FK 506 therapy for refractory renal allograft rejection: lessons from liver transplantation.

FK 506 has proven to be an effective immunosuppressive agent in liver transplantation, but its role in renal transplantation remains to be defined. Since the initial availability of FK 506 for treatment of refractory renal allograft rejection, we have applied an aggressive approach consisting of institution of rescue therapy at an early point in the rejection process combined with assiduous monitoring of FK 506 blood levels and the histologic response to therapy. A total of 17 adult patients were treated for refractory renal allograft rejection with this approach. Median follow-up was 9 months post-initiation of FK 506 therapy. Median time to first rejection was 26 d post-transplant, and median time to FK 506 rescue therapy was 113 d post-transplant. Sixteen of 17 patients received either ATGAM or OKT3 induction therapy. Prior to FK 506 rescue therapy, patients received the following antirejection therapy: corticosteroids 40 + 21 mg/kg (prednisone or Solumedrol), OKT3 (median 14 d), ATGAM (3 patients, 14 d each). FK 506 rescue therapy was successful in reversing the rejection process in all 17 patients. Fifteen patients (88%) demonstrated rapid reversal of rejection (i.e. reversal within 14 d), whereas three patients demonstrated delayed reversal. Nine month actuarial patient and graft survivals were 92% and 84%. When censored for documented noncompliance, nine month actuarial graft survival was 92%. Good long-term renal function was observed (pre-FK 506 baseline creatinine 2.1 +/- 0.5 mg/dl, current serum creatinine 2.1 +/- 0.6 mg/dl. Six recurrent rejection episodes occurred in 5 patients (29%) with a median time to recurrent rejection of 59 d post-initiation of FK 506 rescue therapy. Each recurrent rejection episode was successfully treated by corticosteroids and/or increased FK 506 dose. CMV disease and lymphoma were not observed. Histologic evidence of FK 506 nephrotoxicity (hyaline necrosis in preglomerular arterioles) was observed in 6 patients 30% (median time to diagnosis 49 d). FK 506 blood levels (whole blood TDX) between 10 and 20 ng/ml provided effective reversal in most patients. Current FK 506 dose and blood levels are 0.18 +/- 0.09 mg/kg/d and 7 +/- 2 ng/dl). FK 506 rescue therapy also allowed aggressive reductions in prednisone dose: (mean current prednisone dose 0.08 +/- 0.05 mg/kg/d). In conclusion, an aggressive approach toward FK 506 rescue: 1) provides prompt, effective reversal of refractory renal allograft rejection, 2) good long-term renal allograft function, 3) balanced immunosuppression with respect to recurrent rejection, opportunistic infection and PTLD, 4) acceptable toxicity, and 5) aggressive reduction in corticosteroid dosing. Based on these findings, FK 506 rescue therapy is now the treatment of choice in our program for renal allograft rejection episodes that occur following antilymphocyte antibody therapy.

Treatment of acute glomerular rejection with FK 506.

Acute glomerular rejection is a distinct pathologic subtype of rejection that is often refractory to standard therapy and is associated with significant risk of graft loss. Both cellular and humoral mechanisms have been shown to be involved in the pathophysiology of acute glomerular rejection. FK506, because of its ability to inhibit both cellular and humoral mechanisms of rejection, provides a theoretically attractive approach for treating acute glomerular rejection. This initial experience with FK 506 treatment of acute glomerular rejection occurred in a 58-yr-old woman who received a 0 AB, 2 DR-match cadaveric renal transplant. A renal allograft biopsy performed on post-transplant day 77 for renal dysfunction (serum creatine 1.3-->1.8 mg/dl) revealed moderate cellular and vascular rejection. Corticosteroid therapy provided a transient improvement in renal function; however, a repeat biopsy 7 d later revealed acute glomerular rejection with immunohistologic evidence of antibody-mediated rejection (immunoglobulin and complement deposition in glomerular capillaries). FK 506 therapy was instituted and provided prompt reversal of the acute glomerular rejection as determined by serial renal allograft biopsies. One year later, recurrent rejection has not been observed, and good renal function is present. (Current serum creatine 1.7 mg/dl, creatine clearance 35 ml/min/m2, and 24 h urinary protein 230 mg.) Successful corticosteroid withdrawal has been achieved, and current immunosuppressive therapy consists only of FK 606 and azathioprine. This experience indicates that FK 506 can provide effective therapy for acute glomerular rejection, and that simultaneous treatment with plasmapheresis and an antilymphocyte antibody preparation may not be necessary. This experience also provides further evidence of the ability of FK 506 to inhibit antibody-mediated rejection processes.