The impact of cyclosporine dose reduction with or without the addition of rapamycin on functional, molecular, and histological markers of chronic allograft nephropathy.
BACKGROUND
Overexposure to cyclosporine is a risk factor for chronic allograft nephropathy (CAN) and dose reduction has been advocated. The purpose of this study was to determine the impact of adding the non-nephrotoxic immunosuppressant, rapamycin, after cyclosporine dose reduction in renal-allograft recipients with CAN.


METHODS
Thirty-one patients with biopsy-confirmed CAN were prospectively randomized to receive a 40% cyclosporine dose reduction with (rapamycin, n=16) or without (control, n=15) the addition of rapamycin 2 mg/day. Renal function and side-effect parameters were assessed. Patients had renal allograft biopsies taken at recruitment and after 6 months. Glomeruli were isolated from these and underwent total mRNA extraction followed by RT-PCR-ELISA to assess transforming growth factor-beta1, collagen III, TIMP-1, TIMP-2, and matrix metalloproteinase-2 expression. Samples were also stained with Sirius red and the percentage interstitial volume fraction quantified by computerized histomorphometric analysis. Data are presented as mean (+/-SD).


RESULTS
Patient characteristics and cyclosporine trough levels after dose reduction (rapamycin 68 [+/-21] vs. control 56 [+/-19] ng/mL, P=NS) were similar in both groups. Rapamycin patients had a significant fall in Cr-51 radioisotope glomerular filtration rate (31.6 [+/-8.9] to 27.3 [+/-8.6] mL/min, P<0.01) that was not significant in controls (29.5 [+/-10.4] to 27.0 [+/-8.0] mL/min, P=NS). Transforming growth factor-beta1 expression fell over time in control but remained constant in rapamycin patients. Conversely collagen III expression increased over the 6-month follow-up in rapamycin patients but not in controls. Both had comparable increases in TIMP-1 and matrix metalloproteinase-2 but only rapamycin patients developed a significant increase in TIMP-2. Sirius red-stained interstitial volume fraction fell over the study in controls (15.3-11.2%, P=0.06) but not in rapamycin patients (16.2-16.3%, P=NS).


CONCLUSIONS
Rapamycin (2 mg/day) did not improve functional, molecular, or histological outcome in patients with CAN after cyclosporine dose reduction. Further studies involving larger numbers of patients are necessary to confirm these findings.
Saunders
R N
RN
Department of Transplant Surgery, University of Leicester, Leicester General Hospital, Leicester, United Kingdom.
Bicknell
G R
GR
Nicholson
M L
ML
D000328:Adult; D002908:Chronic Disease; D004396:Coloring Agents; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects; D004359:Drug Therapy, Combination; D005260:Female; D015870:Gene Expression; D006084:Graft Rejection / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007678:Kidney Glomerulus / Q000502:physiology; D016030:Kidney Transplantation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008875:Middle Aged; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects; D013194:Staining and Labeling; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014184:Transplantation, Homologous
D004396:Coloring Agents; D007166:Immunosuppressive Agents; C508960:TGFB1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019716:Tissue Inhibitor of Metalloproteinase-2; D016572:Cyclosporine; D020778:Matrix Metalloproteinase 2; D020123:Sirolimus