Pharmacodynamic immune monitoring of NFAT-regulated genes predicts skin cancer in elderly long-term renal transplant recipients

Clin Transplant. Sep-Oct 2008;22(5):549-54. doi: 10.1111/j.1399-0012.2008.00819.x. Epub 2008 Apr 3.

Abstract

Introduction: 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.

Method: 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).

Conclusion: 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.

MeSH terms

  • Aged
  • Carcinoma, Basal Cell / genetics
  • Carcinoma, Basal Cell / immunology*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / immunology*
  • Cyclosporine / adverse effects
  • Cyclosporine / immunology
  • Cyclosporine / pharmacokinetics
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / immunology
  • Immunosuppressive Agents / pharmacokinetics
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism
  • Kidney Transplantation / adverse effects
  • Kidney Transplantation / immunology*
  • Male
  • Middle Aged
  • NFATC Transcription Factors / genetics*
  • NFATC Transcription Factors / immunology*
  • Neoplasms, Second Primary / immunology
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / immunology*
  • Survivors

Substances

  • IL2 protein, human
  • Immunosuppressive Agents
  • Interleukin-2
  • NFATC Transcription Factors
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Cyclosporine