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Effects of Acoramidis on Kidney Function in Transthyretin Amyloid Cardiomyopathy
Jeffrey M Testani1, Daniel P Judge2, Barry A Borlaug3
1Section of Cardiovascular Medicine, Yale University, New Haven, CT (J.M.T.).
Insights
Acoramidis treatment for transthyretin amyloid cardiomyopathy showed a temporary eGFR dip but improved long-term kidney function and reduced hospitalization risk. This suggests potential kidney-protective hemodynamic effects.
Area of Science:
- Nephrology
- Cardiology
- Pharmacology
Background:
- Acoramidis stabilizes transthyretin (TTR), reducing cardiovascular hospitalizations in TTR amyloid cardiomyopathy (ATTR-CM).
- The impact of acoramidis on kidney function in ATTR-CM patients remains incompletely understood.
Purpose of the Study:
- To characterize the effects of acoramidis on kidney function markers in patients with ATTR-CM.
- To explore the relationship between changes in kidney function and clinical outcomes.
Main Methods:
- Analysis of data from Phase 2 and Phase 3 randomized controlled trials (N=49 and N=632, respectively) in ATTR-CM patients.
- Evaluation of estimated glomerular filtration rate (eGFR) slope using a linear spline mixed-effects model.
- Longitudinal measurement of urinary albumin-to-creatinine ratio (UACR) and analysis of clinical outcomes via Cox proportional hazards models.
Main Results:
- Acoramidis initiation caused a dose-dependent, reversible, acute eGFR dip (mean 8.5±0.48 mL/min/1.73 m² at Day 28) without adverse kidney events.
- Acoramidis significantly improved the chronic eGFR slope (-1.01 vs. -3.48 mL/min/1.73 m²/year; P<0.001) and sustained UACR reduction (13.7%; P=0.026) compared to placebo.
- Patients experiencing an acute eGFR dip ≥ median with acoramidis showed reduced all-cause mortality or cardiovascular hospitalization (HR 0.42; P=0.006).
Conclusions:
- Acoramidis demonstrates beneficial effects on kidney function, including reduced chronic eGFR decline and UACR, without adverse kidney events.
- The acute eGFR dip associated with acoramidis initiation may indicate a favorable hemodynamic effect and is linked to reduced adverse clinical outcomes.
- Acoramidis represents a promising therapeutic option for managing kidney function in ATTR-CM patients.
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 m2; 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 m2 per year; P<0.001), and the reduction in the urinary albumin-to-creatinine ratio was sustained (13.7% [95% CI, 1.7%-24.2%]; 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 m2) 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.
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