Decrease of apoptosis rate in patients with renal transplantation treated with mycophenolate mofetil.
OBJECTIVE
Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF prevents acute graft rejection in organ transplants. The aim of this investigation is to study whether MMF has any influence on apoptosis and proliferation rates of cells other than lymphocytes.


METHODS
We conducted a retrospective study of renal allograft biopsies taken during the 1st week after transplantation in 25 patients receiving triple therapy with prednisone, ciclosporin and azathioprine 75 mg/day and in 25 patients treated with MMF at a dose of 2 g/day instead of azathioprine, in order to investigate the differences in the proliferation and apoptosis rates of the glomerular, tubular, interstitial and endothelial cells of the kidney. Twelve normal kidneys were used as controls. Conventional histopathological techniques were applied as usual for pathological diagnosis. Proliferative activity was assessed by use of MIB-1 antibody. Sections of formalin-fixed, paraffin-embedded tissue blocks were stained for the presence of apoptotic cells by TUNEL assay. Evaluation of proliferative or apoptotic rates was made by counting the number of positive cells in 10 glomeruli and in 10 transversely cut tubuli in each biopsy. The positive cells in the interstitium were counted in ten high-power fields. Positive cells in the endothelium were scored semiquantitatively from 0 to 3: 0 = none, 1 = isolated cells, 2 = small groups of cells, 3 = most endothelial cells. Mann-Whitney U and chi-square tests were used for intergroup comparisons.


RESULTS
All biopsies were normal or had borderline (Banff classification) acute rejection. MIB-1 rates were similar in both groups, without statistical differences (p > 0.05) between them. Significantly lower apoptotic rates were found in the group treated with MMF in tubular epithelium (23.41 +/- 8.86 vs. 57.4 +/- 13.42; p = 0.021), in glomerular (1.25 +/- 0.78 vs. 5.3 +/- 1.66; p = 0.027), and interstitial cells (1.58 +/- 0.6 vs. 5.8 +/- 1.54; p = 0.043). Apoptosis in endothelial cells (p > 0.05) was similar in both groups.


CONCLUSIONS
We conclude that treatment with MMF of kidney transplant patients does not affect the proliferative rate of cells of the allograft, but decreases the number of apoptotic cells in tubular epithelium.
Pardo-Mindán
F J
FJ
Department of Pathology, Clínica Universitaria, Universidad de Navarra, Pamplona, Spain. jpardo@unav.es
Errasti
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Panizo
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Sola
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de Alava
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Lozano
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MD
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001379:Azathioprine / Q000494:pharmacology / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D007678:Kidney Glomerulus / Q000187:drug effects; D016030:Kidney Transplantation / Q000276:immunology*; D007684:Kidney Tubules / Q000187:drug effects; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012189:Retrospective Studies
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D001379:Azathioprine