Daniel Edmonston

Background: Chronic kidney disease (CKD) remains underdiagnosed and undertreated despite substantial cardiovascular and mortality risks. Guidelines recommend annual testing with estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) in at-risk populations, and a growing number of guideline-directed medical therapies (GDMT) improve kidney and cardiovascular outcomes in CKD. We conducted a scoping review of controlled implementation studies to identify effective strategies for improving CKD testing and GDMT delivery and define priorities for future implementation trials. Methods: Following a registered protocol and PRISMA extension for Scoping Reviews (PRISMA-ScR) guidance, we searched MEDLINE, Embase, and the Web of Science Core Collection from database inception through June 9, 2026 for English-language prospective controlled studies. Eligible studies compared an implementation strategy with usual care or another control condition. We charted study characteristics and outcomes using standardized templates and synthesized findings by objective, strategy, setting, design, and target population. Results: We included 26 reports from 24 studies (N=7 testing, N=17 treatment). Six of 7 studies increased CKD testing, with the largest gains from patient-directed home testing and automated laboratory ordering paired with clinical decision support. However, increased testing seldom translated into increased CKD diagnosis or GDMT prescriptions. Of implementation efforts focused on CKD treatment, only 5 of 17 studies increased GDMT prescribing. Passive, single-touch strategies, including isolated alerts, one-time prompts, and registries without active outreach, rarely changed prescribing. In contrast, longitudinal strategies that incorporated pharmacist- or advanced practice provider-led management, nephrologist-supported multidisciplinary care, or proactive registry-based outreach more consistently increased GDMT exposure and sometimes improved intermediate clinical outcomes. Conclusions: Among 24 prospective controlled studies, patient-directed home testing and automated laboratory ordering paired with clinical decision support increased CKD testing, but increased testing seldom led to CKD diagnosis or GDMT prescribing. Only 5 of 17 treatment studies increased GDMT prescribing, all through longitudinal, team-based care.

Key Points: Glucagon-like peptide-1 receptor agonists are increasingly used in patients with kidney failure despite trial exclusion. Initiation was associated with a 13% lower risk of cardiovascular events and 17% lower mortality versus dipeptidyl peptidase-4 inhibitors. Initiation was associated with a 10% lower risk of heart failure hospitalization versus dipeptidyl peptidase-4 inhibitors. Background: Few therapies improve cardiovascular outcomes for people with kidney failure. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) reduce cardiovascular risk in patients with non–dialysis-dependent CKD, but the cardiovascular benefits in patients with kidney failure remain uncertain. The objective of this study was to compare cardiovascular outcomes among patients with kidney failure and type 2 diabetes newly initiated on GLP-1 RA versus other antiglycemic agents. Methods: We analyzed electronic health records, Medicare claims, and Part D data from the United States Renal Data System (2011–2021) to identify new users of GLP-1 RA ( n =3629), dipeptidyl peptidase-4 inhibitors (DPP4i; n =21,369), and sulfonylureas ( n =32,296) among patients with type 2 diabetes receiving maintenance dialysis. For the primary analysis, we performed 1:1 propensity score matching of GLP-1 RA to DPP4i initiators using 61 covariates. A prespecified secondary analysis compared propensity score–matched initiators of GLP-1 RA and sulfonylureas. The primary outcome was a modified major adverse cardiovascular event (MACE) composite of myocardial infarction, stroke, or all-cause mortality. Secondary outcomes included the individual components of the primary outcome and hospitalizations for heart failure. Cause-specific Cox models were used to estimate hazard ratios (HRs). Results: Among 3284 matched pairs of GLP-1 RA and DPP4i initiators, GLP-1 RA use was associated with lower risks of MACE (HR, 0.87; 95% confidence interval [CI], 0.78 to 0.97), all-cause mortality (HR, 0.83; 95% CI, 0.74 to 0.94), and heart failure hospitalization (HR, 0.90; 95% CI, 0.83 to 0.99) over up to 2 years of follow-up. Among 2792 matched pairs, GLP-1 RA and sulfonylurea initiators, GLP-1 RA was associated with lower risks of MACE (HR, 0.83; 95% CI, 0.74 to 0.93) and all-cause mortality (HR, 0.80; 95% CI, 0.69 to 0.91). Conclusions: Among patients with type 2 diabetes receiving maintenance dialysis, GLP-1 RA initiation was associated with lower risk of cardiovascular events and all-cause mortality compared with other commonly prescribed antiglycemic agents. Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2026_06_12_ASN0000001061.mp3

Key Points: The HiLo pragmatic, multicenter randomized trial compared a higher versus lower serum phosphate target in patients undergoing maintenance hemodialysis. The HiLo trial was terminated early due to insufficient enrollment and inadequate phosphate separation between groups. HiLo demonstrated the feasibility of embedding a randomized intervention in routine dialysis care and identified challenges to inform future trials. Background: Serum phosphate targets in maintenance hemodialysis are based on observational studies. The Pragmatic Trial of Higher versus Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis (HiLo) trial aimed to compare the effect of a higher versus a lower phosphate target on clinical events in patients receiving maintenance hemodialysis. Methods: HiLo was a pragmatic, multicenter randomized trial that compared higher (≥6.5 mg/dl; “Hi”) versus lower (<5.5 mg/dl; “Lo”) phosphate targets in patients undergoing maintenance hemodialysis. The goal was to enroll 4400 cluster-randomized patients to assess the primary hierarchical composite outcome of all-cause mortality, followed by all-cause hospitalization using the win ratio. Owing to an imbalance in baseline serum phosphate between groups, raising concern for biased recruitment due to postrandomization consent, HiLo transitioned to individual randomization 23 months after the trial began. Ultimately, HiLo was stopped early due to insufficient enrollment and inadequate phosphate separation between groups. For this report, we combined the cluster-randomized and individually randomized cohorts, analyzing the individually randomized cohort as two additional clusters and applying a variance inflation factor to account for site-level clustering effects. Results: Between March 2020 and November 2023, 352 patients in the Hi group and 441 in the Lo group were enrolled. After a median follow-up of 1.4 years (quartiles 1–3: 0.5–2.8 years), there were 11 deaths per 100 person-years in the Hi group and 13 per 100 person-years in the Lo group. The Hi group experienced 134 hospitalizations per 100 person-years compared with 96 per 100 person-years in the Lo group. The primary hierarchical composite outcome did not differ between groups (win ratio for Hi versus Lo targets was 0.97; 95% confidence interval, 0.55 to 1.71). Conclusions: Insufficient enrollment and inadequate phosphate separation between groups preclude inferences about the effects of phosphate targets on clinical outcomes. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT04095039.

High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69–4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18–3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28–0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28–0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49–1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.

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