Control of antidonor antibody production with tacrolimus and mycophenolatemofetil in renal allograft recipients with chronic rejection

Background. In renal transplantation, chronic rejection is a major cause of late allograft loss. Recent studies indicate that a subset of chronic reje ction is associated with anti-HLA donor specific antibodies (DSA) and compl ement C4d deposition in peritubular capillaries (PTC), Since rescue therapy with tacrolimus and mycophenolate mofetil has been fouled to limit antidon or B-cell responses in recipients with acute humoral rejection, we sought t o determine whether a similar immunosuppressive regimen might be effective in patients with 'chronic humoral rejection'. Methods. Four renal allograft recipients with 'chronic humoral rejection' w ere prospectively identified. The diagnosis was based on: (1) progressive r ise in serum creatinine over 12 months; (2) typical pathologic features by light microscopy (transplant arteriopathy and glomerulopathy); (3) widespre ad C4d dec posits in PTC by immunofluorescence; (4) detection of 'de novo' DSA at the time of biopsy. Maintenance immunosuppression was CsA, prednison e and azathioprine (n=3) or prednisone and azathioprine (n=1), Rescue thera py with tacrolimus and mycophenolate mofetil was initiated in all patients, 12 hr after cyclosporine and azathioprine discontinuation. Results. At diagnosis, the mean serum creatinine was 3.9 mg/dl (range: 3.3 to 5.4 mg/dl), DSA was an IgG directed against HLA class II (n=3) or class I (n=2), that is one patient had both anti-HLA class I and class II antibod ies. Pretreatment antibody titers varied between 1:8 and 1:128, Rescue ther apy was associated with a rapid and sustained decrease in antibody titers I n two patients, DSA became undetectable after 9 months and a repeat biopsy performed after 12 months revealed a decrease in C4d deposition in PTC, Conclusion. These results suggest that a decrease in DSA production can be induced in renal allograft recipients with 'chronic humoral rejection' by u sing an immunosuppressive regimen that combines tacrolimus and mycophenolat e mofetil, Limitation of antidonor antibody synthesis may be important for the treatment or the prevention of chronic rejection in organ transplantati on.