Balancing B cell responses to the allograft: implications for vaccination

Balancing enough immunosuppression to prevent allograft rejection and yet maintaining an intact immune system to respond to vaccinations, eliminate invading pathogens or cancer cells is an ongoing challenge to transplant physicians. Antibody mediated allograft rejection remains problematic in kidney transplantation and is the most common cause of graft loss despite current immunosuppressive therapies. The goal of immunosuppressive therapies is to prevent graft rejection; however, they prevent optimal vaccine responses as well. At the center of acute and chronic antibody mediated rejection and vaccine responses is the B lymphocyte. This review will highlight the role of B cells in alloimmune responses including the dependency on T cells for antibody production. We will discuss the need to improve vaccination rates in transplant recipients and present data on B cell populations and SARS-CoV-2 vaccine response rates in pediatric kidney transplant recipients

Mechanism of cellular rejection in transplantation

The explosion of new discoveries in the field of immunology has provided new insights into mechanisms that promote an immune response directed against a transplanted organ. Central to the allograft response are T lymphocytes. This review summarizes the current literature on allorecognition, costimulation, memory T cells, T cell migration, and their role in both acute and chronic graft destruction. An in depth understanding of the cellular mechanisms that result in both acute and chronic allograft rejection will provide new strategies and targeted therapeutics capable of inducing long-lasting, allograft-specific tolerance

Antibody response to 2- and 3-dose SARS-CoV-2 mRNA vaccination in pediatric and adolescent kidney transplant recipients

BackgroundAdditional "booster" doses of mRNA SARS-CoV-2 vaccines have become standard of care for immunosuppressed patients, including kidney transplant recipients (KTR). While these additional doses have been shown to be efficacious in the adult KTR population, there is paucity of data for pediatric and adolescent KTR.MethodsWe conducted a retrospective single-center observational study to determine the proportion of pediatric and adolescent KTR who seroconverted following two- and three-dose regimens of an mRNA SARS-CoV-2 vaccine series.ResultsForty-three pediatric and adolescent KTR at our center received at least two doses of an mRNA SARS-CoV-2 vaccine. Seroconversion was noted in 56% of those who received a 2-dose series and increased to 85% in those who received a third dose. In the 16 patients who did not seroconvert after a two-dose series, 12 (75%) seroconverted following the third dose. No serious adverse effects of immunization were noted.ConclusionsOur results demonstrate that additional SARS-CoV-2 vaccine doses are not only safe and efficacious in pediatric and adolescent KTR, but may be necessary to optimize antibody response. A higher resolution version of the Graphical abstract is available as Supplementary information

Immunologic response of mRNA SARS-CoV-2 vaccination in adolescent kidney transplant recipients

BackgroundIn the general population, mRNA SARS-CoV-2 vaccines are highly efficacious. Early reports suggest a diminished antibody response in immunosuppressed adult solid organ transplant (SOT) patients, but this has not been reported in pediatrics.MethodsAdolescent kidney transplant recipients (KTR) at our center who received both doses of an mRNA SARS-CoV-2 vaccine had SARS-CoV-2 spike (S) protein antibody presence evaluated 4-8 weeks after their second dose of the vaccine as part of routine clinical care.ResultsThirteen of 25 fully vaccinated patients (52%) had a positive spike antibody. Median age of participants was 19 years old (IQR 18-20) and the median time from transplant was 5 years (IQR 4-9 years). KTR were treated with an immunosuppression regimen including a calcineurin inhibitor, corticosteroid, and antimetabolite (9 with mycophenolate, 3 with azathioprine, and 1 without an antimetabolite due to viremia). Of those who had an antibody response, fewer had a mycophenolate-containing immunosuppressant regimen than non-responders. There was a trend toward better vaccine response and higher anti-S antibody titers at lower doses of mycophenolate. Three patients with prior COVID-19 infection all had a positive antibody response.ConclusionOur results suggest vaccine response in adolescent KRT is lower than that of the general population, but similar to that previously described in adult SOT patients and slightly better than that seen in adult KTR. This data demonstrates vaccination is safe and supports immunizing KTR who remain hesitant. Future studies should focus on better understanding of the cellular immune response to vaccination and strategies to enhance vaccine immunogenicity in pediatric SOT patients

Prevention, diagnosis, and management of donor derived infections in pediatric kidney transplant recipients

Donor derived infections (DDIs) in pediatric kidney transplant recipients remain challenging to diagnose and can result in serious morbidity and mortality. This review summarizes the current guidelines and recommendations for prevention, diagnosis, and treatment of unexpected DDIs in pediatric kidney transplant recipients. We provide a contemporary overview of DDI terminology, surveillance, epidemiology, and recommended approaches for assessing these rare events with an emphasis on the pediatric recipient. To address prevention and risk mitigation, important aspects of donor and pediatric candidate evaluations are reviewed, including current Organ Procurement and Transplantation Network (OPTN) and American Society of Transplantation (AST) recommendations. Common unexpected DDI encountered by pediatric transplant teams including multi-drug resistant organisms, tuberculosis, syphilis, West Nile Virus, toxoplasmosis, Chagas disease, strongyloidiasis, candidiasis, histoplasmosis, coccidioidomycosis, and emerging infections such as COVID-19 are discussed in detail. Finally, we consider the general challenges with management of DDIs and share our experience with a novel application of next generation sequencing (NGS) of microbial cell-free DNA that will likely define a future direction in this field

Implementing a structured transition from pediatric to adult care can impact clinical outcomes in young adult kidney transplant recipients.

Background:The transition period between pediatric and adult care is a challenging time marked with high risk and vulnerability. This is especially true in adolescent patients with a transplanted kidney, which is described as the period with the highest rate of graft loss. Studies demonstrate that 83% of young adult with special health care needs (SHCN) and 86% of young adults without SHCN do not meet the national health care transition (HCT) measures published in a clinical report authored by the AAP in collaboration with the AAFP and ACP. Studies demonstrate that there are adverse effects associated with a lack of structured HCT interventions including medical complications, limitations in health and well-being, problems with treatment and medication adherence, discontinuity of care, patient dissatisfaction, higher emergency department use, and higher costs of care. Data are limited regarding HCT outcomes, but studies in the US and internationally demonstrate improvements in quality of care, terms of service use, and patient and family experience with a structured transition protocol.Description of the Project:Our project aims to assess how well patients are transitioned from pediatric kidney transplant clinic at Rady Children’s Hospital in San Diego (RCHSD) to adult kidney transplant clinic at UC San Diego Health (UCSD). A retrospective chart review of patients who transitioned from RCHSD to UCSD transplant clinic from the years 2020-2023 is currently being performed to examine metrics such as change in creatinine, blood pressure, rates of infection, and episodes of rejection during this period of transition. Additionally, we will look at the time elapsed between patients’ last visit at RCHSD and first visit at UCSD and time between labs to assess for possible areas of improvement. We will also conduct a telephone survey with patients who have completed this transition to understand their perspective of the transition process. We will look at outcomes prior to and following the implementation of our current transitions program which includes strutted transition-specific visits to assess and address individual areas of need before they transition.Lessons Learned/Expected Outcomes:We expect to have more data at the time of the presentation as a chart review is currently underway. We anticipate that the outcome of this project will reveal a few areas of improvement. One area of anticipated improvement would be in decreasing the time between the last visit and last labs performed at RCHSD and the first visit and first set of labs performed at UCSD.Recommendations/Next Steps:The next steps for this project are to further analyze the data collected from chart review and assess for patterns and areas of possible intervention in the current kidney transplant clinic transition process. Following this study which focuses specifically on transitions of care in patients with kidney transplant, the goal will be to perform similar studies assessing how effective our transitions are for patients with various forms of kidney pathology who are seen in other nephrology clinics

Rates of idiopathic childhood nephrotic syndrome relapse are lower during the COVID-19 pandemic

BackgroundInfections are thought to be primarily responsible for triggering relapse in children with steroid-sensitive nephrotic syndrome (NS). The COVID-19 pandemic promoted physical distancing, facial mask wearing, and greater attention to infection-prevention measures resulting in decreased transmission of infections. We hypothesized there would also be a decreased rate of NS relapse during this period.MethodsWe conducted a single-center retrospective chart review of children with steroid-sensitive NS. Demographics, rate of relapses, and rate of hospitalizations were collected for a baseline pre-pandemic period (BPP) and for the social distancing period during the pandemic (SDP).ResultsOne hundred twenty-two children with primary steroid-sensitive NS were identified and 109 were followed for the duration of the study period. The paired rate of relapse per subject per year was significantly lower during the SDP (0.6 relapses per subject per year ± 1 SD) compared to the BPP (1.0 relapses per subject per year ± 0.9 SD), P < 0.01. A subgroup of 32 subjects who were newly diagnosed with NS during the BPP similarly had significantly fewer relapses during the SDP (0.8 ± 1 SD) than during the BPP (1.4 ± 1 SD), P = 0.01.ConclusionsOur results support the hypothesis of lower rates of NS relapse and hospitalizations during social distancing for all subjects in our cohort and a subgroup of those newly diagnosed. Lower relapse rates were likely attributable to decreased transmission of infections and greater attention to infection prevention. A higher resolution version of the Graphical abstract is available as Supplementary information