Late Acute Rejection Episodes After Vascularized Pancreas Transplantation R.J. Stratta
ITH improvements in organ retrieval technology, surgical techniques, clinical immunosuppression, anti-microbial prophylaxis, and diagnostic methodology, success rates for vascularized pancreas transplantation (PTX) have steadily increased. As a result, PTX, particularly simultaneous kidney–pancreas transplantation (SKPT), has become an accepted treatment option in appropriately selected diabetic patients. However, a major challenge in the posttransplant setting is the prevention, early diagnosis, and treatment of allograft rejection. In spite of advances in immunosuppression, rejection remains the major cause of graft loss (GL) after PTX. With the emergence of several safe and reliable techniques of pancreas allograft biopsy, the timely diagnosis of pancreas allograft rejection has become less of a problem. Consequently, a resurgence of interest has occurred in solitary PTX, either PTX alone (PTA) or sequential pancreas after kidney transplantation (PAKT). Late acute rejection (LAR, defined as biopsy-proven AR occurring more than 12 months after transplant) is uncommon after renal transplantation and has been associated with an increased risk of chronic rejection and immunologic GL.1,2 Although there is some evidence to suggest that a pancreas allograft may be more immunogenic than a renal allograft,3 there is little data available on LAR after PTX.4
MATERIALS AND METHODS To study this phenomenon, a retrospective analysis was conducted to identify all episodes of LAR involving the pancreas allograft in 156 patients with graft function for at least 1 year, including 118 SKPT, 26 PTA, and 12 PAKT recipients. All patients underwent whole-organ PTX with bladder drainage and received triple maintenance therapy with cyclosporine (CSA) or Prograf, Prednisone (PRED), and Azathioprine (AZA). Cyclosporine dosing was adjusted to maintain 12-hour whole blood polyclonal trough TDX (Therapeutic drug analyzer, Abbott Laboratories) CSA levels above 400 ng/mL. The diagnosis of LAR was confirmed by pancreas allograft biopsy in 31 cases (91%), with the remaining cases based on kidney biopsy after SKPT concomitant with biochemical evidence of pancreas allograft dysfunction (n 5 2) or
clinical criteria alone after PTA in one patient who refused a biopsy.
A total of 34 episodes of LAR occurred in 26 patients (17%) at a mean of 23 months after PTX. No episodes of noncompliance were documented. The incidence of LAR varied directly according to type of transplant: SKPT (10%); PAKT (25%); and PTA (42%) (P , .001). LAR occurred at a mean of 30 6 14 months after SKPT versus 19 6 8.5 months after solitary PTX (P 5 .03). Numerous demographic, clinical, and immunologic variables involving the donor and recipient were analyzed pre- and posttransplant to determine their predictive value on the subsequent development of LAR. Pharmacologic and biochemical data were further analyzed at 1 year after PTX and at the time of diagnosis of LAR. In the SKPT group, 14 episodes of LAR were diagnosed in 12 patients. Eight patients (67%) had episodes of early AR in the first year after SKPT. At the time of LAR, three patients had CSA levels below 400 ng/mL, five had total CSA doses below 4.0 mg/kg/d, and two were no longer on AZA. Of the 14 episodes of LAR, seven were treated with steroids alone, seven with anti–T-cell therapy, and one was converted to Cellcept. Patient survival was 100% and pancreas graft survival was 83% with a mean follow-up of 25 months after LAR. Two pancreas GLs occurred: one at the time of LAR and the other 12 months later. No risk factors predictive for LAR were identified. In the PTA and PAKT group, 20 episodes of LAR occurred in 14 patients. Eight were treated with steroids alone, 11 with anti–T-cell therapy, and one with Prograf. An additional five patients were converted to Prograf and two to Cellcept. Again, no significant risk factors for LAR were identified. Thirteen patients (93%) had episodes of early From the University of Tennessee-Memphis and the University of Nebraska Medical Center. Address reprint requests to Dr R.J. Stratta, University of Tennessee—Memphis, Department of Surgery, Suite A202, 956 Court Ave, Memphis, TN 38163-2116.
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Transplantation Proceedings, 30, 1560–1561 (1998)
LATE ACUTE REJECTION
AR. Nine patients were on CSA-based and five on Prografbased therapy at the time of LAR. Drug doses and levels were subtherapeutic in five patients, and five patients had undergone AZA withdrawal. Patient survival was 92% and pancreas graft survival was 42% (P 5 .04 versus SKPT) with a mean follow-up of 14 months after LAR. Seven patients experienced pancreas GL, ranging from 3 days to 20 months (mean, 9 months) after the diagnosis of LAR. DISCUSSION
According to Registry data, about 40% of GLs after PTX are due to immunologic causes.5 A number of studies have reported an increased risk of renal allograft rejection in diabetic recipients after SKPT as compared to kidney transplantation alone. In these studies, most episodes of AR were reversible and kidney graft survival did not differ between groups at 1 or 5 years. It is generally accepted that the major advantage of SKPT is the so-called “protective” effect of the renal allograft in terms of following renal function as an early marker for subsequent pancreas allograft rejection. However, the true incidence of pancreas allograft rejection in this setting is unknown. Recent pancreas biopsy experiences from several centers have documented that the pancreas allograft may reject independent of the kidney from the same donor. Previous studies have also noted not only a hierarchy of rejection when considering multi-organ transplants, but a differing incidence of rejection when comparing single versus dual organ transplantation. UNOS Registry data clearly show an increased rate of GL due to rejection after PTA or PAKT versus SKPT.
Although discordant rejection and GL may occur after SKPT, solitary PTX may be associated with a higher intrinsic rate of immunologic failure. Previous studies of immunogenicity after PTX have focused predominantly on either early AR or chronic rejection. A report by Walker et al.4 analyzed late episodes of pancreas allograft rejection, which were correlated with low CSA levels. In other solid organ transplants, LAR has been related to factors such as noncompliance and under-immunosuppression.1,2 In this study, LAR was not uncommon, particularly after solitary PTX. Late acute rejection after solitary PTX occurred earlier and had more adverse consequences compared to SKPT. There were no identifiable specific risk factors predictive for LAR other than type of transplant, suggesting that a solitary pancreas graft may be more immunogenic than a pancreas transplanted simultaneous with a kidney. With increasing interest occuring in solitary PTX, immunosuppressive strategies must be tailored to prevent the occurrence of LAR after solitary PTX. REFERENCES 1. Legget JE Jr, Ojo AO, Leichtman AB, et al: Transplantation 63:1268, 1997 2. Matas AJ, Gillingham KJ, Payne WD, et al: Transplantation 57:857, 1994 3. Gruessner RWG, Nakhleh R, Tzardis P, et al: Transplantation 56:1053, 1993 4. Walker JA, Klassen DK, Hooper FJ, et al: Transplantation 62:539, 1996 5. Sutherland DER, Gruessner A: In: Cecka JM, Terasaki PI (eds.): Clinical Transplants 1996. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1997, p 47