence interval 0.56-0.70). The frequency of adverse events was similar across tertiles of ARR. CONCLUSIONS:We have generated a model that can predict individual patient response to methylprednisolone so that corticosteroids can be targeted to those most likely to benefit.

Introduction and Objective: Evaluate the effect of semaglutide (sema) on COVID-19-related complications and all-cause death. Methods: SELECT (n=17,604), FLOW (n=3533), and SOUL (n=9650) randomized participants (pts) with ASCVD/overweight/obesity without T2D (SELECT), T2D/CKD (FLOW), and T2D+ASCVD and/or CKD (SOUL), to sema vs placebo (pbo). Mean follow-up ranged 3.3-4 years, spanning the COVID-19 pandemic (53% of pts enrolled pre-Feb 2, 2020). Cause of death was adjudicated. Reported COVID-19-related infections, SAEs, and hospitalizations, and COVID-19-related deaths were analyzed. Results: Of 2444 deaths, 1398 (57.2%) were CV and 1046 (42.7) were non-CV, including 338 (13.8%) COVID-19 related deaths. Sema vs pbo reduced all-cause death (1130 vs 1314; [HR 0.85 [CI 0.78, 0.92]; p<0.001), CV death (647 vs 751; 0.85 [0.77, 0.95]; p=0.003), and non-CV death (483 vs 563; 0.85 [0.75, 0.96]; p=0.008). Sema reduced the incidence of COVID-19 infections (3542 vs 3685, HR 0.95; p=0.018), COVID-19-related SAEs (605 vs 749, HR 0.80; p<0.001), COVID-19-related hospitalizations (577 vs 705, HR 0.81; p<0.001), and COVID-19-related deaths (141 vs 197, HR 0.71; p=0.002; Fig). There was no heterogeneity in COVID outcomes by study. Conclusion: In addition to reducing the risk of death across multiple studies, sema reduced the risk of COVID-19 and its complications, which is notable and warrants further investigation. Disclosure B. Scirica: Research Support; Current; Amgen Inc., Novo Nordisk, Merck & Co., Inc., Boehringer Ingelheim International GmbH, AstraZeneca, Milestone, Foresite Labs, Pfizer Inc., Verse. J.B. Buse: Consultant; Current; Aardvark Therapeutics, Altimmune, Alveus Therapeutics, Amgen Inc., Antag Therapeutics, Aqua Medical, AstraZeneca, Boehringer Ingelheim International GmbH. Other - Consultant and clinical trial support; Current; Corcept Therapeutics. Consultant; Ended; Dexcom, Inc. Consultant; Current; Eli Lilly and Company. Consultant; Ended; embecta. Consultant; Current; General Medicines Inc. Other - Consultant and clinical trial support; Current; GentiBio. Consultant; Ended; Insulet Corporation. Consultant; Current; Kayothera. Other - Consultant and stock options; Current; Metsera. Other - Expert witness; Ended; Medtronic. Other - Consultant and investigator; Current; Novo Nordisk. Consultant; Current; Recordati S.p.A, Sparrow Pharmaceuticals. Consultant; Ended; Tandem Diabetes Care, Inc. Consultant; Current; Vertex Pharmaceuticals Incorporated, vTv Therapeutics, Zealand Pharma A/S. A. Catarig: Employee; Current; Novo Nordisk. Stock/Shareholder; Current; Novo Nordisk. O.K. Jeppesen: Employee; Current; Novo Nordisk A/S. Stock/Shareholder; Current; Novo Nordisk A/S. A.M. Lincoff: Consultant; Current; Novo Nordisk, Eli Lilly and Company. Stock/Shareholder; Current; Canary Cure. Research Support; Current; Novartis AG. Consultant; Ended; Alnylam Pharmaceuticals, Inc., Amgen Inc., Ardelyx, Brainstom Cell, Capricor, Johnson & Johnson. D. Mcguire: Consultant; Current; Novo Nordisk, Lilly, Boehringer Ingelheim International GmbH. Consultant; Ended; NewAmsterdam. Consultant; Current; Metsera, Amgen Inc., Novartis AG, Lexicon Pharmaceuticals, Inc. Consultant; Ended; Neurotronic. Consultant; Current; Kailera. V. Perkovic: Consultant; Current; AstraZeneca, Bayer AG, Biogen, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., GlaxoSmithKline plc., Incyte, Janssen Global Services, LLC, Novo Nordisk, Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Inc., Tricida, Inc., Vifor Pharma Management Ltd., Minerlays, Guard Therapeutics, Shanxi Micot, Travere. R. Pratley: Consultant; Current; Lilly USA LLC. Research Support; Current; National Institutes of Health, Novo Nordisk. Speaker's Bureau; Current; Novo Nordisk. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Novo Nordisk. Consultant; Current; Pfizer Inc., Recordati Rare Diseases Inc., Regeneron Pharmaceuticals Inc., Response Pharmaceuticals, Rona Therapeutics Ltd. Research Support; Current; Sanofi. Consultant; Current; Scholar Rock Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Sun Pharmaceutical Industries Ltd. Consultant; Current; Third Rock Ventures, Verdiva Bio Dev Limited. Research Support; Current; AstraZeneca AB, Boehringer Ingelheim International GmbH, Abbott Laboratories. Consultant; Current; Abbott Laboratories, AbbVie Inc. Other - Consulting; stock options; Current; Altanine, Inc. Consultant; Current; Amgen Inc., AstraZeneca Pharmaceuticals LP. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Bayer AG, Bayer HealthCare Pharmaceuticals Inc. Research Support; Current; Biomea Fusion. Consultant; Current; Boehringer Ingelheim Pharmaceuticals Inc., Carmot Therapeutics, Inc., Corcept Therapeutics. Research Support; Current; Dompé, Eli Lilly and Company. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Eli Lilly and Company. Research Support; Current; Endogenex Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Current; Endogenex Inc. Consultant; Current; F. Hoffmann-La Roche Ltd. Research Support; Current; Fractyl Health, Inc. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Ended; Gasherbrum Bio Inc., Genprex. Consultant; Current; Hanmi Pharm. Co., Ltd. Other - Consulting: Thru 12/31/2023 payment directed to Dr. Pratley's employer; as of 1/1/2024 payment directed to Dr. Pratley personally.; Ended; Intas Pharmaceuticals Ltd. Research Support; Current; Lexicon Pharmaceuticals, Inc. Consultant; Current; Lexicon Pharmaceuticals, Inc. Speaker's Bureau; Current; Lilly USA LLC. S. Stensen: Employee; Current; Novo Nordisk A/S. M. Tran: None. D. Ryan: Advisory Panel; Current; Abbvie, Altimmune, Amgen, AstraZenica, Boehringer Ingelheim, Biohaven, Carmot/Roche/Genentech. Advisory Panel; Ended; eMed, Fractyl, Nestle. Consultant; Current; Pfizer, Source Bio, Protagonist, PPD, Regeneron, Regor. Advisory Panel; Current; Currax, Structure Therapeutics, Tenvie, Kailera. Speaker's Bureau; Current; LIlly, Novo Nordisk,. Other - I am a consultant to both and received stock options and consulting fees.; Current; Calibrate, Epitomee. Other - Data Monitoring Committee member; Current; CinRx, Rhythm, Lilly. Advisory Panel; Current; Viking, Weight Watchers, Wonder Health, Zealand. Other - ! received non-negotiable stock options from these companies years ago and have not worked for them in years.; Ended; Roman, Scientific Intake. Funding SELECT, FLOW, and SOUL Trials were supported by NovoNordisk A/S