Because the best treatment of rejection is prevention, the most efficacious regimen of immunosuppressive drugs should be used first.
Quadruple-drug immunosuppressive regimens, including the use of antithymocyte globulin (ATGAM) or OKT3, have been accepted as standard at most pancreas transplant centers. Recent data from the United Network for Organ Sharing and several smaller retrospective comparative trials provide evidence that anti-T-cell antibody induction therapy may lessen the severity and delay the onset of rejection and may improve short-term graft survival in recipients of simultaneous pancreas-kidney (SPK) transplants [1,7,8]. This is the current practice. The development of newer more specific immuno-suppressive agents, however, recently has changed the face of modern immunosuppression in solid organ transplantation and raises the possibility of successful pancreas transplantation without induction therapy. Mycophenolate mofetil (MMF) has recently replaced azathioprine (AZA) as maintenance immunosuppressive therapy in kidney transplantation alone, SPK, and pancreas transplantation alone. MMF is a potent noncompetitive reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an essential enzyme in the de novo purine synthetic pathway upon which lymphocyte DNA synthesis and proliferation are strictly dependent. Compared with AZA, MMF has no association with pancreatitis and has less association with leukopenia. Moreover, whereas AZA is not useful in treating ongoing rejection, MMF can salvage refractory acute renal allograft rejection in up to half of patients. By virtue of this mechanism of action, MMF provides more effective and specific immunosuppression with less risk compared with AZA.
Similarly, Neoral, a microemulsified formulation of cyclosporine (CsA) has replaced standard CsA therapy with Sandimmune (both drugs from Sandoz Pharmaceuticals, East Hanover, NJ). Because of gastroparesis and autonomic dysfunction, patients with diabetes exhibit unpredictable absorption of CsA. The new formulation of CsA has an increased rate and extent of drug absorption with lower inter- and intra-individual pharmacokinetic variability than does Sandimmune, particularly in patients with diabetes. Improved bioavailability and more reliable pharmacokinetics may translate into fewer rejection episodes and improved graft survival. Experience with tacrolimus (FK506) in pancreas transplantation for induction, maintenance, and rescue therapy has demonstrated that it is safe, well tolerated, and has a low risk of glucose intolerance. Moreover, particularly for solitary pancreas transplants, strikingly improved short-term graft survival results have been reported [9,10]. The mechanism of action of FK506 as a calcineurin inhibitor is similar to that of CsA. FK506 has a better side-effect profile compared with CsA, causing less hirsutism, less hyperlipidemia, but somewhat more neurotoxicity. Unlike CsA, FK506 can rescue patients with refractory rejection and treat ongoing rejection. One caveat when using FK506 in combination with MMF is the risk of over-immunosuppression. Several studies have highlighted the fact that FK506 may increase blood levels of the active metabolite of MMF, mycophenolic acid, in a clinically relevant manner . By reducing the incidence of rejection, these modern immunosuppressants have resulted in improved short- and long-term graft survival. Fewer rejection episodes will likely translate into an overall reduction in the glucocorticoid dosage being given in the perioperative period. This reduction may favorably impact short-term infectious complications and long-term steroid-related adverse side effects.
FIGURE 15-13 (see Color Plate)
FIGURE 15-13 (see Color Plate)
Pancreas transplantation biopsy. Pancreas allograft biopsy is the gold standard for evaluating pancreas allograft dysfunction and for diagnosing acute rejection. In a pancreas transplantation recipient, indications for the need of a biopsy to rule out rejection include elevated amylase or lipase levels, unexplained fever, and glucose intolerance. In patients with simultaneous pancreas-kidney (SPK) transplantation, pancreas rejection most commonly (about 90%) occurs simultaneously with kidney rejection. As a result, a diagnosis of rejection relies almost entirely on serum creatinine, ^-microglobulin, and renal allograft biopsy. However, in the setting of sequential pancreas after kidney transplantation or pancreas transplantation alone (PTA) in which isolated pancreas rejection occurs, predicting rejection with a serologic or urinary marker is more difficult. To date, no marker has been identified that can predict rejection accurately enough to warrant treatment without first performing a biopsy. Thus, the ability to perform pancreas allograft biopsy is essential in the postoperative care of recipients of PTA. In addition to a biopsy, radio-logic evaluation of the allograft with ultrasonography (to evaluate vascular flow) and computed tomography (CT) scan (to rule out pancreatic enzyme leaks and fluid collections) are complementary studies that deserve consideration for all episodes of allograft dysfunction.
Percutaneous core biopsies of the pancreas allograft with realtime ultrasonography or CT guidance have been shown to be safe and reliable [12-14]. A and B, After the gland is assessed for vascular patency an appropriate portion of the pancreas is identified that is free of major vessels and overlying viscera (usually the body or tail). C, A 20-gauge automated biopsy needle is advanced into the pancreas graft under real-time ultrasonography, and a biopsy is obtained. In pancreaticoduodenal grafts with bladder drainage (BD) a cytoscopic transduodenal biopsy offers the opportunity to obtain biopsy specimens from both the pancreas and duodenum. Success rates for obtaining tissue for pathologic review in both techniques are 85% to 95%. Firm adherence of the pancreas to surrounding structures and use of real-time ultrasonography reduce the risks of complications related to biopsy. Overall, complications occur in 5% to 10% of patients, which can include bleeding, pancreatic duct leak, hematuria (in BD pancreas transplants), and asymptomatic transient hyperamylasemia. Rarely does a complication require a repeat operation or result in graft loss.
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