Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens.
BACKGROUND
Long-term administration of cyclosporin carries a risk of renal toxicity, and immunosuppressants are associated with an increased rate of malignant disorders. We undertook an open randomised study of the risks and benefits of two long-term maintenance regimens of cyclosporin in kidney-allograft recipients. The primary endpoint was graft function; secondary endpoints were survival and occurrence of cancer and rejection.


METHODS
231 recipients of a first allograft with at most one previous rejection episode were randomised 1 year after transplantation. Most were receiving cyclosporin and azathioprine. One group received cyclosporin doses adjusted to yield trough blood concentrations of 75-125 ng/mL (low-dose group); the second received doses that yielded trough concentrations of 150-250 ng/mL (normal-dose group). Analysis was by intention to treat.


RESULTS
At 66 months' follow-up, the low-dose and normal-dose groups were similar in mean serum creatinine (182 [SD 160] vs 184 [157] micromol/L; p=0.9) and mean creatinine clearance (47.5 [25.1] vs 45.3 (22.5] mL/min; p=0.6). Nine of 116 patients in the low-dose group and one of 115 in the normal-dose group had symptoms of rejection (p<0.02). There was no difference between the low-dose and normal-dose groups in survival (95 vs 92%; p=0.7) or graft survival (89 vs 82%; p=0.17) at 6 years. 60 patients developed cancers, 37 in the normal-dose group and 23 in the low-dose group (p<0.034); 66% were skin cancers (26 vs 17; p<0.05).


CONCLUSIONS
We found no evidence that halving of trough blood cyclosporin concentrations significantly changes graft function or graft survival. The low-dose regimen was associated with fewer malignant disorders but more frequent rejection. The design of long-term maintenance protocols for transplant recipients based on powerful immunosuppressant combinations should take these potential risks into account.
Dantal
J
J
Institut de Transplantation et de Recherche en Transplantation and Institut National de la Santé et de la Recherche Médicale U437, CHU Hotel Dieu, Nantes, France.
Hourmant
M
M
Cantarovich
D
D
Giral
M
M
Blancho
G
G
Dreno
B
B
Soulillou
J P
JP
D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001379:Azathioprine / Q000008:administration & dosage / Q000009:adverse effects; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000139:chemically induced / Q000453:epidemiology*; D011239:Prednisolone / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D012307:Risk Factors; D013223:Statistics as Topic
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone; D001379:Azathioprine