David Z. I. Cherney

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), together with newer multi-hormone receptor modulators that target glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin, have emerged as promising therapies for chronic kidney disease. This review examines the mechanisms through which these agents may protect the kidney and summarizes the emerging clinical evidence in populations without diabetes. Kidney protection appears to arise through complementary direct and indirect routes. Direct effects include natriuresis through inhibition of the sodium-hydrogen exchanger (NHE)-3, modulation of glomerular hemodynamics through effects on afferent arteriolar tone and vasoconstrictor pathways, and attenuation of renal inflammation; mechanisms that are largely independent of glucose lowering. Indirect mechanisms include reductions in the metabolic, hemodynamic and cardiac burden on the kidney through weight loss, blood pressure lowering, and improvement of heart failure. Beyond selective GLP-1R-agonism, the added hormonal components of multi-hormone receptor modulators engage distinct physiological pathways whose interactions may be additive, synergistic or counteracting, but remain incompletely understood. The efficacy of GLP-1 RAs and multi-hormone receptor modulators in people without diabetes is currently supported by results from secondary kidney endpoints in phase-3 obesity and cardiovascular outcome trials, including reductions in albuminuria and preservation of estimated glomerular filtration rate. Several dedicated outcome studies of GLP-1 RAs and multi-hormone receptor modulators are now underway and will determine whether these therapies become a new pillar of care in nondiabetic kidney disease.

Background: Clinical guidelines recommend combined use of renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1RA) and nonsteroidal mineralocorticoid receptor antagonists (nsMRA) to reduce cardiorenal risk. However, eligibility for combination treatment and the potential effects of implementation on preventing mortality remain unclear. Methods: We conducted a microsimulation study using data from the National Health and Nutrition Examination Survey (NHANES 2007–2016 and 2017–2020). The model incorporated acute treatment effects of RASi, SGLT2i, GLP1RA, and nsMRA on estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and serum potassium. Eligibility for combination treatment was assessed for each participant according to 73 clinical practice guideline recommendations and inclusion criteria from recently published clinical trials. Primary outcomes included: 1) the percentage of participants eligible for single or combination treatment with RASi, SGLT2i, GLP1RA, and nsMRA, and 2) the projected potential number of annually averted all-cause and cardiovascular deaths. Results: Of 8,152 adults, 15% had type 2 diabetes (DM), 14% had chronic kidney disease (CKD) and 5% had DM and CKD (DKD). Among all U.S. adults, 19% were treated with RASi, 1% with SGLT2i, 1% with GLP1RA and none with nsMRA. The dual-therapy associated with the highest eligibility was RASi+SGLT2i, with 15% of the U.S. population eligible (DM subgroup: 70%; CKD subgroup: 50%; DKD subgroup: 84%). The triple-therapy with the highest eligibility was RASi+SGLT2i+GLP1RA, with 11% overall eligibility (DM: 69%; CKD: 33%; DKD: 83%). Eligibility for quadruple-therapy was 4% overall (DM: 22%; CKD: 17%; DKD: 40%). Based on our microsimulation model, fewer individuals with diabetes were eligible for triple-therapy with RASi+SGLT2i+GLP1RA compared to dual-therapy with RASi+SGLT2i, but triple-therapy was projected to prevent 2-fold more potential all-cause and cardiovascular deaths versus dual-therapy. Conclusions: Under the assumptions of our microsimulation model, eligibility for combined treatment with cardiorenal protective therapies was prevalent, particularly in adults with type 2 diabetes and/or CKD.

The GLP-1 receptor agonist semaglutide preserves kidney function in people with type 2 diabetes and chronic kidney disease, but the underlying mechanisms are unclear. Here we report a 52-week randomized trial of subcutaneous semaglutide 1 mg once weekly versus placebo (n = 106 (n = 25 women, n = 81 men)) in participants with type 2 diabetes and chronic kidney disease. To identify kidney-specific mechanisms of action for semaglutide, we performed integrated multiparametric magnetic resonance imaging of the kidney and biopsy for histology (n = 33), alongside single-nucleus (n = 22) and spatial transcriptomics (n = 13) on paired samples with before- and after-treatment measurements. Coprimary magnetic resonance imaging outcomes (oxygenation by R2*, global perfusion and tissue inflammation by T1 mapping) were not significantly altered by semaglutide versus placebo treatment. Secondary outcomes revealed that semaglutide treatment, as compared to placebo, was associated with a significantly reduced renal artery resistive index and stabilization of the apparent diffusion coefficient, indicating prevention of fibrosis progression. Moreover, secondary transcriptomic outcomes revealed pronounced effects of semaglutide on glomerular endothelial cells, consistent with the results of spatial analyses indicating reduced numbers of immune cells in the proximity of these endothelial cells. The results from this trial indicate that mechanisms of kidney protection by semaglutide may include reduced vascular resistance, prevention of fibrosis and improved underlying molecular programs promoting endothelial cell health. ClinicalTrials.gov identifier: NCT04865770.

1. Diabetic kidney disease (DKD) is one of the most common complications of diabetes and a leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. Its global bu...

1. Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by (near-)complete loss of insulin-producing pancreatic β-cells, resulting in lifelong dependence on exogenous insulin. Globa...

BACKGROUND: Acoramidis achieves near-complete (≥90%) transthyretin stabilization and is approved to reduce cardiovascular-related mortality and hospitalization in transthyretin amyloid cardiomyopathy. Its effects on kidney function are not well characterized. METHODS: Data from randomized phase 2 (N=49) and phase 3 (N=632) studies in transthyretin amyloid cardiomyopathy were included. The estimated glomerular filtration rate (eGFR) slope was generated using a linear spline mixed-effects model. The urinary albumin-to-creatinine ratio was measured longitudinally. Relationships between changes in kidney function and clinical outcomes were explored using Cox proportional hazards models. RESULTS: Acoramidis initiation resulted in a modest acute dip in eGFR that was dose-dependent, reversible, and not associated with adverse kidney-related events. At Day 28, the mean (±SE) dip in eGFR from baseline with acoramidis was 8.5±0.48 mL/min per 1.73 m ² ; the placebo-corrected reduction in the urinary albumin-to-creatinine ratio was 15.5% (95% CI, 0.4%–28.4%; P =0.044). The rate of decline in kidney function (chronic eGFR slope) was significantly improved with acoramidis versus placebo (−1.01 versus −3.48 mL/min per 1.73 m ² per year; P P =0.026) over time. Concomitant tafamidis use did not influence the chronic eGFR slope in either arm. Comparing acoramidis versus placebo subgroups with acute eGFR dips ≥ the median (4.89 mL/min per 1.73 m ² ) favored acoramidis for all-cause mortality or cardiovascular-related hospitalization (hazard ratio, 0.42 [95% CI, 0.22–0.78]; P =0.006; P interaction=0.043) and cardiovascular-related hospitalization (hazard ratio, 0.34 [95% CI, 0.17–0.66]; P =0.002, P interaction=0.025). Within the placebo arm, eGFR dips portended worse outcomes. CONCLUSIONS: Acoramidis initiation resulted in an acute dip in eGFR and reductions in both the chronic eGFR slope and urinary albumin-to-creatinine ratio versus placebo without adverse kidney-related events. Acoramidis effects on kidney function may be mediated through direct kidney-protective hemodynamic effects. Importantly, the acute dip in eGFR was associated with a reduced risk of adverse clinical outcomes within the first year. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT03458130, NCT03536767, NCT03860935, NCT04988386.

Albuminuria, typically measured by urinary albumin-to-creatinine ratio, is present in nearly half of all patients with heart failure. Even at low levels, albuminuria is a well-established, independent risk marker for incident heart failure and adverse outcomes in those with pre-existing heart failure. Currently, routine urinary albumin-to-creatinine ratio screening is not universally recommended in heart failure guidelines, unlike in guidelines for Type 2 diabetes, chronic kidney disease, and hypertension. Emerging data suggest that this may limit opportunities for early detection, risk stratification, and pharmacologic intervention to improve outcomes. Clinical trials of guideline-directed therapies, including renin-angiotensin inhibitors, sodium-glucose cotransporter 2 inhibitors and finerenone show that reductions in urinary albumin-to-creatinine ratio is associated with risk reductions for cardiovascular, heart failure, and chronic kidney disease outcomes, indicating that albuminuria may function as both a marker of risk and potentially a modifiable factor. This review evaluates the role of albuminuria in predicting heart failure development and progression, its potential as a modifiable risk factor, approaches for measurement, current guideline recommendations for testing, and how heart failure therapies influence albuminuria and associated outcomes.