Basiliximab plus low-dose cyclosporin vs. OKT3 for induction immunosuppression following renal transplantation

BACKGROUND: Current immunosuppressive therapies are very effective in preventing acute rejection (AR) and graft loss following renal transplantation. Newer agents now make it possible to develop equally efficacious but better tolerated and less toxic strategies. This is especially relevant for our ageing recipients. We now compare the efficacy of basiliximab combined with early low-dose cyclosporin therapy to standard OKT3 induction therapy. METHODS: In this single-centre study, 100 consecutive recipients of cadaveric kidney transplants from November 1998 to August 2000 were treated with basiliximab combined with early low-dose cyclosporin, reduced steroids and mycophenolate mofetil (MMF). Clinical outcomes at 100 d and 1 yr were compared with a group of 26 patients transplanted from March 1995 to November 1998 who received OKT3, delayed full-dose cyclosporin, high-dose steroids and MMF. Amongst basiliximab treated patients, we compared clinical outcomes in those older and younger than 60 yr. RESULTS: Both groups were similar except for a shorter cold ischaemic time in the basiliximab group. Length of stay, number of readmissions, total hospitalization days and cytomegalovirus infections were lower in the basiliximab group. Despite a 40% reduction in steroids, basiliximab-treated patients had fewer biopsy-proven episodes of AR (basiliximab 14% vs. OKT3 35%) and required less antilymphocyte antibody therapy. Clinical outcomes including patient and graft survival were no different between groups. Long-term graft survival for patients over 60 yr was limited primarily by mortality. CONCLUSIONS: Compared with OKT3 induction therapy, the combination of early low-dose cyclosporin and basiliximab is steroid sparing, effective, well tolerated and relatively safe.     

Effects of immunosuppressive agents on Th17 cells involved in transplantation

The lymphocyte‐derived helper T (Th) cells are critical regulators of the adaptive immune response and are associated with inflammatory disease. The most recently recognized Th‐cell lineage, Th17, plays an important role in host defense against extracellular pathogens by secreting the proinflammatory cytokine, interleukin 17, and recruiting reactive oxygen species (ROS)‐producing monocytes to the site of infection. However, accumulating evidence has implicated Th17‐cell dysregulation as an underlying cause for some immune‐related pathogenic conditions, including allograft rejection. Recent studies of human transplant patients have indicated that Th17 cells exhibit resistance to current immunosuppressive therapies that would otherwise prevent allograft rejection. In this review, we will discuss the most current research findings related to Th17‐cell function in various kinds of allografts.     

Long-term graft survival after conversion from cyclosporin to azathioprine 1 year after renal transplantation. A prospective, randomized study from 1 to 6 years after transplantation

Cyclosporin has improved graft survival after renal transplantation,but cyclosporin nephrotoxicity is a severe clinical problem.Conversion from cyclosporin to azathioprine 1 year after transplantationmight improve long-term graft survival by avoidance of cyclosporinnephrotoxicity. After treatment with cyclosporin and prednisoloneduring the first year after renal transplantation, 106 patientswere consecutively randomized to treatment with either azathiprineand prednisolone or cyclosporin and prednisolone in a prospective,controlled study during the following 5 years, i.e. 6 yearsafter transplantation. Actuarial estimates of graft survivalrates after inclusion in the study were obtained by the product-limitmethod of Kaplan-Meier, and the Mantel-Cox log rank test wasused to compare the two treatment regimens. When the end-pointsin the analyses were cessation of graft function or withdrawalof immunosuppressive treatment due to side-effects, and whenpatients alive with graft function or who had died with a functioninggraft were treated as censored observations, graft survival5 years after inclusion in the study was 57.7±5.2% inthe total material and was the same in both the azathioprinegroup (52.4±7.7%) and the cyclosporin group (63.3±6.7%)(log rank=0.40, P=0.53). When cessation of graft function wasthe only end-point, graft survival 5 years after inclusion inthe study was 73.7±5.2% for the total material with nosignificant differences between the two groups (log rank=0.58,P=0.45). Assuming that cyclosporin and prednisolone were usedduring the first year after renal transplantation, it can beconcluded that conversion to treatment with azathioprine andprednisolone does not deviate from continued treatment withcyclosporin and prednisolone with regard to long-term graftsurvival for the following 5 years.     

Five-year results of renal transplantation on immunosuppressive triple therapy with mycophenolate mofetil

Mycophenolate mofetil (MMF) combined with cyclosporine and prednisolone significantly lowers acute rejection frequency in the early post-renal transplantation phase. To date only registry data with very high transplant numbers have shown that MMF significantly influences long-term outcome. A comparative retrospective analysis of the 5-yr results with MMF in a single transplant center was thus undertaken vs. other standard immunosuppressive regimens. The results of 1579 renal transplantations were grouped by treatment modality, subjected to Kaplan-Meier analysis, and compared using the log rank test. Both the total population and subgroups showed a non-significant trend towards better graft survival with MMF, evident at 2 yr and persisting for 5 yr. Extrapolation indicates that on combination therapy with MMF vs. azathioprine, approximately 10% more patients will be alive at 10 yr with a functional graft.     

The use of eculizumab in renal transplantation

The complement system plays a vital role in mediating disease processes within renal allografts. Eculizumab is a humanized monoclonal antibody that targets complement protein C5, inhibiting cleavage into C5a and C5b, and therefore preventing formation of the membrane attack complex (MAC). It has been used primarily within renal transplantation to treat atypical hemolytic‐uremic syndrome (aHUS) and antibody‐mediated rejection (AMR) post‐transplant, and also as prophylaxis in transplants at high risk for these conditions. Eculizumab appears to be effective in protecting renal allografts when post‐transplant aHUS or AMR occur, although the published cases report relatively short follow‐up. It is unclear how long treatment should continue (a particularly important issue given the expense of the drug), or whether eculizumab contributes to the development of accommodation in humans. When used for prophylaxis, eculizumab also appears to be effective. Some highly sensitized patients have developed either acute AMR or features of chronic AMR despite administration of the drug – this suggests that complement activation is not the only mechanism responsible for AMR. All patients should receive vaccination against Neisseria meningitidis prior to receiving eculizumab. Clinical trials, predominantly in antibody‐incompatible renal transplantation, are ongoing to determine the optimal use of C5 inhibition.     

Conversion to belatacept within 1-year of renal transplantation in a diverse cohort including patients with donor-specific antibodies

Early conversion from a calcineurin inhibitor to belatacept has the potential to improve long-term renal allograft function; however, there remains limited experience with this strategy among African Americans and patients with preformed donor-specific antibodies (DSA). To examine these subgroups, we performed a single-center review of kidney transplant recipients converted to belatacept within 1-year of transplant between 01/2011 and 10/2017. All patients received lymphocyte-depleting induction with maintenance tacrolimus and mycophenolate +/− corticosteroids. Patients were switched to belatacept for clinical indication and followed from date of conversion until allograft failure or study conclusion. The primary endpoint at 1-year was a composite of allograft loss, biopsy proven rejection, de novo DSA formation, proteinuria, and declining renal function. Thirty-two patients were included in the review. The majority were African American, and 28.1% had DSA at transplant. Patient and allograft survival at 1-year was 96.9% and 93.8%, respectively, and estimated glomerular filtration rate improved from 41.9 to 58.4 mL/min. No African Americans or patients with pretreatment DSA developed rejection or allograft failure within 1-year. The only clinical variable correlated with suboptimal allograft function was baseline weight ≥80 kg (OR = 6.2; 95% CI, 1.2-32.3). Early conversion to belatacept appears safe for select patients with DSA and African Americans receiving lymphocyte-depleting induction.