INTRODUCTION:

Despite its use to prevent acute rejection, lifelong immunosuppression can adversely impact long-term patient and graft outcomes. In theory, immunosuppression withdrawal is the ultimate goal of kidney transplantation, and is made possible by the induction of immunological tolerance. The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism-based and non-chimerism-based. The impact of these strategies on transplant outcomes, including acute rejection, allograft function and survival, cost, and immune monitoring, will also be discussed.

MATERIALS AND METHODS:

Databases such as PubMed, Scopus, and Web of Science, as well as additional online resources such as EBSCO, were exhaustively searched. Adult living-donor kidney transplant recipients who developed chimerism-based tolerance after concurrent bone marrow or hematopoietic stem cell transplantation or those who received non-chimerism-based, non-hematopoietic cell therapy using mesenchymal stromal cells, dendritic cells, or regulatory T cells were studied between 2000 and 2021. Individual sources of evidence were evaluated critically, and the strength of evidence and risk of bias for each outcome of the transplant tolerance study were assessed.

RESULTS:

From 28,173 citations, 245 studies were retrieved after suitable exclusion and duplicate removal. Of these, 22 studies (2 RCTs, 11 cohort studies, 6 case-control studies, and 3 case reports) explicitly related to both interventions (chimerism- and non-chimerism-based immune tolerance) were used in the final review process and were critically appraised. According to the findings, chimerism-based strategies fostered immunotolerance, allowing for the safe withdrawal of immunosuppressive medications. Cell-based therapy, on the other hand, frequently did not induce tolerance except for minimising immunosuppression. As a result, the rejection rates, renal allograft function, and survival rates could not be directly compared between these two groups. While chimerism-based tolerance protocols posed safety concerns due to myelosuppression, including infections and graft-versus-host disease, cell-based strategies lacked these adverse effects and were largely safe. There was a lack of direct comparisons between HLA-identical and HLA-disparate recipients, and the cost implications were not examined in several of the retrieved studies. Most studies reported successful immunosuppressive weaning lasting at least 3 years (ranging up to 11.4 years in some studies), particularly with chimerism-based therapy, while only a few investigators used immune surveillance techniques. The studies reviewed were often limited by selection, classification, ascertainment, performance, and attrition bias.

CONCLUSIONS:

This review demonstrates that chimerism-based hematopoietic strategies induce immune tolerance, and a substantial number of patients are successfully weaned off immunosuppression. Despite the risk of complications associated with myelosuppression. Non-chimerism-based, non-hematopoietic cell protocols, on the other hand, have been proven to facilitate immunosuppression minimization but seldom elicit immunological tolerance. However, the results of this review must be interpreted with caution because of the non-randomised study design, potential confounding, and small sample size of the included studies. Further validation and refinement of tolerogenic protocols in accordance with local practice preferences is also warranted, with an emphasis on patient selection, cost ramifications, and immunological surveillance based on reliable tolerance assays.

BACKGROUND:

Kidney transplant (KT) recipients of HLA identical siblings (HLAid) have lower immunological risk, but there are no specific recommendations for immunosuppression. Our aim was to analyze evidence about results from HLAid living-donor recipients under different immunosuppression in the current era of immunological risk assessment.

METHODS:

Systematic review of studies describing associations between outcomes of HLAid living-donor KT recipients according to their immunological risk and applied immunosuppression.

RESULTS:

From 1351 studies, 16 (5636 KT recipients) were included in the analysis. All studies were retrospective, ten comparing immunosuppression strategies, and six immunological risk strata. Of those ten, six studies were published in 1990 or earlier and only three included tacrolimus. The evidence is poor, and the inclusion of calcineurin inhibitors does not demonstrate better results. Furthermore, only few studies describe different immunosuppression regimens according to the patient immunological risk and, in general, they do not include the assessment with new solid phase assays.

CONCLUSIONS:

There are no studies analyzing the association of outcomes of HLAid KT recipients with current immunological risk tools. In the absence of evidence, no decision or proposal of immunosuppression adapted to modern immunological risk assessment can be made currently by the Descartes Working Group.

In March 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a virtual Controversies Conference to address the important but rarely examined phase during which the kidney transplant is failing or has failed. In addition to discussing the definition of a failing allograft, 4 broad areas were considered in the context of a declining functioning graft: prognosis and kidney failure trajectory; immunosuppression strategies; management of medical and psychological complications, and patient factors; and choice of kidney replacement therapy or supportive care following graft loss. Identifying and paying special attention to individuals with failing allografts was felt to be important in order to prepare patients psychologically, manage immunosuppression, address complications, prepare for dialysis and/or retransplantation, and transition to supportive care. Accurate prognostication tools, although not yet widely available, were embraced as necessary to define allograft survival trajectories and the likelihood of allograft failure. The decision of whether to withdraw or continue immunosuppression after allograft failure was deemed to be based most appropriately on risk-benefit analysis and likelihood of retransplantation within a few months. Psychological preparation and support was identified as a critical factor in patient adjustment to graft failure, as was early communication. Several models of care were noted that enabled a medically supportive transition back to dialysis or retransplantation. Emphasis was placed on the importance of dialysis-access readiness before initiation of dialysis, in order to avoid use of central venous catheters. The centrality of the patient to all management decisions and discussions was deemed to be paramount. Patient "activation," which can be defined as engaged agency, was seen as the most effective way to achieve success. Unresolved controversies, gaps in knowledge, and areas for research were also stressed in the conference deliberations.

BACKGROUND:

Solid organ transplant (SOT) recipients with cystic fibrosis (CF) may benefit from the pulmonary and extrapulmonary benefits associated with CF transmembrane conductance regulator modulators. Nevertheless, evolution of modulator safety and efficacy data prompts consideration.

METHODS:

The search terms "transplant" AND "ivacaftor"(IVA) OR "lumacaftor"(LUM) OR "tezacaftor" (TEZ) OR "elexacaftor" (ELX) were utilized to conduct a scoping review of English articles from the period of January 1, 2012 to December 31, 2022. Search results from PubMed and Embase databases were reviewed by title and abstract for relevance. Included studies reported efficacy and safety outcomes of modulators in SOT recipients.

RESULTS:

One hundred thirty-six patients from one cohort study (90 lung transplant recipients) and eight case reports and series (29 lung transplant recipients, 16 liver transplant recipients and one lung/liver transplant patient) were included. Post-modulator initiation, 33 patients did not necessitate tacrolimus dose adjustments, 10 required dose uptitration, and 43 required dose reductions. Moreover, LUM/IVA use with azole antifungals may lead to subtherapeutic levels but opposing effects sustained tacrolimus levels. Liver transplant recipients were more likely to experience elevations in transaminases requiring pharmacologic or medical interventions. Majority of patients experienced improvements in pulmonary function, fasting blood glucose, hemoglobin, body mass index, and rhinosinusitis symptoms. However, intolerance or lack of benefit prompted discontinuation of ELX/TEZ/IVA in over 40% of lung-transplant recipients in one study.

CONCLUSION:

Modulator therapy has been reported to produce pulmonary and extra-pulmonary benefits in the CF population with SOT. Considerations for modulator therapy initiation ought to include modulator pharmacokinetics, concomitant medications, and transplant type due to the complex nature of SOT recipients.

BACKGROUND:

The selection of antiviral therapy for BK polyomavirus (BKPyV) infection has been extensively debated. Our study aimed to assess the efficacy and safety of various treatments for BKPyV infection.

METHODS:

We searched PubMed, EMBASE, and Web of Science databases for relevant studies regarding drug treatments for BKPyV viremia/DNAemia published between January 1, 1970 and September 30, 2022. Two independent authors screened the published studies, extracted pertinent data, and evaluated their methodological quality. A meta-analysis was performed using the RevMan software version 4.2.2.

RESULTS:

A total of 33 published studies involving 986 patients were included in the meta-analysis. Overall, therapeutic interventions comprised immunosuppression reduction alone or in combination with leflunomide, intravenous immunoglobulin (IVIG), cidofovir, or mTOR inhibitor (mTORi) therapy. The meta-analysis revealed that the efficacy of immunosuppression reduction alone for serum BKPyV clearance was 68% (95% confidence interval [CI]: 0.58-0.77; I2 = 78%). Moreover, the efficacy of immunosuppression reduction in combination with leflunomide, cidofovir, IVIG, or mTORi therapy for serum BKPyV clearance was 61% (95% CI: 0.47-0.74; I2 = 83%), 71% (95% CI: 0.63-0.78; I2 = 0), 87% (95% CI: 0.82-0.93; I2 = 45%), and 80% (95% CI: 0.59-1.00; I2 = 58%), respectively. Compared to immunosuppression reduction alone, immunosuppression reduction combined with IVIG therapy offered a statistically significant benefit in serum BKPyV clearance (P < 0.01) with minimal adverse reactions, whereas other adjunctive drug treatments did not demonstrate considerable effects.

CONCLUSIONS:

Reducing immunosuppression remains the primary approach for treating BKPyV infection. Although the combination treatment with IVIG proved to be most effective, other agents might offer varied antiviral advantages of high heterogeneity, which should be substantiated in future long-term randomized controlled trials.

More favorable clinical outcomes with medium-term follow-up have been reported among kidney transplant recipients receiving maintenance therapy consisting of "reduced-tacrolimus (TAC) dosing," mycophenolate mofetil (MMF), and low-dose corticosteroids. However, it is not clear whether long-term maintenance therapy with reduced-calcineurin inhibitor (CNI) dosing still leads to reduced renal function. A prospectively followed cohort of 150 kidney transplant recipients randomized to receive TAC/sirolimus (SRL) versus TAC/MMF versus cyclosporine microemulsion (CSA)/SRL, plus low-dose maintenance corticosteroids, now has 20 years of post-transplant follow-up. Average CNI trough levels over time among patients who were still alive with functioning grafts at 60, 120, and 180 months post-transplant were determined and ranked from smallest-to-largest for both TAC and CSA. Stepwise linear regression was used to determine whether these ranked average trough levels were associated with the patient's estimated glomerular filtration rate (eGFR) at those times, particularly after controlling for other significant multivariable predictors. Experiencing biopsy-proven acute rejection (BPAR) and older donor age were the two most significant multivariable predictors of poorer eGFR at 60, 120, and 180 months post-transplant (p < 000001 and 0.000003 for older donor age at 60 and 120 months; p = 0.00008 and <0.000001 for previous BPAR at 60 and 120 months). Assignment to CSA also implied a significantly poorer eGFR (but with less magnitudes of effect) in multivariable analysis at 60 and 120 months (p = 0.01 and 0.002). Higher ranked average CNI trough levels had no association with eGFR at any timepoint in either univariable or multivariable analysis (p > 0.70). Long-term maintenance therapy with reduced-CNI dosing does not appear to cause reduced renal function.

This study aimed to synthesize the available evidence on the immunogenicity, safety, and effectiveness of live-attenuated varicella vaccine in solid organ transplant recipients. Medline and EMBASE were searched using predefined search terms to identify relevant studies. The included articles reported varicella vaccine administration in the posttransplant period in children and adults. A pooled proportion of transplant recipients who seroconverted and who developed vaccine-strain varicella and varicella disease was generated. Eighteen articles (14 observational studies and 4 case reports) were included, reporting on 711 transplant recipients who received the varicella vaccine. The pooled proportion was 88.2% (95% confidence interval 78.0%-96.0%, 13 studies) for vaccinees who seroconverted, 0% (0%-1.2%, 13 studies) for vaccine-strain varicella, and 0.8% (0%-4.9%, 9 studies) for varicella disease. Most studies followed clinical guidelines for administering live-attenuated vaccines, with criteria that could include being at least 1 year posttransplant, 2 months postrejection episode, and on low-dose immunosuppressive medications. Varicella vaccination in transplant recipients was overall safe in the included studies, with few cases of vaccine-strain-induced varicella or vaccine failure, and although it was immunogenic, the proportion of recipients who seroconverted was lower than that seen in the general population. Our data support varicella vaccination in select pediatric solid organ transplant recipients.

A meta-analysis investigation was executed to measurethe wound complications (WCs) frequency in heart transplant (HT) recipients on mammalian target of rapamycin inhibitors (MTRIs). A comprehensive literature investigation till February 2023 was applied and 978 interrelated investigations were reviewed. The 10 chosen investigations enclosed 2173 individuals with HT were in the chosen investigations' starting point, 1164 of them were utilising MTRIs, and 1009 were utilising control. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were utilised to compute the value of the WCs frequency in HT recipients on MTRIs by the dichotomous approaches and a fixed or random model. MTRIs had significantly higher WCs (OR, 1.53; 95% CI, 1.19-1.98, P = .001) compared with those with control in individuals with HT. MTRIs had significantly higher WCs compared with those with control in individuals with HT. However, care must be exercised when dealing with its values because of the low number of the nominated investigations and the low sample size of some of the nominated investigations for the meta-analysis.

BACKGROUND & AIMS:

Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term "pre-withdrawal time". To clarify the impact of pre-withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta-analysis.

METHODS:

We systematically interrogated the literature for LT recipient ISW studies reporting pre-withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre-withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time-response curves were calculated using random-effects meta-analyses.

RESULTS:

We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study-level risk of bias was heterogeneous. Mean pre-withdrawal time was greater by 427 days [95% confidence interval (CI) 67-788] in OT compared to non-OT patients. This increase was potentiated to 799 days (95% CI 369-1229) or 1074 days (95% CI 685-1463) when restricting analysis to adult or European study participants. In time-response meta-analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4-10%) per year after LT (GRADE low- and moderate-certainty of evidence, respectively).

CONCLUSIONS:

Our data support the impact of pre-withdrawal time in ISW decision-making for adult and European LT recipients.

PROSPERO REGISTRATION:

CRD42021272995.