Background: Nephrotoxicity is a major side effect of calcineurin inhibitors (CNI). Earlier we reported 8% of our heart transplant recipients reaching end-stage renal failure (ESRF). Now, with an extended follow up of 20 years, we re-evaluated the development of ESRF and studied its influence on survival and the impact of polymorphisms in codon 10 and 25 of the promoter region of transforming growth factor (TGF)-beta on the risk of ESRF.
Methods: In all, 465 patients were transplanted between June 1984 and June 2005. All were on maintenance CNI treatment. Development of ESRF was studied in 402/465 (86.5%) patients surviving at least one year. Their median follow up was eight years, total observation time of 3,414 years. TGF-beta polymorphisms in codon 10 (Leu to Pro) and codon 25 (Arg to Pro) were analyzed with real-time polymerase chain reaction in a cohort of 237 patients, with an observation time of 2,329 years.
Results: Ten-year survival of patients surviving at least one year was 58.5%. Seventy-three patients (18.2%) developed ESRF. Dialysis-free survival was 60% at 15 years. The relative risk for ESRF in Pro carriers was 2.9 (CI 1.5-5.8) compared to patients with the Leu/Leu genotype (P = 0.002), while Pro carriers had a RR of 2.6 (CI 1.4-4.8) compared to the Arg/Arg25 genotype (P = 0.002). Survival of patients with ESRF was 1.5 years (median).
Conclusion: We found a highly significant association between TGF-beta polymorphisms and CNI induced ESRF after heart transplantation (HTx). Pro carriers of either codon 10 or 25 had a 2.6 to 2.9 times increased risk of developing ESRF. As ESRF after HTx results in high mortality rates these patients should no longer receive CNI-based immunosuppression.