M.W.F. van den Hoogen

Rituximab as induction therapy after renal transplantation: a randomized, double-blind, placebo-controlled study of efficacy and safety

We evaluated the efficacy and safety of rituximab as induction therapy in renal transplant patients. In a double‐blind, placebo‐controlled study, 280 adult renal transplant patients were randomized between a single dose of rituximab (375 mg/m2) or placebo during transplant surgery. Patients were stratified according to panel‐reactive antibody (PRA) value and rank number of transplantation. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil and steroids. The primary endpoint was the incidence of biopsy proven acute rejection (BPAR) within 6 months after transplantation. The incidence of BPAR was comparable between rituximab‐treated (23/138, 16.7%) and placebo‐treated patients (30/142, 21.2%, p = 0.25). Immunologically high‐risk patients (PRA >6% or re‐transplant) not receiving rituximab had a significantly higher incidence of rejection (13/34, 38.2%) compared to other treatment groups (rituximab‐treated immunologically high‐risk patients, and rituximab‐ or placebo‐treated immunologically low‐risk (PRA ≤ 6% or first transplant) patients (17.9%, 16.4% and 15.7%, p = 0.004). Neutropenia (<1.5 × 109/L) occurred more frequently in rituximab‐treated patients (24.3% vs. 2.2%, p < 0.001). After 24 months, the cumulative incidence of infections and malignancies was comparable. A single dose of rituximab as induction therapy did not reduce the overall incidence of BPAR, but might be beneficial in immunologically high‐risk patients. Treatment with rituximab was safe.

Treatment of Steroid-Resistant Acute Renal Allograft Rejection With Alemtuzumab

Steroid‐resistant renal allograft rejections are commonly treated with rabbit antithymocyte globulin (RATG), but alemtuzumab could be an effective, safe and more convenient alternative. Adult patients with steroid‐resistant renal allograft rejection treated with alemtuzumab (15–30 mg s.c. on 2 subsequent days) from 2008 to 2012 (n = 11) were compared to patients treated with RATG (2.5‐4.0 mg/kg bodyweight i.v. for 10–14 days; n = 20). We assessed treatment‐failure (graft loss, lack of improvement of graft function or need for additional anti‐rejection treatment), infections during the first 3 months after treatment and infusion‐related side effects. In both groups, the median time‐interval between rejection and transplantation was 2 weeks, and approximately 75% of rejections were classified as Banff‐IIA or higher. Three alemtuzumab‐treated patients (27%) experienced treatment failure, compared to eight RATG treated patients (40%, p = 0.70). There was no difference in the incidence of infections. There were mild infusion‐related side‐effects in three alemtuzumab‐treated patients (27%), and more severe infusion‐related side effects in 17 RATG‐treated patients (85%, p = 0.013). Drug related costs of alemtuzumab‐treatment were lower than of RATG‐treatment (€1050 vs. €2024; p < 0.01). Alemtuzumab might be an effective therapy for steroid‐resistant renal allograft rejections. In contrast to RATG, alemtuzumab is nearly devoid of infusion‐related side‐effects. These data warrant a prospective trial.

Anti-B cell therapy with rituximab as induction therapy in renal transplantation.

Traditionally, antirejection therapy in organ transplantation has mainly been directed at T cells. During recent years, the role of B cells in acute rejection has attracted more attention. In the Radboud University Medical Center (Nijmegen, The Netherlands) we performed a randomized, placebo controlled study to assess the efficacy and safety of rituximab as induction therapy after renal transplantation. In parallel we investigated the effects of rituximab on the numbers and function of B and T cells. An overview of the results, which have largely been published in peer reviewed papers, is presented below.

Cytokine Release After Treatment With Rituximab in Renal Transplant Recipients

Background Treatment with rituximab may be accompanied by a systemic cytokine release. We studied the effects of a single dose of rituximab on cytokine levels in transplant patients and examined the underlying mechanism. Methods Twenty renal transplant recipients (10 rituximab-treated, 10 placebo-treated) were recruited from a randomized clinical trial. Rituximab or placebo was infused during surgery, and blood samples were taken before, during, and after surgery and analyzed for interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12, IL-17, interferon-&ggr;, macrophage inflammatory protein (MIP)-1&bgr;, transforming growth factor-&bgr;, and tumor necrosis factor-&agr;. in vitro, healthy donor peripheral blood mononuclear cells, purified B cells, monocytes, natural killer (NK) cells, or combinations thereof were incubated with rituximab, rituximab-F(ab′)2, or medium and MIP-1&bgr;, IL-10, interferon-&ggr;, and tumor necrosis factor-&agr; levels were measured in the supernatant. Results Rituximab-treated patients had higher serum levels of IL-10 (101 ± 35 pg/mL vs 41 ± 9 pg/mL; P < 0.01) and MIP-1&bgr; (950 ± 418 pg/mL vs 125 ± 32 pg/mL; P < 0.001) compared to placebo-treated patients at 2 hours after start of infusion. There was no difference in the level of other cytokines. In vitro, the addition of rituximab, but not rituximab-F(ab′)2 fragments, only led to significantly increased levels of MIP-1&bgr; in co-cultures of B and NK cells. Levels of MIP-1&bgr; were higher in patients with a high affinity Fc-receptor compared to those with a lower affinity Fc&ggr;RIIIa (1356 ± 184 pg/mL vs 679 ± 273 pg/mL; P < 0.01). Conclusions In addition to B-cell depletion, rituximab can modulate the immune response by inducing cytokine secretion, especially IL-10 and MIP-1&bgr;. Rituximab-induced MIP-1&bgr; secretion depends on the combined presence of B cells and FcR-bearing cells, especially NK cells.

Insulin requirement after a renal transplant in patients with type 2 diabetes: the choice of calcineurin inhibitors.

OBJECTIVES Hyperglycemia is a common adverse event of immunosuppressive drugs used in organ transplant. Because cyclosporine is less diabetogenic than tacrolimus is, cyclosporine may be preferred in patients with pre-existing diabetes mellitus type 2, to prevent insulin treatment after a transplant. PATIENTS AND METHODS From March 2005 to June 2011, adult renal transplant patients with pre-existing diabetes mellitus type 2, who were not treated with insulin before a transplant, were treated with cyclosporine in combination with mycophenolate mofetil and corticosteroids. For comparison, we used historical controls who were treated with tacrolimus instead of cyclosporine. RESULTS Of the 16 patients treated with cyclosporine, only 4 remained free of insulin treatment after a follow-up of least 1 year, compared with 2 of 12 patients who were treated with tacrolimus (25% vs 17%; P = .67). Almost all patients required insulin treatment within 2 months of the transplant, and patients required comparable doses of insulin at different times after the transplant in both groups. None of the baseline characteristics could sufficiently predict the need to start insulin treatment. CONCLUSIONS Cyclosporine cannot be preferred over tacrolimus to minimize either the chance of requiring insulin treatment posttransplant or the dosage of insulin in patients with pre-existing diabetes mellitus type 2.

Three-Year Outcomes of Belatacept Studies; Reason to Be Optimistic?

van den Hoogen, M W F Pipeleers, L Comment Letter United States Am J Transplant. 2012 Aug;12(8):2259; discussion 2260. doi: 10.1111/j.1600-6143.2012.04165.x. Epub 2012 Jul 3.