Pharmacodynamic immune monitoring of NFAT-regulated genes predicts skin cancer in elderly long-term renal transplant recipients.
BACKGROUND
Among elderly allograft recipients non-melanoma skin cancer (NMSC) is the most common malignancy. We have previously shown that malignancies are associated with a higher intensity of ciclosporin A (CsA)-induced immunosuppression.


METHODS
Fifty-five long-term elderly renal transplant patients with a stable transplant function had regular skin examinations. The expression of the nuclear factor of activated T cells (NFAT)-regulated genes (interleukin-2, granulocyte-macrophage colony stimulating-factor, interferon-gamma) was determined by real-time PCR at CsA trough levels and two h after oral intake.


RESULTS
The CsA dose was 2.0 mg/kg (0.95-3.50), with CsA trough level (C0) level 97 microg/L (33-157) and CsA two-h level (C2) 538 microg/L (350-1228). NMSC was diagnosed in 14/55 patients (25.4%). A total of 85.7% of allograft recipients with NMSC were male (p < 0.005). Age, time after transplantation, CsA dose, CsA C0 and C2 level were comparable in both groups. NFAT-regulated gene expression was signficantly lower in patients with skin cancer compared with patients without skin cancer [4.94% (0.91-13.4) vs. 11.6% (3.3-40.8), p < 0.001).


CONCLUSIONS
The unproportional high incidence of NMSC in elderly long-term kidney-transplanted patients correlates with a lower NFAT-regulated gene expression which is a surrogate biomarker for a higher degree of functional immunosuppression. Further studies are required to determine whether the reduction of CsA with an increased NFAT-regulated gene expression is associated with a lower NMSC incidence.
Sommerer
Claudia
C
Department of Nephrology, University Hospital, University of Heidelberg, Germany. claudia.sommerer@med.uni-heidelberg.de
Hartschuh
Wolfgang
W
Enk
Alexander
A
Meuer
Stefan
S
Zeier
Martin
M
Giese
Thomas
T
D000368:Aged; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology*; D016572:Cyclosporine / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000276:immunology*; D016609:Neoplasms, Second Primary / Q000276:immunology; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology*; D017741:Survivors
C508594:IL2 protein, human; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine