Biomedical subjects
Publications and source records attributed to M R First.
Transplantation with EDKs is a cost-effective therapy for ESRD as compared to hemodialysis across a variety of clinical and financial scenarios. In many cases the costs of pursuing transplantation with these donors will exceed hospital reimbursement for the procedure, providing a financial disincentive to pursuing a clearly cost-effective therapy.
Recent advances in immunosuppression have focused on more effective, safer, and targeted therapies that have resulted in improved short- and intermediate-term renal allograft survival. During the past decade there has been a marked decrease in acute rejection rates following renal transplantation because of the use of newer immunosuppressive agents. Recent data indicate that the average yearly reduction in the relative hazard of graft failure beyond 1 year was 4.2% for all recipients (0.4% for those recipients who had an acute rejection episode and 6.3% for those who did not have an acute rejection). Despite these improvements the currently available immunosuppressive agents are associated with significant cardiovascular risk factors, an increased risk of infection, and the development of malignancies in the long term. Predictive parameters of donor-specific hyporesponsiveness are needed so as to allow identification of patients in whom immunosuppressive therapy can be safely reduced. Immunosuppressive agents that have recently been approved for use in the United States and those that are in clinical and preclinical studies are discussed.
BACKGROUND: Hypertension in kidney transplant (KT) patients may result from attenuated whole-body nitric oxide (NO) content and abnormal NO-mediated vasodilation. Increasing NO bioavailability with L-arginine (ARG) could theoretically restore the NO-mediated vasodilatory response and lower blood pressure. METHODS: In a prospective pilot study, 6 normotensive volunteers and 10 KT patients received oral supplements of ARG (9.0 g/d) for 9 days, then 18.0 g/d for 9 more days. Six hemodialysis (HD) and 4 peritoneal dialysis patients received the same dose for 14 days. Five KT patients received 30 mL/d of canola oil (CanO) in addition to ARG. Systolic (SBP) and diastolic (DBP) blood pressure, creatinine clearance (CCr), and serum creatinine (Cr) were measured at baseline, day 9, and day 18. In a subsequent study, 20 hypertensive KT patients with stable but abnormal renal function were randomized in a crossover study to start ARG-only or ARG+CanO supplements for two 2-month periods with an intervening month of no supplementation. SBP, DBP, CCr, and Cr were measured monthly for 7 months. RESULTS: In the pilot study, ARG reduced the SBP in HD patients from 171.5 +/- 7.5 mmHg (baseline) to 142.8 +/- 8.3 mmHg (p = .028). In the crossover study, SBP was reduced from baseline (155.9 +/- 5.0 mmHg), after the first 2 months (143.2 +/- 3.2 mmHg; p = .03) and subsequent 2 months (143.3 +/- 2.5 mmHg; p = .014) of supplementation. DBP was also reduced after supplementation in both studies. CanO had no effect on blood pressure. Renal function did not change. CONCLUSIONS: Oral preparations of ARG (+/-CanO) were well tolerated for up to 60 consecutive days and had favorable effects on SBP and DBP in hypertensive KT and HD patients.
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Muromonab-CD3 monoclonal antibody (Orthoclone OKT3) was used 146 times in 123 transplant recipients to treat or prevent rejection. Reversal and prevention of rejection were evaluated 1 week and 1 year after OKT3 therapy. Eighty-one percent (73 of 90) of the rejection episodes in kidney transplant patients were reversed with 67% of these grafts functioning at 1 year. Eighteen of 20 (90%) rejection episodes in liver transplant recipients were reversed, as were 11 of 13 (85%) heart transplant rejection episodes. Only one of five pancreas transplant episodes were reversed. OKT3 was used prophylactically in 18 transplant recipients (13 kidney, four heart, one liver). Immunologic monitoring (lymphocyte subsets, serum OKT3 levels, and antimurine antibodies) was performed during and after OKT3 therapy. Antimurine antibody formation rate was 28% (26 of 94 patients monitored). OKT3 therapy resulted in a rapid depletion of CD3+ cells from the peripheral circulation (less than 20/mm3) and trough serum OKT3 levels of greater than 800 ng/ml by the third day of therapy in all transplant types. Twenty-three patients (14 kidney, five liver, three heart, and one pancreas) were retreated with OKT3; reversal of rejection occurred in 87% of patients (13 of 15) with no antimurine antibodies and in 83% of patients (five of six) with a low antibody titer but did not occur in the two patients with a high antibody titer. Retreatment of patients with no anti-OKT3 antibody resulted in a depletion of CD3+ cells from the peripheral blood, but it took longer than in patients treated with OKT3 for the first time. Similarly, serum OKT3 levels increased slower in retreated patients compared with first treatment. In retreatment patients with a low titer antimurine antibody, often it was necessary to increase the dose of OKT3 to achieve adequate serum OKT3 levels and to deplete CD3+ cells. Antimurine antibody developed de novo in four of the 15 antibody negative patients (27%) who were retreated. Overall, OKT3 was an effective agent in reversing and preventing rejection in solid organ transplantation with few severe side effects and a low mortality. Retreatment with OKT3 should not be considered unless the antibody status of the patient is known. Development of low titer antibodies does not preclude successful retreatment with OKT3. Alternate antirejection therapy, however, should be used in patients with high titer antimurine responses.
Oral cyclosporine therapy immediately after heart transplantation is erratic and difficult to predict. The purpose of this study was to evaluate the relative efficacy and safety of cyclosporine when administered by constant-rate infusion immediately after transplantation. Nineteen patients (17 men and two women) aged 50 years (range 25 to 61 years) who weighed 71 +/- 9 kg, participated in the study and received cyclosporine, 7 to 10 mg/hr (117 +/- 15 micrograms/kg/hr). The infusions were initially maintained for 26 +/- 5 hours (range 18 to 42 hours) without adjustments in dosage. Whole blood samples were obtained at hourly intervals for the first 8 to 12 hours and then daily throughout the 7-day study period and were analyzed by high-performance liquid chromatography. Constant-rate cyclosporine infusion resulted in therapeutic blood levels (350 to 450 ng/ml) at 6 hours. These levels remained relatively steady throughout the 7-day infusion, requiring only minimal dosage adjustments. Kidney function was not altered significantly after 7 days of intravenous cyclosporine therapy as evidenced by a mean serum creatinine level of 1.3 mg/dl before therapy and 1.4 mg/dl after therapy. There, however, was a transient rise in serum creatinine level in most patients on the second or third day after transplantation that resolved without a reduction in cyclosporine dosage. The mean endomyocardial biopsy score at 1 week after transplantation was 0.1, and only four of the patients required additional immunosuppressive therapy to treat rejection during the first 6 weeks after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
A cyclosporine-ketoconazole drug interaction was first described in 1981. It has been suggested that the two drugs should not be used concomitantly because of the danger of severe nephrotoxicity. Two reported cases indicate that cyclosporine and ketoconazole can be safely coadministered, provided that the dosage of cyclosporine is reduced appropriately. Two patients were initially given 8 mg/kg/day of cyclosporine at the time of heart transplantation, and the dosage was tapered to meet appropriate blood levels (250 to 350 ng/ml by whole blood high-performance liquid chromatography). During ketoconazole therapy (400 mg daily for 4 weeks), patient 1 received 80 to 100 mg/day of cyclosporine, which is equal to approximately 1 mg/kg/day, and patient 2 received between 40 and 80 mg/day of cyclosporine, which is equivalent to 0.4 to 0.8 mg/kg/day. Neither patient exhibited a creatinine value above 1.4 mg/dl while on combined therapy, and there were no problems with allograft rejection. Both patients had inappropriately high cyclosporine blood levels even with this marked reduction in dosage (patient 1, 520 to 1310 ng/ml and patient 2, 320 to 600 ng/ml). Thus it appears that cyclosporine and ketoconazole can be administered together safely, provided that there is an appropriate reduction in the dosage of cyclosporine; this results in the maintenance of adequate immunosuppression without development of nephrotoxicity.
A LMC micromethod using specific B lymphocyte target cells labeled with a fluorescent dye has been developed to select matched donors and recipients for kidney allotransplantation. The fluorescence of the B lymphocyte target cells was 85% or less of control levels in 9 of 28 patients. In 8 of these 9 hosts graft loss occurred. Nineteen sets of target cells showed 90-95% of control fluorescence. Only 5 of these recipients lost their transplants (p less than 0.01). The fluorescent LMC test correlates with successful renal transplant outcome when the target cells are purified B cells.