Safety and infectious outcomes in pediatric kidney transplant recipients after COVID-19 vaccination: A pediatric nephrology research consortium study.

BACKGROUND: Adult kidney transplant recipients (KTRs) fully vaccinated against COVID-19 have substantial morbidity and mortality related to SARS-CoV-2 infection compared with the general population. However, little is known regarding the safety and efficacy of the COVID-19 vaccination series in pediatric KTRs. METHODS: A multicenter, retrospective observational study was performed across nine pediatric transplantation centers. Eligible KTRs fully vaccinated against COVID-19 were enrolled and data were collected pertaining to SARS-CoV-2 infection incidence and severity, graft outcomes and post-vaccination safety profile, as well as overall patient survival. RESULTS: A total of 247 patients were included in this investigation with a median age at transplantation of 11 years (IQR 5-15). SARS-CoV-2 infection was observed in 30/110 (27.27%) of fully vaccinated patients, tested post-transplant, within the defined follow-up period. Of these patients, 6/30 (18.18%) required hospitalization and 3/30 (12.12%) required reduction in immunosuppression, with no reported deaths. De novo donor-specific antibodies (DSAs) were found in 8/86 (9.30%) of DSA-tested patients with two experiencing rejection and subsequent graft loss. The overall incidence of rejection and graft loss among the total cohort was 11/247 (4.45%) and 6/247 (3.64%), respectively. A 100% patient survival was observed. CONCLUSIONS: Observationally, infectious outcomes of SARS-CoV-2 in fully vaccinated pediatric KTRs are excellent, with a low incidence of infection requiring hospitalization and no associated deaths. Though de novo DSAs were observed, there was minimal graft rejection and graft loss reported in the total cohort.

High-resolution HLA genotyping improves PIRCHE-II assessment of molecular mismatching in kidney transplantation.

HLA matching in solid organ transplant is performed with the aim of assessing immunologic compatibility in order to avoid hyperacute rejection and assess the risk of future rejection events. Molecular mismatch algorithms are intended to improve granularity in histocompatibility assessment and risk stratification. PIRCHE-II uses HLA genotyping to predict indirectly presented mismatched donor HLA peptides, though most clinical validation studies rely on imputing high resolution (HR) genotypes from low resolution (LR) typing data. We hypothesized that use of bona fide HR typing could overcome limitations in imputation, improving accuracy and predictive ability for donor-specific antibody development and acute rejection. We performed a retrospective analysis of adult and pediatric kidney transplant donor/recipient pairs (N = 419) with HR typing and compared the use of imputed LR genotyping verses HR genotyping for PIRCHE-II analysis and outcomes. Imputation success was highly dependent on the reference population used, as using historic Caucasian reference populations resulted in 10 % of pairs with unsuccessful imputation while multiethnic reference populations improved successful imputation with only 1 % unable to be imputed. Comparing PIRCHE-II analysis with HR and LR genotyping produced notably different results, with 20 % of patients discrepantly classified to immunologic risk groups. These data emphasize the importance of using multiethnic reference panels when performing imputation and indicate HR HLA genotyping has clinically meaningful benefit for PIRCHE-II analysis compared to imputed LR typing.

Predicting pediatric kidney disease progression-are 3 variables all you need?

Accurate estimation of chronic kidney disease (CKD) progression risk is vital for clinical decision-making. Existing risk equations lack validation in pediatric CKD populations. Ng et al. developed new risk equations using the CKD in Children and European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients cohorts. The elementary model, incorporating estimated glomerular filtration rate, urine protein-creatinine ratio, and diagnosis, exhibited excellent discrimination and calibration at external validation. External validation of enriched models is pending. The equations have the potential to aid pediatric CKD centers in patient counseling and care planning.

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.

Anaphylaxis From Ethylene Oxide-Sterilized Dialysis Tubing and Needles: A Case Report.

Hypersensitivity reactions to ethylene oxide-sterilized dialyzers have been well described. Although ethylene oxide is no longer used to sterilize most dialyzers, it is used on other pieces of dialysis equipment. We present a case of a 78-year-old man who experienced dialysis-related anaphylaxis attributed to an IgE-mediated allergy to dialysis tubing and needles sterilized with ethylene oxide. Shortly after transitioning from a tunneled catheter to an arteriovenous fistula, he developed multiple episodes of intradialytic hypotension and syncope within minutes of starting dialysis. Laboratory evaluation revealed marked leukocytosis, eosinophilia, and elevated anti-ethylene oxide IgE antibody. After pretreatment with corticosteroids and antihistamines, the rinsing of dialysis tubing, and transition of access back to a tunneled catheter, he tolerated subsequent dialysis treatments. Review of his history revealed chronic eosinophilia since the time of hemodialysis initiation. We hypothesize his eosinophilia and mast cell degranulation began upon initial exposure to ethylene oxide and hemodialysis equipment. When use of the arteriovenous fistula was resumed, he was exposed to a higher "dose" of ethylene oxide due to the use of needles. The higher antigenic stimuli triggered a memory immune response, leading to mast cell degranulation and repeated anaphylactic episodes that were overcome by minimization of ethylene oxide-sterilized equipment, corticosteroid pretreatment, and the anti-IgE Fc monoclonal omalizumab.

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

BACKGROUND: Additional "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. METHODS: We 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. RESULTS: Forty-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. CONCLUSIONS: Our 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.

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.

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

BACKGROUND: Infections 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. METHODS: We 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). RESULTS: One 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. CONCLUSIONS: Our 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.

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

BACKGROUND: In 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. METHODS: Adolescent 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. RESULTS: Thirteen 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. CONCLUSION: Our 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.