Is There Sufficient Evidence Justifying Limited Access of Jehovah's Witness Patients to Kidney Transplantation?

BACKGROUND: Jehovah's Witnesses (JWs) refuse blood transfusions due to religious issues. This situation may impact kidney transplantation (KT) outcomes in case of hemorrhagic complications. We evaluated demographic characteristics of this population, hematologic safety, and graft outcomes. METHODS: This was a retrospective, single-center study comparing KT outcomes in JW patients versus a non-JW control group. Hematologic endpoints included clinical indication for blood transfusion (hemoglobin <7 g/dL), decrease of hemoglobin >2 g/dL or hematocrit >5% in the first week after KT, hemorrhagic complications requiring surgery, and de novo prescription of erythropoiesis-stimulating agents. Secondary endpoints included delayed graft function, treated biopsy-proven acute rejection, renal function, mortality, and graft survival at 12 months. RESULTS: From January 1989 to September 2018, we identified 143 JW (10 pediatric) and selected 142 matched control (non-JW) patients. There were no differences in the incidence of clinical indication for transfusion (13.3% versus 11.3%, P = 0.640), but a higher proportion of non-JW patients received transfusions (2.1% versus 9.2%, P = 0.010). There were no differences in the proportion of patients with decreased hemoglobin concentration, in reinterventions due to hemorrhagic complications, in the use of erythropoiesis-stimulating agents at hospital discharge, in the incidence of acute rejection, in renal function, and in mortality or graft survival rate at 12 months. CONCLUSIONS: In summary, this matched control cohort study suggests that, when clinically indicated, blood transfusions can be safely avoided in the majority of JW kidney transplant, who achieve and maintain comparable hemoglobin concentrations during the first year after transplantation compared with non-JW patients.

Long-Term Follow-Up of De Novo Use of mTOR and Calcineurin Inhibitors After Kidney Transplantation.

BACKGROUND: Long-term efficacy and safety of de novo use of the mammalian target of rapamycin inhibitors (mTORi) have been evaluated primarily using registry data. METHODS: This was a pooled retrospective analysis of data obtained from 10 prospective randomized trials in de novo kidney transplant recipients (n = 581) receiving calcineurin inhibitors (CNIs) combined with sirolimus (n = 329), everolimus (n = 128), or antimetabolites (n = 124). RESULTS: There were no differences in patient (84.5 versus 80.9 versus 89.7%, P = 0.996), graft (65.4 versus 59.5 versus 73.1%, P = 0.868), and biopsy-confirmed acute rejection-free (78.1 versus 77.3 versus 79.0%, P = 0.976) survivals, respectively. The incidence of cytomegalovirus infection was lower (6 versus 3 versus 11%, P = 0.024) but treatment discontinuation was higher among patients receiving mTORi (66.0 versus 47.7 versus 31.5%, P < 0.001), respectively. At 5 years, median estimated glomerular filtration rate (49.6 versus 43.9 versus 53.2 mL/min, P = 0.006) was lower and the proportion of patients with proteinuria (53 versus 40 versus 23%, P < 0.001) was higher among patients receiving mTORi, respectively. CONCLUSIONS: The efficacy of de novo use of mTORi is comparable with that of antimetabolites in kidney transplant recipients receiving calcineurin inhibitor. Apart from the lower cytomegalovirus infection rate, the safety profile is unfavorable, showing higher treatment discontinuation rates and higher incidence of proteinuria.

Reviewing 15 years of experience with sirolimus.

Here, we review 15 years of clinical use of sirolimus in our transplant center, in context with the developing immunosuppressive strategies use worldwide. The majority of studies were conducted in de novo kidney transplant recipients, using sirolimus (SRL) in combination with calcineurin inhibitors (CNIs). We also explored steroid (ST) or CNI-sparing therapies, including CNI minimization, elimination, or conversion strategies in combination with mycophenolate (MMF/MPS). Pooled long-term outcomes were comparable with those obtained with CNI and antimetabolite combination. Surprisingly, there are still several areas that need further investigation to improve the risk/benefit profile of SRL in kidney transplantation, including pharmacokinetic/pharmacodynamic drug-to-drug interaction with cyclosporine (CsA) or tacrolimus (TAC), mechanisms of SRL-associated adverse reactions and combinations with other drugs such as belatacept and once-daily TAC, possibly leading to improved long-term adherence. These studies, along with others investigating the benefits of SRL associated lower viral infections and malignancies, are essential as we do not expect the introduction of new immunosuppressive drugs in the near future.

Immunotherapy for De Novo renal transplantation: what's in the pipeline?

Immunosuppressive drugs have been traditionally developed to prevent acute rejection and to improve short-term kidney transplant outcomes. There is still a medical need to improve outcomes among subgroups of patients at higher risk for graft loss and to reduce cardiovascular, infectious and malignancy-associated morbidity and mortality, and improve long-term adherence. Several new immunosuppressive agents and formulations are undergoing clinical investigation and are discussed in this review.A modified release tacrolimus formulation (MR4) for once-daily administration is undergoing phase III trials. It has been developed to be administered de novo or for maintenance using the same therapeutic target tacrolimus trough concentrations as for the original formulation. Belatacept (LEA29Y), a second generation cytotoxic-T-lymphocyte-associated antigen immunoglobulin (CTLA4-Ig), blocks the interaction between CD80/86 and CD28 costimulatory pathways. In phase II trials, belatacept was as effective as ciclosporin (cyclosporine) when administered in combination with basiliximab, mycophenolate mofetil (MMF) and corticosteroids. Currently, belatacept is undergoing phase III trials including one study in recipients of organs from expanded criteria donors. Inhibitors of the Janus protein tyrosine kinase (JAK)-3 show some selectivity for cells of the lymphoid lineage and have been shown to be effective in late preclinical transplant models. The most frequent adverse effects have been related to nonspecific binding to JAK2 kinases. CP-690550, a JAK3 inhibitor is currently in phase II clinical trials.FK778, is a synthetic malononitrilamide that targets the critical enzyme of the de novo pyrimidine synthesis, dihydroorotic acid dehydrogenase, and receptor-associated tyrosine kinases has completed phase II trials. FK778 also shows antiviral activities that have been tested in patients with polyomavirus nephropathy. Fingolimod (FTY720), a synthetic sphingosine phosphate receptor modulator that reduces the recirculation of lymphocytes to blood and peripheral tissues including inflammatory lesions and graft sites is undergoing phase III trials. Although the efficacy of fingolimod is similar to MMF in patients receiving full doses of ciclosporin, safety issues such as a negative chronotropic effect, macular oedema, pulmonary adverse reactions and graft function resulted in premature discontinuation of the development programme for kidney transplantation. Because there was no clear clinical benefit over treatment options, the clinical development programme of FK778 was discontinued.Finally, a new evolving strategy with powerful induction-induced prolonged T-cell depletion followed by low-dose immunosuppressive monotherapy is showing promising results.