Evaluation of the genetic background of standard-immunosuppressant-related toxicity in a cohort of 200 paediatric renal allograft recipients--a retrospective study.
BACKGROUND
Immunosuppressant toxicity is a limiting factor for the efficacy and safety of long-term therapy. Whether it stems solely from drug exposure, remains unclear.


METHODS
Overall, 207 children and adolescents at the mean age of 11+/-4.4, with primary renal allograft were analyzed. Immunosuppression regimens included CsA or TAC, combined with AZA or MMF and steroids. Drug-specific toxicities were diagnosed by renal biopsy and/or clinical criteria. Genotyping for MDR1, CYP3A5, IL1B, IL1RN, IL-6, IL-10, MCP-1, TGFB1, CCR5, VEGF and TNF-alpha gene polymorphisms was performed with the use of PCR and PCR-RFLP techniques.


RESULTS
Nephrotoxicity was seen in 38.5% of patients treated with CsA and 29.5% - with TAC, while gingival hypertrophy was observed in 28% of CsA patients. Myelotoxicity was found in 3% of AZA-treated and 6.4% of MMF-treated patients. No significant correlation was seen between the patient's age, gender, type of pre-transplantation dialysis, donor age, graft origin or cold ischemia time, and the occurrence of drug-related toxicity. For CNIs, the drug exposure and the duration of treatment did not prove of significance either. TAC associated nephrotoxicity correlated with the CCR5 gene polymorphism, as the wt/32 genotype was found in 21% of patients with no detected toxicity (p<0.041) and in none of the nephrotoxicity cases. The presence of this genotype was also associated with significantly better graft function at 1 year post-transplant (GFR 115.104+/-28.40 vs 86.434+/-29.96; p=0.022). An association was seen between the MMF-induced myelotoxicity and the TNF-alpha G(-308)A polymorphism (p<0.005), but the MMF exposure was higher in patients who developed toxicity.


CONCLUSIONS
Genetic background should be regarded one of the risk factors for immunosuppressant related toxicity in renal transplantation.
Grenda
Ryszard
R
Department of Nephrology, Kidney Transplantation and Hypertension Children's Memorial Health Institute, Warsaw, Poland. r.grenda@czd.pl
Prokurat
Sylwester
S
Ciechanowicz
Andrzej
A
Piatosa
Barbara
B
Kaliciński
Piotr
P
D000293:Adolescent; D001379:Azathioprine / Q000009:adverse effects; D001483:Base Sequence; D065095:Calcineurin Inhibitors; D002648:Child; D015331:Cohort Studies; D016572:Cyclosporine / Q000009:adverse effects; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology*; D008297:Male; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000235:genetics; D012189:Retrospective Studies; D016559:Tacrolimus / Q000009:adverse effects
D065095:Calcineurin Inhibitors; D017931:DNA Primers; D007166:Immunosuppressive Agents; D019713:Receptors, CCR5; D016572:Cyclosporine; D009173:Mycophenolic Acid; D001379:Azathioprine; D016559:Tacrolimus