Induction immunosuppression in kidney transplant recipients older than 60 years of age : safety and efficacy of ATGAM, OKT3 and Simulect.

BACKGROUND: The choice of induction immunosuppression for kidney transplantation in elderly recipients is dictated by the consideration of the risk of infection as well as efficacy in the prevention of acute rejection, thus allowing a reduction in subsequent maintenance immunosuppression and its attendant long-term adverse effects. OBJECTIVE: To compare the efficacy and safety of the antibody induction immunosuppression strategies in elderly recipients of kidney transplants. PATIENTS AND METHODS: We present retrospective data analysis on 183 kidney transplant recipients > or = 60 years of age at Hahnemann University Hospital (Philadelphia, PA, USA) over a 12-year period. We compared four consecutive cohorts of kidney transplant recipients receiving lymphocyte immune globulin, equine antithymocyte globulin (ATGAM) [n = 29]; muromonab CD3 (OKT3) [n = 45]; basiliximab (Simulect) with corticosteroid maintenance [n = 40]; and Simulect without corticosteroid maintenance (n = 69). RESULTS: Delayed graft function (DGF) was observed in 48% of patients receiving ATGAM, 35.6% in the OKT3 group and 35% in the Simulect group with corticosteroid maintenance and 36.2% in the Simulect group without corticosteroid maintenance. The rejection rate within the first 3 months was 31% in the ATGAM and OKT3 groups, 17.5% in the Simulect group with corticosteroid maintenance and 14.5% in the Simulect group without corticosteroid maintenance. These differences for DGF and acute rejection were statistically significant between patients receiving ATGAM and OKT3, ATGAM or OKT3 and both groups of Simulect (all p < 0.05). Patients receiving Simulect were free of adverse effects typically encountered by patients receiving polyclonal and monoclonal antibodies for induction. Patients receiving Simulect had much shorter hospital stays and benefited from significant reduction of costs compared with other groups. CONCLUSION: Our data indicate that kidney transplant recipients > or = 60 years of age benefit from induction therapy with Simulect followed by corticosteroid-free maintenance immunosuppression.

Prevention of OKT3 nephrotoxicity after kidney transplantation.

In our experience the use of OKT3 as prophylaxis in renal transplantation has been associated with an increased incidence of both delayed graft function and thromboses of graft vessels. OKT3 nephrotoxicity might have been favored by restriction of perioperative fluid infusion to prevent pulmonary edema and by the use of very high dose (30 mg/kg) of methylprednisolone (mPDS) before the first OKT3 injection to reduce the release of cytokines. This led us to modify our perioperative management in three ways: (1) hydration status was optimalized; (2) the calcium-channel blocker diltiazem, considered beneficial for recovery of graft function, was administered on the day of transplantation; and (3) the dose of mPDS given before the first OKT3 injection was fixed at 8 mg/kg. Comparison of two consecutive series of patients (group 1, control patients, N = 172; group 2, managed as described above, N = 173) showed that: (1) the incidence of delayed graft function fell from 52% in group 1 to 22% in group 2 (P < 0.0001): (2) the incidence of pulmonary edema was not significantly increased in group 2 (3.5% vs. 1.7% in group 1, P = 0.5); and (3) the frequency of intragraft thrombosis fell from 7.6% in group 1 to 1.2% in group 2 (P = 0.0034). Multivariate analysis showed that the volemia/diltiazem program and avoidance of high mPDS dose were the most important factors responsible for the reduced occurrence of delayed graft function and graft vessels thrombosis, respectively. We conclude that a combined strategy of appropriate dosage of steroids before the first OKT3 injection, administration of a calcium-channel blocker and optimalization of volemia is safe and efficiently prevents against OKT3 nephrotoxic effects.

Prevention and management of the adverse effects associated with immunosuppressive therapy.

Advances in immunosuppressive therapy have resulted in significantly improved patient and graft survival after solid organ transplantation. However, increased use has brought attention to specific toxicities associated with the use of these agents. Corticosteroid therapy can result in a wide array of short and long term toxicities. Management of these effects has focused on alternate day and dosage reduction protocols. Myelosuppression, hepatotoxicity, alopecia and gastrointestinal adverse effects are associated with azathioprine and generally respond to a reduction in dosage or withdrawal. Cyclophosphamide myelosuppression is managed in a similar manner. Use of cyclosporin, while the mainstay of immunosuppressive therapy, is often complicated by several well documented adverse effects. Short and long term nephrotoxicity is often managed through pharmacokinetic dosing strategies as well as pharmacological intervention with calcium channel blockers, prostaglandin analogues, pentoxifylline and thromboxane antagonists. Cyclosporin-induced hypertension, hyperlipidaemia, hyperkalaemia and hyperuricaemia are generally responsive to appropriate dietary restrictions and pharmacological therapies. The adverse effects associated with polyclonal antilymphocyte agents (fever, chills, rash, arthralgias) occur in response to the administration of foreign protein substances but can be prevented by pretreatment with corticosteroids, diphenhydramine and paracetamol (acetaminophen). The administration of muromonab CD3 (OKT3) stimulates the release of cytokines resulting in potentially severe complications seen during the first 1 or 2 doses. Pretreatment with diphenhydramine, low dose corticosteroids and paracetamol as well as proper fluid management has reduced the incidence of this syndrome. However, agents such as high dose corticosteroids, indomethacin, pentoxifylline and anti-tumour necrosis factor monoclonal antibodies may further decrease the severity of cytokine-induced toxicity. Antimurine antibodies may also develop during muromonab CD3 therapy, potentially limiting the efficacy of this agent. However, continued concomitant immunosuppressive therapy has significantly reduced antibody formation. In summary, as newer agents are developed with narrow therapeutic windows, it will be critical to identify specific drug toxicity and to develop preventative and management therapeutic strategies.

Cardiovascular side effects after renal allograft rejection therapy with Orthoclone: prevention with nitrendipine.

Orthoclone (OKT-3), a monoclonal antibody, is an effective immunosuppressant in organ graft recipients. One of the reported side effects is serious pulmonary edema, heart failure, hyperdynamia, and elevation of blood pressure. It should be assessed whether patients treated with OKT-3 benefit from antihypertensive therapy with a calcium channel blocker before and during the allograft rejection therapy to prevent from cardiovascular side effects. To assess a preventive cardiovascular effect of therapy with nitrendipine before and during the OKT-3 rejection therapy, the patients studied (n = 28) were randomly allocated to two study groups. Group a without nitrendipine comprised 15 patients, and group b with 2 x 10 mg of nitrendipine daily comprised 13 patients. In study group a (without nitrendipine therapy), in 8 of 15 patients, there was a short-lasting increase in blood pressure during 3 h after the first injection of OKT-3 by 20.0 +/- 12.8 (systolic)/10.1 +/- 6.7 (diastolic) mm Hg. Whereas this initial rise of blood pressure on the first day was accompanied by an increase in heart rate by 24.1 +/- 10.8 beats/min, the longer-lasting increase in blood pressure at day 2 was not associated with significant changes in heart rate. In group b (patients receiving 2 x 10 mg of nitrendipine before OKT-3 therapy was started and during the whole treatment course), in 3 of 13 patients, a short increase in blood pressure (13.7 +/- 2.9/7.8 +/- 5.1 mm Hg) was recorded 5 h after the first dose of OKT-3.(ABSTRACT TRUNCATED AT 250 WORDS)