Abstract: FR-PO0841
Assessing the Effect of Tacrolimus-Associated Pharmacogenetic Variants on Kidney Function over Time in Nephrotic Syndrome in the NEPTUNE Cohort
Session Information
- Glomerular Diseases: Practice and New Concepts Shaping Modern Care
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Authors
- Felipe, Diana E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Giannini, Courtney, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Murphy, Jessica, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Hendricks, Audrey E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Joy, Melanie S., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Cole, Joanne B., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
Background
Pharmacogenetic variants can influence the efficacy of drugs, typically through absorption or metabolism. Although many pharmacogenetic variants associated with tacrolimus response have been identified, few have been studied in nephrotic syndrome (NS), despite the frequent use of tacrolimus in this population. Therefore, we tested whether known pharmacogenetic variants modify the effect of tacrolimus on estimated glomerular filtration rate (eGFR) trajectory in individuals with NS.
Methods
We tested the effect of four known tacrolimus-associated pharmacogenetic variants (selected for their highest level of evidence impacting kidney outcomes in ClinPGx) on kidney function by eGFR measurements for individuals on tacrolimus (N=115) in the Nephrotic Syndrome Study Network (NEPTUNE). We fit a longitudinal mixed-effects model adjusting for age, sex, NS subtype, genetic ancestry, and urine protein-creatinine ratio at baseline.
Results
We identified two common genetic variants (rs2242480 and rs4646437) in partial linkage disequilibrium (r2=0.7) within the CYP3A4 gene associated with an annual eGFR decline of ~2.2 mL/min/1.73m^2 (95% CI: (0.73, 3.65), p=0.01). In stratified analyses, the estimated annual decline was faster among those who self-identified as White (-6.21 per year, 5% CI: (-9.13, 3.29), p≈4x10-5, N = 58) but was attenuated in those who self-identified as African-American (-0.22 per year, 95% CI: (-6.94, 6.57), p≈0.7, N = 30).
Conclusion
Our findings suggest that NS patients carrying risk alleles at two variants in the CYP3A4 gene experience faster kidney function decline. Prior studies have shown that these variants are associated with increased tacrolimus metabolism, consistent with CYP3A4’s role as a primary metabolizing enzyme, supporting a potential mechanism for this gene-drug interaction. These findings highlight the need for more individualized tacrolimus management in NS, similar to approaches adopted in kidney transplantation. As pharmacogenetic testing becomes increasingly accessible, there are enhanced opportunities for individualized care of patients with NS.