Background: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction). Methods: In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. Results: At randomization, eGFR was 63±19 mL·min ^–1 ·1.73 m ^– 2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33–0.77]; P =0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min ^–1 ·1.73 m ^–2 ( P -interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (–2.0 [95% CI, –2.2 to –1.9] versus –2.7 [95% CI, –2.8 to –2.5] mL·min ^–1 ·1.73 m ^–2 per year). Conclusions: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.

Individuals with ESKD requiring maintenance hemodialysis face a unique hemodynamic challenge, typically on a thrice-weekly basis. In an effort to achieve some degree of euvolemia, ultrafiltration goals often involve removal of the equivalent of an entire plasma volume. Maintenance of adequate end-organ perfusion in this setting is dependent on the institution of a variety of complex compensatory mechanisms. Unfortunately, secondary to a myriad of patient- and dialysis-related factors, this compensation often falls short and results in intradialytic hypotension. Physicians and patients have developed a greater appreciation for the breadth of adverse outcomes associated with intradialytic hypotension, including higher cardiovascular and all-cause mortality. In this review, we summarize the evidence for adverse outcomes associated with intradialytic hypotension, explore the underlying pathophysiology, and use this as a basis to introduce potential strategies for its prevention and treatment.

Importance: Sodium-glucose cotransporter 2 inhibitors are known to reduce heart failure events and slow progression of kidney disease among patients with heart failure and a reduced ejection fraction.Objective: To determine the effect of dapagliflozin on cardiovascular and kidney outcomes and the influence of baseline kidney disease among patients with heart failure and a mildly reduced or preserved ejection fraction enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.Design, Setting, and Participants: This was a prespecified analysis conducted from July 1 to September 18, 2022 of the DELIVER randomized clinical trial. This was an international, multicenter trial including patients with ejection fraction greater than 40% and estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m² or higher.Interventions: Dapagliflozin, 10 mg, per day or placebo.Main Outcomes and Measures: Outcomes assessed were whether baseline kidney function modified the treatment effect on the primary outcome (cardiovascular death or worsening heart failure). Also examined was the treatment effect on the prespecified outcomes of eGFR slope and a post hoc composite kidney outcome (first ≥50% decline in eGFR from baseline; first eGFR <15 mL/min/1.73 m²; end-stage kidney disease; death from kidney causes).Results: A total of 6262 patients (mean [SD] age, 72 [10] years; 3516 male [56%]) had mean (SD) eGFR measurements available: 61 (19) mL/min/1.73 m²; 3070 patients (49%) had an eGFR less than 60 mL/min/1.73 m². The effect of dapagliflozin on the primary outcome was not influenced by baseline eGFR category (eGFR ≥60 mL/min/1.73 m²: hazard ratio [HR], 0.84; 95% CI, 0.70-1.00; eGFR 45-<60 mL/min/1.73 m²: HR, 0.68; 95% CI, 0.54-0.87; eGFR <45 mL/min/1.73 m²: HR, 0.93; 95% CI, 0.76-1.14; P for interaction = .16). Over a median (IQR) follow-up of 2.3 (1.7-2.8) years, the overall incidence rate of the kidney composite outcome was low (1.1 events per 100 patient-years) and was not affected by treatment with dapagliflozin (HR, 1.08; 95% CI, 0.79-1.49). However, dapagliflozin attenuated the decline in eGFR from baseline (difference, 0.5; 95% CI, 0.1-0.9 mL/min/1.73 m² per year; P = .01) and from month 1 to 36 (difference, 1.4; 95% CI, 1.0-1.8) mL/min/1.73 m² per year; P < .001).Conclusions and Relevance: Results of this prespecified analysis showed that baseline kidney function did not modify the benefit of dapagliflozin in patients with heart failure and a mildly reduced or preserved ejection fraction. Dapagliflozin did not significantly reduce the frequency of the kidney composite outcome, although the overall event rate was low. However, dapagliflozin slowed the rate of decline in eGFR compared with placebo.Trial Registration: ClinicalTrials.gov Identifier: NCT03619213

Finerenone has kidney protective effects in patients with chronic kidney disease (CKD) with type 2 diabetes, but effects on kidney outcomes in patients with heart failure (HF) with and without diabetes and/or CKD are not known. Examine the effects of finerenone on kidney outcomes in FINEARTS-HF, a randomized trial of finerenone vs. placebo among patients with HF with mildly reduced or preserved ejection fraction. We explored the effects of finerenone on the secondary outcome of a sustained ≥50% eGFR decline or kidney failure (sustained eGFR decline <15 mL/min/1.73 m²; initiation of maintenance dialysis; renal transplant). In this prespecified analysis, we also report effects of finerenone on: 1) sustained ≥57% eGFR decline or kidney failure; 2) eGFR slope; 3) changes in urine albumin/creatinine ratio (UACR). Among 6,001 participants, mean baseline eGFR was 62 ±20mL/min/1.73m²; 48% had eGFR <60mL/min/1.73m². Overall, 5,797 had baseline UACR data (median 18 [7,67]mg/g). Over 2.6 years median follow-up, the incidence of the composite kidney outcome (≥50% eGFR decline or kidney failure) was numerically, but non-significantly, higher for finerenone vs. placebo (75 vs. 55 events; HR 1.33; 95%CI 0.94, 1.89). Similar results were observed for the composite of ≥57% eGFR decline or kidney failure (41 vs. 31 events; HR 1.28; 95%CI 0.80, 2.05), though the overall event frequency was relatively low. During the first 3 months, finerenone led to an acute decline in eGFR of -2.9 mL/min/1.73m² (95%CI -3.4, -2.4) but did not alter chronic (from 3 months) eGFR slope (+0.2 mL/min/1.73m²/year; 95%CI -0.1, +0.4), vs. placebo. The difference in total slope was -0.7 (95%CI -0.9 to -0.4) mL/min/1.73 m²/year. Finerenone reduced UACR by 30% (95%CI 25%, 34%) over 6 months vs. placebo, an effect that persisted throughout follow-up. Finerenone reduced the risk of new-onset of micro- and macroalbuminuria by 24% (HR 0.76; 95%CI 0.68, 0.83) and 38% (HR 0.62; 95%CI 0.53, 0.73), respectively. In FINEARTS-HF, a population at low risk of adverse kidney outcomes, finerenone did not significantly modify the kidney composite outcomes. Finerenone led to a greater reduction in initial eGFR, but did not result in a significant difference in chronic eGFR slope, vs. placebo. Finerenone led to early and sustained reductions in albuminuria and reduced the risk of new-onset micro- and macroalbuminuria.

Background and objectives: Despite high rates of complications in patients with CKD without diabetes, the implementation of proven therapies in this group remains low. Expressing the clinical benefit of a therapy in terms of extra years free from the disease or death may facilitate implementation. We estimated lifetime survival free of kidney failure for patients with albuminuric CKD without diabetes treated with the combination therapy of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and sodium-glucose cotransporter-2 (SGLT2) inhibitors relative to patients not treated. Design, setting, participants, & measurements: We used trial-level estimates of the effect of treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ramipril/benazepril; n=690) and SGLT2 inhibitors (dapagliflozin; n=1398) compared with placebo to derive the effect of combination therapy versus no treatment. Using this effect, we estimated treatment effect of combination therapy to the active treatment group of patients with albuminuric CKD without diabetes participating in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial (n=697) and projected eventfree and overall survival for those treated and not treated with combination therapy. We also performed our calculations anticipating lower adherence and less pronounced benefits than were observed in the clinical trials. The primary outcome was a composite of doubling of serum creatinine, kidney failure, or death. Results: The aggregate estimated hazard ratio comparing combination therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and SGLT2 inhibitor versus no treatment for the primary end point was 0.35 (95% confidence interval, 0.30 to 0.41). For a 50-year-old patient until the age of 75 years, the estimated survival free from the primary composite end point was 17.0 (95% confidence interval, 12.4 to 19.6) years with the combination therapy and 9.6 years (95% confidence interval, 8.4 to 10.7) with no treatment with any of these agents, corresponding to a gain in eventfree survival of 7.4 (95% confidence interval, 6.4 to 8.7) years. When assuming lower adherence and less pronounced efficacy of combination therapy, the gain in eventfree survival ranged from 5.3 years (95% confidence interval, 4.4 to 6.1) to 5.8 years (95% confidence interval, 4.8 to 6.8). Conclusions: Treatment with the combination of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and SGLT2 inhibitor in patients with albuminuric CKD without diabetes is expected to substantially increase kidney failure–free survival. Clinical Trial registry name and registration number: Benazepril for Advanced Chronic Renal Insufficiency, NCT00270426, and a Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (Dapa-CKD), NCT03036150