Highlight
– Acoramidis initiation induces a dose-dependent, reversible acute dip in estimated glomerular filtration rate (eGFR) without kidney-related adverse events.
– Treatment results in a significant slowing of chronic eGFR decline and sustained reduction in urinary albumin-to-creatinine ratio versus placebo.
– The acute eGFR dip correlates with improved clinical outcomes, including lower all-cause mortality and cardiovascular hospitalization.
– Concomitant use of tafamidis does not impact the renal benefits observed with acoramidis.
Study Background
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease characterized by amyloid deposits of misfolded transthyretin protein in cardiac tissue. This cardiomyopathy significantly increases morbidity and mortality, with limited therapeutic options until recent advances. Acoramidis, a highly potent transthyretin stabilizer approved to reduce cardiovascular-related hospitalization, offers promising cardioprotective effects. Despite the growing use of acoramidis in clinical practice, its influence on kidney function—a critical concern especially in patients with amyloidosis and cardiac compromise—has not been fully elucidated. Given the importance of renal function in managing complex cardiac patients and the delicate balance of hemodynamics, understanding how acoramidis affects renal parameters is crucial for optimized patient care.
Study Design
This analysis integrated data from randomized controlled phase 2 (N=49) and phase 3 (N=632) clinical trials of acoramidis in patients with transthyretin amyloid cardiomyopathy. Participants received acoramidis versus placebo, enabling robust comparisons of renal function over time. The primary renal endpoints included the slope of estimated glomerular filtration rate (eGFR) decline—modeled using a linear spline mixed-effects approach—and longitudinal measures of urinary albumin-to-creatinine ratio, a marker of glomerular injury and proteinuria. To explore clinical relevance, relationships between kidney function changes and major clinical outcomes, such as all-cause mortality and cardiovascular-related hospitalizations, were assessed using Cox proportional hazards regression. The inclusion of concomitant tafamidis use was considered to examine potential interactions with acoramidis’ renal effects.
Key Findings
Acute eGFR Changes and Safety: Initiation of acoramidis treatment was associated with a modest, acute, and dose-dependent drop in eGFR, averaging 8.5±0.48 mL/min per 1.73 m2 at Day 28. Importantly, this initial decline was reversible and not associated with adverse kidney events, consistent with a hemodynamic mechanism rather than structural kidney injury. Urinary albumin-to-creatinine ratio was concomitantly reduced by 15.5% compared to placebo (95% CI, 0.4%–28.4%; P=0.044), indicating improved glomerular barrier function or reduced renal stress early in treatment.
Long-term Renal Outcomes: Over the chronic treatment period, the rate of eGFR decline was significantly slower with acoramidis versus placebo (-1.01 vs. -3.48 mL/min per 1.73 m2/year; P<0.001). This finding demonstrates a protective effect on kidney function beyond initial hemodynamic shifts. The urinary albumin-to-creatinine ratio reduction was sustained at 13.7% over time (95% CI, 1.7%–24.2%; P=0.026), reinforcing a persistent benefit on renal integrity. Notably, concomitant tafamidis administration did not modify the chronic eGFR slope in either treatment arm, indicating independent renal protective mechanisms of acoramidis.
Clinical Outcomes Correlated with Renal Changes: Patients experiencing acute eGFR dips at or above the median value (≥4.89 mL/min per 1.73 m2) had significantly better outcomes when treated with acoramidis compared to placebo, including a 58% reduction in risk for all-cause mortality or cardiovascular-related hospitalization (hazard ratio 0.42; 95% CI, 0.22–0.78; P=0.006) and a 66% reduction in hospitalization alone (hazard ratio 0.34; 95% CI, 0.17–0.66; P=0.002). Conversely, within the placebo group, acute eGFR dips were indicative of worse clinical prognosis, highlighting the distinct pathophysiology under acoramidis therapy. These data support that the acute eGFR dip with acoramidis represents a benign, hemodynamic modulation linked to improved systemic and renal outcomes.
Expert Commentary
The renal effects of acoramidis in ATTR-CM patients reveal a nuanced interplay between cardiac and kidney physiology. The initial reversible eGFR decline is reminiscent of hemodynamic changes observed with other heart failure medications where transient kidney function dips precede long-term nephroprotection. This suggests acoramidis may modulate renal perfusion pressures and glomerular filtration dynamics beneficially. The sustained reduction in albuminuria underscores improved glomerular barrier integrity, potentially by mitigating pathogenic amyloid deposits or reducing inflammatory pathways. Importantly, the lack of adverse renal events affirms the safety of initiating acoramidis even in patients at risk for kidney impairment.
These findings align with growing evidence that effective transthyretin stabilization not only preserves cardiac function but also supports renal health in amyloidosis patients. The results should encourage clinicians to monitor eGFR trends closely but not prematurely discontinue acoramidis upon observing initial declines. Further research into mechanistic insights could elucidate pathways by which acoramidis confers renal protection and help optimize integrated cardio-renal management strategies. A limitation remains the relatively small phase 2 sample size and short-term analysis in that cohort, but the large phase 3 dataset strengthens confidence in observed effects.
Conclusion
Acoramidis demonstrates a complex but favorable renal profile in transthyretin amyloid cardiomyopathy. While inducing a modest acute and reversible decrease in eGFR, it confers significant chronic kidney function preservation and reduces albuminuria. The acute dip in eGFR correlates with improved clinical outcomes, suggesting a hemodynamic, kidney-protective mechanism rather than injury. These findings support the continued use of acoramidis as a dual cardiac and renal protective agent in ATTR-CM and highlight the importance of integrated monitoring during therapy. Future studies should investigate the long-term renal effects and mechanistic underpinnings to optimize patient outcomes further.
Funding and Clinical Trials Registration
This research was supported by clinical trial registrations at ClinicalTrials.gov with identifiers NCT03458130, NCT03536767, NCT03860935, and NCT04988386.
References
Testani JM, Judge DP, Borlaug BA, Cherney D, Cox ZL, Gillmore JD, Lewis JB, Adler SH, Cao X, Castaño A, Fox JC, Katz L, Mathur V, Xiong K, Butler J, Masri A. Effects of Acoramidis on Kidney Function in Transthyretin Amyloid Cardiomyopathy. Circulation. Heart failure. 2026 Jul 2:e014656. PMID: 42389794. Available at: https://pubmed.ncbi.nlm.nih.gov/42389794/