C. J. Hesse

Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients.

BACKGROUND Triple drug treatment consisting of mycophenolate mofetil (MMF), in a standard dose of 2 g daily, combined with cyclosporine (CsA) and prednisone, has become the standard immunosuppressive regimen after kidney transplantation in many centers. The need for therapeutic drug monitoring of mycophenolic acid (MPA) has not yet been established. Several drug interactions with MMF are known. We investigated the influence of CsA withdrawal on MPA trough levels in renal transplant patients. METHODS Fifty-two patients were treated with 1 g of MMF twice daily, and prednisone and CsA targeted between 125 and 175 ng/ml for 6 months after transplantation. At 6 months after transplantation, 19 patients were randomized for continuation of triple therapy (group A), 19 patients discontinued CsA (group B), and 14 patients discontinued prednisone (group C). We compared 12-hr fasted MPA trough levels at 6 and 9 months after transplantation within and between these groups. RESULTS MPA trough levels during treatment with CsA, MMF, and prednisone were significantly lower than those during treatment with MMF and prednisone only (group B); median levels were 1.87 mg/L (range: 0.56-5.27) vs. 3.16 mg/L (range: 0.32-7.78), respectively (P=0.002). MPA trough levels in groups A and C did not change between 6 and 9 months after transplantation; group A median levels were 1.87 (range: 0.31-4.32) vs. 1.53 mg/L (range: 0.36-3.70), and group C median levels were 1.62 (range: 0.69-10.34) vs. 1.79 mg/L (range: 0.54-6.00), respectively. At 9 months after transplantation, patients in whom CsA was discontinued had higher MPA trough levels as compared with patients who continued the use of triple therapy (P=0.001) or patients in whom steroids were withdrawn (P=0.014). CONCLUSION A significant increase of MPA trough levels was found after discontinuation of CsA (6 months after transplantation), resulting in almost a doubling of MPA trough levels at 9 months after transplantation. This resulted in increased MPA levels in patients without CsA as compared to MPA levels in patients continuing triple therapy or discontinuing prednisone.

A double-blind, placebo-controlled study of monoclonal anti-interleukin-2 receptor antibody (BT563) administration to prevent acute rejection after kidney transplantation.

In a double-blind, randomized, placebo-controlled trial, BT563, a murine IgGt anti-IL-2R antibody, was given as a rejection prophylaxis after kidney transplantation. Drug-related side effects were not observed. During the 10-day course of BT563, no rejections (0/27) were found, whereas a rejection episode occurred in 7 patients (7/29) (P=0.01) during placebo treatment. Within the first 4 postoperative weeks, freedom from rejection in the BT563 group and in the placebo group was 96% vs. 76% (P=0.05). Due to rejection in the placebo group, 2 grafts were lost. At 3 months, an overall rejection incidence in the BT563 and placebo group was found of 3/27 (11%) vs. 8/29 (28%) patients (P=0.18). Infectious complications were distributed equally between the 2 groups. CMV disease, found in 3 placebo-treated patients, occurred after rejection treatment (2/3). Within the BT563 group, 1 patient lost his graft due to renal artery thrombosis, 2 grafts were lost as a result of technical failure, and 2 patients had a squamous cell carcinoma that could be treated curatively. We conclude that the use of the anti-IL-2R mAb BT563 effectively prevents rejection after kidney transplantation without increasing infectious complications.

A randomized trial comparing safety and efficacy of OKT3 and a monoclonal anti-interleukin-2 receptor antibody (BT563) in the prevention of acute rejection after heart transplantation

In a prospective randomized trial, BT563, a murine IgG, anti-interleukin-2 receptor antibody, was compared with OKT3 for use as an early rejection prophylaxis after heart transplantation. Patients received either BT563 (n=31) or OKT3 (n=29) during the first 7 days after transplantation; cyclosporine was started on day 3. Median follow-up was 34 months. A cytokine release syndrome occurred in the majority of patients of the OKT3-treated group but in none of the BT563 recipients. The mean duration of electrical stimulation of the heart in the BT563 group was longer than in the OKT3 group (5.1 vs. 2.1 days). In both groups, one patient required insertion of a permanent pacemaker. Freedom from acute rejection at 3 months was not significantly different between the two groups (BT563: 5/29, 17%; OKT3: 6/29, 21%). In the BT563 group, however, rejection tended to occur earlier after transplantation. There was no difference in the overall incidence of rejection. The incidence of infectious complications was evenly distributed in both groups. Malignancies occurred in two patients, both in the OKT3 group. In conclusion, the use of this anti-interleukin-2 receptor monoclonal antibody in heart transplant recipients is safe and devoid of the side effects that accompany the use of OKT3. OKT3 and BT563 result in a similar freedom from rejection at 3 and 12 months after heart transplantation.

Single‐shot, high‐dose rabbit ATG for rejection prophylaxis after kidney transplantation

We studied the effects of a single intravenous injection of rabbit ATG (RIVM, Bilthoven, The Netherlands) in a dose of 8 mg/kg body weight administered 6 h after kidney transplantation on graft survival, rejection incidence, T-cell subsets, and cost-effectiveness. A total of 58 (37 male/21 female) consecutive renal allograft recipients were entered in this trial. Treatment results were compared with 56 patients treated with intravenous cyclosporin (CyA). In all patients concomitant medication consisted of steroids and azathioprine, followed by oral CyA. Following rabbit ATG, T cells (WT31) quickly disappeared from the peripheral blood and a return to greater than 100/mm3 was observed at a median of 7 (range 3–21) days. Graft survival was the same in both groups, as was the incidence of primary nonfunction. The rate of acute rejection was significantly lower in the rabbit ATG-treated patients (12% vs 50%). We conclude that a single shot of rabbit ATG is an attractive, easy, and cost-effective induction scheme with a low incidence of delayed graft function and acute rejection episodes. A relatively high incidence of vascular thrombosis of the graft, however, warrants further study before this treatment regimen can be generally applied.

Mycophenolic acid trough levels after kidney transplantation in a cyclosporine-free protocol

Abstract Twenty‐seven stable kidney transplant recipients treated with cyclosporine and prednisone were converted to mycophenolate mofetil (MMF) and prednisone 1 year after transplantation. After conversion the patients were treated with a standard daily dose of 1 g MMF b.i.d. and 10 mg prednisone for 4 months. Thereafter, two MMF dose reductions were performed with a 4‐month interval. Mycophenolic acid (MPA) trough levels were measured at regular intervals. A relation was found between MPA trough levels and MMF dose. The median MPA trough level for patients treated with 1 g MMF b. i. d. was 4.3 μg/ml (0.95‐15.5) and 3.0 μg/ml (0.73‐7.8) for patients treated with 750 mg b. i. d. (P = 0.0002). The MPA trough levels further decreased from 3.0 to 2.3 μg/ml (0.6‐6.63) in patients treated with 500 mg MMF b. i. d. (P = 0.01). Dose reduction of MMF from 1 g to 750 mg b.i.d. could be performed without acute rejections. A further dose reduction to 500 mg b.i.d. elicited 3 rejections. Patients experiencing an acute rejection had a median MPA trough level of 2.3 μg/ml (1.26‐3.38) compared to 3.8 μg/ml (1.48‐6.52) in patients without an acute rejection (P = 0.25). We conclude that there is a significant relation between MPA trough levels and MMF dose. MPA trough levels were not predictive of rejection in the present study.

In vitro and in vivo effects of BT563, an anti‐interleukin‐2 receptor monoclonal antibody

Abstract BT563, a murine anti‐IL‐2R MoAb, was found to be more potent than anti‐Tac in inhibiting proliferation in the mixed lymphocyte reaction. Results obtained with 33 B3.1 in these experiments were similar to those with BT563. The anti‐IL‐2R MoAb 2A3 was shown to be a suitable agent for monitoring the effect of BT563 on peripheral blood. IL‐2R‐positive cells were not detected in peripheral blood samples from 1 h after the first dose until 8 days after the last dose. Plasma trough levels were measured in patients receiving 5 or 10 mg daily. The administration of BT563 to allograft recipients did not lead to clinically significant side effects.

Pharmacodynamics of prophylactic antirej ection therapy with an anti interleukin-2 receptor monoclonal antibody (BT563) after heart and kidney transplantation

Abstract A mouse monoclonal antibody (BT563) directed to the α-chain of the IL-2 receptor was administrated immediately after transplantation in a dose of 10 mg/day prophylactically to 30 heart transplant recipients (HTx) and 40 renal transplant recipients (RTx) to induce immunosuppression. Plasma levels increased to a plateau level of 5300 ng/ml in HTx and 5900 ng/ml in RTx. BT563 plasma disappearance curves gives a mean T1/2, of respectively 39 h (range 14–112 h) and 42 h (range 8–122 h) for HTx and RTx respectively. The CD25 marker (IL-2R) on the peripheral blood lymphocytes disappeared within hours after the first gift and returned to normal within 0–20 days after the last gift. In HTx more often CD25+ cells were found in the presence of BT563 and more rejections occurred shortly after discontinuation of BT563 compared to the RTx group. Rejectors and non-rejectors within the HTX group did not differ with respect to the period of depletion of CD25 positive cells in the peripheral blood. In 56% of the patients a substantial IgM antibody response was detected. This response was similar for HTx and RTx and not related to rejection. The frequency of IgG responses was low in both HTx (13%) and RTx (21%) patients and the IgG response was not related with graft rejection or with antirejection treatment. Peripheral monitoring showed that mAb plasma levels, antimurine antibody responses and number of CD25 positive cells were not related with the clinical results. The mAb BT563 proved to be safe with respect to the generation of antimurine antibodies and, when given in combination with CsA, is a therapy with a potential for high efficacy.

Comparison of four different cyclosporine immunoassays in heart and kidney transplant recipients

Four different immunoassays were used to measure cyclosporine A (CsA) plasma (20°C) levels in heart and kidney transplant recipients. Two radioimmunoassays (RIAs) (Sandimmune and Cyclotrac) and the fluorescence polarization immunoassay (FPIA) were based on polyclonal antibodies, whereas the fourth (Cyclotrac-SP) used a CsA-specific mouse monoclonal antibody. We found considerable differences in measured CsA concentrations, which were dependent on the method used and the clinical situation of the patient. Correlation coefficients between the nonspecific assays ranged from 0.899 to 0.901 with plasma values increasing in the order Sandimmune < Cyclotrac < FPIA. In the CsA-specific RIA, values were lower, and the correlation with the nonspecific assays ranged from 0.761 to 0.795. In the first 21 days posttransplantation, the heart transplant group showed a higher ratio of nonspecific/specific CsA (mean 4.0) compared with the subsequent period (mean 2.3) or with renal transplant recipients (mean 2.4). The TDX method showed the best assay characteristics. In heart transplant patients with specific and nonspecific 125I-RIA methods, mean CsA levels were 25% lower during rejection periods compared with periods without signs of rejection.