The impact of transforming growth factor-beta1 gene polymorphism on end-stage renal failure after heart transplantation.
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).


CONCLUSIONS
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.
van de Wetering
Jacqueline
J
Department of Internal Medicine, Erasmus MC, University Hospital Rotterdam, the Netherlands. j.vandewetering.1@erasmusmc.nl
Weimar
Charlotte H E
CH
Balk
Aggie H M M
AH
Roodnat
Joke I
JI
Holweg
Cécile T J
CT
Baan
Carla C
CC
van Domburg
Ron T
RT
Weimar
Willem
W
D000293:Adolescent; D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors; D002648:Child; D002675:Child, Preschool; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007676:Kidney Failure, Chronic / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D053773:Transforming Growth Factor beta1