Suppression of allograft rejection is central to successful organ transplantation; thus, immunosuppressive agents are crucial for successful allograft function. Immunosuppressive drugs are used for induction (intense immunosuppression in the initial days after transplantation), maintenance, and reversal of established rejection. This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.

https://www.nejm.org/doi/pdf/10.1056/NEJMra033540

Immunosuppressive Drugs for Kidney Transplantation

Currently, adrenal masses are discovered incidentally in 0.35–5% of patients imaged with computed tomography (CT) and are referred to as adrenal incidentalomas [1,2]. As a result, the diagnostic dilemma of separating the small fraction of hypersecretory and/or malignant masses from the majority that are nonhypersecretory adrenal adenomas has become common. Given the fourfold greater autopsy incidence of adrenal adenomas compared with the radiographic incidence, and the oncology data that only 20–41% of adrenal metastases are detected by CT [1,3], it is likely that an increase in prevalence will occur if the spatial resolving capacity of abdominal imaging improves, if abdominal imaging occurs more frequently, and if routine abdominal imaging slice thickness is decreased.

Incidentally discovered adrenal masses

Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients

Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.

Primary sclerosing cholangitis

Background Acute rejection is still a major problem in renal transplantation and is one of the most important causes of chronic graft dysfunction and late graft loss. Selective immunosuppression with a humanized antibody against the alpha-chain of the interleukin (IL)-2 receptor (CD25) was evaluated to demonstrate the efficacy of this type of immunoprophylaxis in combination with dual immunosuppression. Methods We studied the effect of daclizumab, a humanized monoclonal antibody against the alpha-chain of the IL-2 receptor, in a randomized double-blind, prospective phase III clinical trial in 275 patients receiving a first cadaveric renal allograft. Among them 111 (83%) in the placebo arm and 116 (82%) in the daclizumab arm received the full regimen of five doses (1.0 mg/kg) every other week. Baseline immunosuppression consisted of cyclosporine and corticosteroids. Results At 6 months, 39 (28%) of the patients in the daclizumab group had biopsy-proven rejections, as compared with 63 (47%) in the placebo group (P=0.001). The need for additional antilymphocyte therapy, antithymocyte globulin, antilymphocyte globulin (ATG, ALG, OKT3) was also lower in the daclizumab group (8% vs. 16%, P=0.02), and they required significantly lower mean (+/- SD) cumulative doses of prednisone (3750+/-1981 mg vs. 4438+/-2667 mg in the placebo group, P=0.01). Graft function was significantly better (P=0.02) in the daclizumab group (graft function rate: 58 vs. 51 ml/min, mean) as was patient survival (P=0.01, 99% vs. 94%). No specific adverse events were observed in daclizumab-treated patients. Patients receiving daclizumab experienced fewer cytomegalovirus infections (18% vs. 25%), and none died from severe infectious complications, compared to four patients in the placebo arm. No patient in the daclizumab group had a lymphoproliferative disorder or any other form of immunosuppression-related tumor during the first year after transplant. Conclusions Administration of daclizumab in addition to dual immunosuppression therapy significantly reduced biopsy-proven acute rejection after renal transplantation, improved patient survival, and did not add to the toxicity of the immunosuppressive regimen.

Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.510230526

Biliary malignancies in primary sclerosing cholangitis: Timing for liver transplantation

Background. Although most transplanted patients with underlying IgA nephropathy (IgAN) develop histological recurrence, its clinical relevance is considered low. Methods. We performed a single-center analysis of 61 renal transplant patients with IgAN. Results. Forty-four percent of the patients showed a stable graft function. Progressive graft dysfunction apparently due to recurrent IgAN occurred in 23% of the patients (16% required dialysis). Five patients were retransplanted, and three again developed dialysis-dependent renal failure apparently due to recurrent IgAN. In 20% of the patients, chronic transplant dysfunction was due to other reasons, whereas no reason was identified in 13% of the patients. Neither findings before transplantation, the ACE genotype, the type of immunosuppression, nor the course after transplantation predicted transplant dysfunction due to recurrent IgAN. Follow-up after transplantation was longer in the group with dysfunction due to recurrent disease than in the group with dysfunction due to chronic rejection or in the stable group. Conclusion. Recurrent IgAN is a clinically relevant problem in renal transplant patients. Its importance may have been underestimated in the past due to inadequate lengths of follow-up.

Recurrent immunoglobulin A nephropathy after renal transplantation: a significant contributor to graft loss.

The immunosuppressive effect of a monoclonal antibody (moAb), BT563, directed to the alpha-chain of the IL-2R (CD25), was analyzed in a prospective nonrandomized trial and a prospective randomized trial. Primary objectives were evaluation of the incidence of acute rejections and infections; secondary objectives were safety and tolerability of the moAb. A total of 28 patients were enrolled (phase II) to receive 10 mg/day of BT563 (12 days) as immunoprophylaxis in combination with cyclosporine, azathioprine, and low-dose steroids. Subsequently 32 patients were randomly assigned (phase III) to receive BT563 (10 mg/day) for 12 days or ATG (5 mg/kg/day) for 7 days in addition to cyclosporine and low-dose steroids. No side effects of the BT563 treatment were noted. The actuarial survival was 82% at 12 months in the phase II trial and 92% at 12 months in both arms of the phase III trial. There was one acute rejection in the phase II trial. No acute rejections were noted in the BT arm of the phase III trial and 5 acute rejections were treated in the ATG arm. In the phase II trial 7 infectious episodes were observed, while one infection was seen in the BT arm and 7 in the ATG arm of the triple immunosuppression phase III trial. In all patients circulation of coated CD25+ lymphocytes was observed during BT563 treatment; there was no evidence of depletion or modulation of CD25+ cells. Mean serum levels of BT563 ranged from 1.6 to 7.6 microgram/ml throughout the therapy. An antimurine response was seen in 82% (phase II) and 100% (phase III) of the patients. Antirabbit antibodies were found in 56% of the patients treated with ATG. Analysis of the antimurine response specificity revealed in 56% blocking anti-isotypic antibodies and only in 3% of the patients an anti-idiotypic response. The data of the study presented suggest that therapy with an anti IL-2R moAb is at least equal to ATG application according to the incidence of acute rejections and infections.

Immunoprophylaxis with a monoclonal anti-IL-2 receptor antibody in liver transplant patients.

Background. In patients with autoimmune diseases such as vasculitis or systemic lupus erythematosus (SLE), end-stage renal disease develops in a high percentage of patients, and kidney transplantation has become a therapeutic option. However, only limited data about the prognosis and outcome after kidney transplantation are available. Methods. Long-term graft survival and graft function of renal transplant recipients with SLE, Wegener's granulomatosis, microscopic polyangiitis, Goodpasture's syndrome, and Henoch-Schonlein purpura were evaluated in a single center. In addition, the incidence of renal and extrarenal relapses and the impact of the immunosuppressive therapy on the course of the autoimmune disease were studied. Results. Renal transplant recipients with autoimmune diseases such as vasculitis and SLE had a patient survival rate (94% after 5 years) and a graft survival rate (65% after 5 years) comparable to those of patients with other causes of end-stage renal disease (patient survival 88% and graft survival 71% after 5 years). Graft losses due to the underlying disease were rare. Extrarenal relapses occurred in three patients with Wegener's granulomatosis, one patient with microscopic polyangiitis, and three patients with SLE, but were less frequent compared with the period with chronic dialysis therapy. Autoantibody levels in patients with SLE, Wegener's granulomatosis, or microscopic polyangiitis did not seem to influence the outcome. Conclusions. Renal transplantation should be offered to patients with autoimmune diseases. Follow-up should include the short-term control of renal and extrarenal disease activity.

B. Nashan

Papers

Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group.

Biliary malignancies in primary sclerosing cholangitis: Timing for liver transplantation

Recurrent immunoglobulin A nephropathy after renal transplantation: a significant contributor to graft loss.

Immunoprophylaxis with a monoclonal anti-IL-2 receptor antibody in liver transplant patients.

Renal transplantation for patients with autoimmune diseases : Single-center experience with 42 patients