Immune monitoring in pediatric kidney transplant.

BACKGROUND: Long-term outcomes in pediatric kidney transplantation remain suboptimal, largely related to chronic rejection. Creatinine is a late marker of renal injury, and more sensitive, early markers of allograft injury are an active area of current research. METHODS: This is an educational review summarizing existing strategies for monitoring for rejection in kidney transplant recipients. RESULTS: We summarize supporting currently available clinical tests, including surveillance biopsy, donor specific antibodies, and donor-derived cell free DNA, as well as the potential limitations of these studies. In addition, we review the current avenues of active research, including transcriptomics, proteomics, metabolomics, and torque tenovirus levels. CONCLUSION: Advancing the use of noninvasive immune monitoring will depend on well-designed multicenter trials that include patients with stable graft function, include biopsy results on all patients, and can demonstrate both association with a patient-relevant clinical endpoint such as graft survival or change in glomerular filtration rate and a potential timepoint for intervention.

Adult and late adolescent complications of pediatric solid organ transplantation.

BACKGROUND: There have been over 51 000 pediatric solid organ transplants since 1988 in the United States alone, leading to a growing population of long-term survivors who face complications of childhood organ failure and long-term immunosuppression. AIMS: This is an educational review of existing literature. RESULTS: Pediatric solid organ transplant recipients are at increased risk for risk for cardiovascular and kidney disease, skin cancers, and growth problems, though the severity of impact may vary by organ type. Pediatric recipients often are able to complete schooling, maintain a job, and form family and social networks in adulthood, though at somewhat lower rates than the general population, but face additional challenges related to neurocognitive deficits, mental health disorders, and discrimination. CONCLUSIONS: Transplant centers and research programs should expand their focus to include long-term well-being. Increased collaboration between pediatric and adult transplant specialists will be necessary to better understand and manage long-term complications.

Long-term outcomes of two-dose alemtuzumab induction in pediatric kidney transplantation.

BACKGROUND: Alemtuzumab is a lymphocyte depleting agent used for induction in kidney transplant, but long-term information on its use in pediatric recipients remains sparse. METHODS: We performed a single-center retrospective cohort study of 57 pediatric kidney transplant recipients receiving alemtuzumab 20 mg/m2/dose ×2 doses for induction immunosuppression. All patients underwent surveillance biopsies, and 91.3% underwent steroid withdrawal by day 4 post-transplant. Outcomes of interest included graft survival, development of donor specific antibodies (DSA), incidence of viremia and PTLD, and duration of lymphopenia. RESULTS: Median follow-up time was 7.9 years (IQR 5-13.6 years). Median graft survival was 16.5 years (95% CI 11.6-unknown). DSA developed in 36.5% at a median of 944 days (IQR 252-2113 days). Incidences of BK polyomavirus DNAemia (BKPyV-DNAemia), CMV DNAemia, and EBV DNAemia were 38.6%, 22.8%, and 14%, respectively; one patient developed PTLD at 13.3 years post-transplant. Median duration of lymphopenia was 365 days (IQR 168-713 days); 19.3% of patients remained lymphopenic at 3 years post-transplant. There was no association between duration of lymphopenia and graft survival, rejection, DSA detection, or viremia. CONCLUSIONS: A two-dose alemtuzumab induction protocol can have excellent outcomes with a steroid-free maintenance immunosuppression regimen. More comprehensive, multicenter, comparative studies of pediatric kidney transplant are needed to improve long-term outcomes.

Antibody-mediated rejection in pediatric kidney transplant recipients: A report from the Pediatric Nephrology Research Consortium.

BACKGROUND: Antibody-mediated rejection (AMR) is a major cause of kidney allograft loss. There is a paucity of large-scale pediatric-specific data regarding AMR treatment outcomes. METHODS: Data were obtained from 14 centers within the Pediatric Nephrology Research Consortium. Kidney transplant recipients aged 1-18 years at transplant with biopsy-proven AMR between 2009 and 2019 and at least 12 months of follow-up were included. The primary outcome was graft failure or an eGFR <20 mL/min/1.73 m2 at 12 months following AMR treatment. AMR treatment choice, histopathology, and DSA class were also examined. RESULTS: We reviewed 123 AMR episodes. Median age at diagnosis was 15 years at a median 22 months post-transplant. The primary outcome developed in 27.6%. eGFR <30 m/min/1.73 m2 at AMR diagnosis was associated with a 5.6-fold higher risk of reaching the composite outcome. There were no significant differences in outcome by treatment modality. Histopathology scores and DSA class at time of AMR diagnosis were not significantly associated with the primary outcome. CONCLUSIONS: In this large cohort of pediatric kidney transplant recipients with AMR, nearly one-third of patients experienced graft failure or significant graft dysfunction within 12 months of diagnosis. Poor graft function at time of diagnosis was associated with higher odds of graft failure.

Evaluation and post-transplant management of children after multi-organ-with-kidney transplantation.

Multi-organ transplantation involves the transplant of two or more organs from a single donor into a single recipient; in most cases, one of these organs is a kidney. Multi-organ transplantation is uncommon in pediatric transplantation but can be life-saving or significantly life-improving for children with rare diseases, including primary heart, liver, pancreas, or intestinal failure with secondary kidney failure, metabolic disorders, and genetic conditions causing multi-organ dysfunction. This manuscript reviews the current state of pediatric multi-organ transplantation that includes a kidney, with a focus on indications, evaluation, and key differences in management compared to kidney-alone transplantation. Guidelines and consensus statements for pediatric multi-organ transplantation are nonexistent; this review condenses reported statistics and peer-reviewed expert opinion while highlighting areas in need of further research.

Pediatric priority in kidney allocation after the age of 18 years.

Children registered for kidney transplants prior to the age of 18 years retain "pediatric" allocation status after their 18th birthday. There are no data on the impact of this policy. We performed a retrospective cohort study of 7097 candidates listed for kidney transplant prior to 18 years of age who remained on the waitlist after their 18th birthday between January 1, 2015, and April 1, 2022, using United Network for Organ Sharing data. A total of 1193 candidates remained on the waitlist after their 18th birthday. The median age at listing was 17 years (IQR: 17-17 years). A total of 588 candidates (8% of 7097 pediatric candidates) received a kidney transplant with pediatric status at the age of 18 years or older; 465 (79%) were deceased-donor transplants. The median age at deceased-donor transplants was 18 years (IQR: 18-19 years); 97% were performed before the age of 21 years. In the 7.25 years of the study, 12 adults aged 21 years and older received a deceased-donor kidney transplant with pediatric allocation priority. Deceased-donor transplants with pediatric priority after the age of 18 years are rare, comprising an estimated 0.4% of all adult deceased-donor transplants. Candidates with pediatric priority after 18 years of age typically progress to transplant within 3 years. Ongoing monitoring of this population is important to fully understand the allocation policy.

Risk for graft loss in pediatric and young adult kidney transplant recipients due to recurrent IgA nephropathy.

IgA nephropathy (IgAN) is associated with a risk for posttransplant recurrence. Data are limited regarding graft loss attributable to recurrence of IgAN among pediatric and young adult kidney transplant (KT) recipients. This was a retrospective cohort study of patients aged 0 to 25 years from the Scientific Registry of Transplant Recipients who received a primary KT for IgAN. Patients with history of KT attributable to renal dysplasia were comparators. Outcomes included the incidence of graft loss attributable to IgAN recurrence, association with donor type, and posttransplant corticosteroid use. In total, 5475 transplant recipients were included, with 1915 patients with IgAN and 3560 patients with renal dysplasia. In a multivariable Cox proportional hazards model, IgAN was associated with higher risk of graft loss (adjusted hazard ratio [aHR], 1.35; 95% CI, 1.21-1.50; P < .001) compared with dysplasia. Graft loss was attributed to recurrent disease in 5.4% of patients with IgAN. In a multivariable competing risks analysis, patients with IgAN receiving a parental living-donor kidney were more likely to report graft loss from recurrent disease compared with patients with a nonparental living donor (aHR, 0.52; 95% CI, 0.31-0.91; P = .02). Posttransplant prednisone use was not associated with improved graft survival (P = .2). These data challenge existing paradigms in posttransplant management of patients with IgAN.

Continuous allocation: The problem with EPTS and pediatric kidney candidates.

BACKGROUND: The 2014 Kidney Allocation System (KAS) introduced longevity matching for adult candidates using the Estimated Post-Transplant Survival (EPTS) score, which includes candidate age, time on dialysis, diabetes status, and number of previous solid organ transplants. The proposed continuous distribution framework may expand the use of this attribute to pediatric candidates, but there is no data on its performance among pediatric kidney transplant recipients. METHODS: We performed a retrospective cohort study of 6800 pediatric kidney transplant recipients from 2001 to 2011 using Organ Procurement and Transplantation Network (OPTN) data. EPTS score was calculated for each patient and compared to reported patient survival to estimate the validity of the score in children. RESULTS: The median age of patients was 14.01 years (IQR 9.29-16.37 years), and dialysis vintage was 0.67 years (IQR 0-1.82 years). 18.2% of the cohort had a prior transplant and 1% had diabetes. Median EPTS score was 2 (IQR 1-2). Seven percent of patients died during the study period and 54.7% of the cohort was censored prior to 10 years. The c-statistic was 0.505 (95% CI: 0.49-0.53). CONCLUSION: Overall, EPTS is not a valid predictor of patient survival among pediatric kidney transplant recipients.

Pediatric impacts of multiorgan transplant allocation policy in the United States.

BACKGROUND: Multiorgan transplantation is increasingly common, driving recent increased attention to multiorgan allocation policies. METHODS: In this review, we summarize current multiorgan transplant allocation policies in the United States, with attention to recent and proposed changes and their impact on pediatric candidates. RESULTS: Existing multiorgan transplant policies attempt to balance equity and utility. Currently, there are clear allocation policies for some, but not all, multiorgan transplant combinations, and there are no mandatory outcomes reporting. Multiorgan candidates are prioritized above all kidney-alone transplant candidates, which negatively affect pediatric kidney transplant wait times. Pediatric candidates are typically exempt from multiorgan listing criteria. CONCLUSION: Multiorgan transplant allocation presents unique challenges for policy development. As the United States Network for Organ Sharing begins exploring continuous distribution allocation, multiorgan allocation will require special consideration and the development of clear and equitable policies.

Neutropenia in pediatric solid organ transplant.

Neutropenia is generally defined as an absolute neutrophil count in the circulation of less than 1500/mm3 and occurs in up to 25%-30% of pediatric solid organ transplant recipients (SOT) within the first year after transplantation. In the SOT population, neutropenia is most often a result of drug-induced bone marrow suppression but can also be secondary to viral infection, nutritional deficiencies, lymphoproliferative infiltrate, and inherited causes. Outcomes for patients with neutropenia vary by degree of neutropenia and type of solid organ transplant. Management of neutropenia should begin by addressing the underlying cause, including reducing or removing medications when appropriate, treating infections, and addressing nutrient deficiencies; however, consultation with an experienced pediatric hematologist and use of granulocyte colony-stimulating factor (G-CSF) may be helpful in some cases. Overall, data on clinical outcomes for G-CSF use remain limited, but observational studies may support its use in patients with infections or severe neutropenia.

The kidney allocation system and pediatric transplantation at 5 years.

BACKGROUND: A new Kidney Allocation System (KAS) was implemented in the United States in 2014 with the goal of improving equity and utility. METHODS: In this study, we compare outcomes for kidney-alone candidates less than 18 years of age, at the time of listing, in the 5 years prior to and following policy implementation using Organ Procurement and Transplantation Network data. RESULTS: While the pediatric deceased donor transplant rate increased under KAS, this increase was due solely to improved access for children aged 11-17 years; there was an 18.9% decrease in the deceased donor transplant rate among children 0-5 years old, from 117.94 to 95.8 transplants per 100 person-years (p = .001). The cumulative incidence of deceased donor transplantation by 1 year after listing decreased from 39.3% in the pre-KAS era to 35.5% in the post-KAS era (p = .004), a decline that was driven entirely by longer wait times for children 0-5 years old (p = .017). Candidates with a calculated panel reactive antibody of 98%-100% experienced a significant increase in transplant rate, but there was no change in transplant rate for Black or Hispanic candidates. CONCLUSION: Overall, KAS increased transplantation access for teenaged and highly sensitized candidates but resulted in decreased access for the youngest children with no improvement in racial/ethnic equality.

Focal segmental glomerulosclerosis: Risk for recurrence and interventions to optimize outcomes following recurrence.

BACKGROUND: FSGS is a common indication for kidney transplant with a high-risk of posttransplant recurrence. METHODS: In this review, we summarize current knowledge about FSGS recurrence after kidney transplantation, including epidemiology, pretransplant planning, posttransplant management, and investigational treatments. RESULTS: FSGS recurs in 14%-60% of first transplants, likely associated with a circulating permeability factor. Pretransplant counseling regarding recurrence is critical, and patients with FSGS should undergo pretransplant genetic screening. Rapid progression to ESKD, initial steroid responsiveness, younger age at diagnosis, race/ethnicity, and mesangial hypercellularity or minimal change histology on native biopsy may be associated with recurrence. Living donation is not contraindicated but does not result in improved graft survival relative to deceased donation. Pretransplant nephrectomy may be performed for a variety of reasons, but does not decrease recurrence. Pretransplant therapy with rituximab and/or PE is understudied but not clearly effective at preventing recurrence. Patients with FSGS typically present early with rapid-onset severe proteinuria. Diagnosis can be confirmed by biopsy showing foot process effacement; typical FSGS lesions are not seen on light microscopy in the early stages. There is no established effective treatment for recurrent FSGS, but renin-angiotensin-aldosterone system inhibition and extracorporeal therapies, including PE and IA, are most commonly used. Adjunct or alternative therapies may include rituximab, lipopheresis, and cyclosporine.

Multisite Retrospective Review of Outcomes in Renal Replacement Therapy for Neonates with Inborn Errors of Metabolism.

OBJECTIVE: To assess the outcomes of neonates in a contemporary multi-institutional cohort who receive renal replacement therapy (RRT) for hyperammonemia. STUDY DESIGN: We performed a retrospective analysis of 51 neonatal patients with confirmed inborn errors of metabolism that were treated at 9 different children's hospitals in the US between 2000 and 2015. RESULTS: Twenty-nine patients received hemodialysis (57%), 21 patients received continuous renal replacement therapy (41%), and 1 patient received peritoneal dialysis (2%). The median age at admission of both survivors (n = 33 [65%]) and nonsurvivors (n = 18) was 3 days. Peak ammonia and ammonia at admission were not significantly different between survivors and nonsurvivors. Hemodialysis, having more than 1 indication for RRT in addition to hyperammonemia, and complications during RRT were all risk factors for mortality. After accounting for multiple patient factors by multivariable analyses, hemodialysis was associated with a higher risk of death compared with continuous renal replacement therapy. When clinical factors including evidence of renal dysfunction, number of complications, concurrent extracorporeal membrane oxygenation, vasopressor requirement, and degree of hyperammonemia were held constant in a single Cox regression model, the hazard ratio for death with hemodialysis was 4.07 (95% CI 0.908-18.2, P value = .067). To help providers caring for neonates with hyperammonemia understand their patient's likelihood of survival, we created a predictive model with input variables known at the start of RRT. CONCLUSIONS: Our large, multicenter retrospective review supports the use of continuous renal replacement therapy for neonatal hyperammonemia.

Nondestructive versus advanced post-transplant lymphoproliferative disorder in a single-center pediatric kidney transplant population.

BACKGROUND: Pediatric kidney transplant recipients are at risk for the development of post-transplant lymphoproliferative disorders (PTLD), a group of potentially devastating diseases that present on a spectrum of severity ranging from nondestructive PTLD to more histologically destructive lesions. Currently, there is inadequate evidence to guide evaluation and management of nondestructive PTLD. METHODS: This is a single-center case series of pediatric kidney transplant recipients between January 1, 2008 and December 31, 2019, who were diagnosed with PTLD. The aim was to describe clinical characteristics, presentation, and management of nondestructive versus advanced PTLD. RESULTS: Eighteen patients were diagnosed with nondestructive PTLD and seven with more advanced PTLD histopathology. The majority (66.7%) of nondestructive PTLD patients (n = 16) presented with tonsillar hypertrophy and/or snoring and were managed conservatively, with minimal reduction in tacrolimus dose and no further evaluation. No patient progressed to more advanced PTLD. Advanced PTLD patients (n = 7) were more likely to present with fever, elevated creatinine, a new mass of gastrointestinal symptoms. They received workup with imaging and oncology consultation, and were managed with chemotherapy. CONCLUSIONS: Patients with nondestructive PTLD often present with symptoms of sleep-disordered breathing and can be managed conservatively with excellent clinical outcomes. More study is needed to guide care of this under-researched population.

Outcomes of granulocyte colony-stimulating factor use in pediatric kidney transplant recipients: A Pediatric Nephrology Research Consortium study.

BACKGROUND: Neutropenia is common in the first year after pediatric kidney transplant and is associated with an increased risk of infection, allograft loss, and death. Granulocyte colony-stimulating factor (G-CSF) increases neutrophil production, but its use in pediatric solid organ transplant recipients remains largely undescribed. METHODS: We performed a multicenter retrospective cohort study of children with neutropenia within the first 180 days after kidney transplant. Multivariable linear regression and Poisson regression were used to assess duration of neutropenia and incidence of hospitalization, infection, and rejection. RESULTS: Of 341 neutropenic patients, 83 received G-CSF during their first episode of neutropenia. Median dose of G-CSF was 5 mcg/kg for 3 (IQR 2-7) doses. G-CSF use was associated with transplant center, induction immunosuppression, steroid-free maintenance immunosuppression, hospitalization, and decreases in mycophenolate mofetil, valganciclovir, and trimethoprim-sulfamethoxazole dosing. Absolute neutrophil count nadir was also significantly lower among those treated with G-CSF. G-CSF use was not associated with a shorter duration of neutropenia (p = .313) and was associated with a higher rate of neutropenia relapse (p = .002) in adjusted analysis. G-CSF use was associated with a decreased risk of hospitalization (aIRR 0.25 (95%CI 0.12-0.53) p < .001) but there was no association with incidence of bacterial infection or rejection within 90 days of neutropenic episode. CONCLUSION: G-CSF use for neutropenia in pediatric kidney transplant recipients did not shorten the overall duration of neutropenia but was associated with lower risk of hospitalization. Prospective studies are needed to determine which patients may benefit from G-CSF treatment.

Eculizumab exposure in children and young adults: indications, practice patterns, and outcomes-a Pediatric Nephrology Research Consortium study.

BACKGROUND: Eculizumab is approved for the treatment of atypical hemolytic uremic syndrome (aHUS). Its use off-label is frequently reported. The aim of this study was to describe the broader use and outcomes of a cohort of pediatric patients exposed to eculizumab. METHODS: A retrospective, cohort analysis was performed on the clinical and biomarker characteristics of eculizumab-exposed patients < 25 years of age seen across 21 centers of the Pediatric Nephrology Research Consortium. Patients were included if they received at least one dose of eculizumab between 2008 and 2015. Traditional summary statistics were applied to demographic and clinical data. RESULTS: A total of 152 patients were identified, mean age 9.1 (+/-6.8) years. Eculizumab was used "off-label" in 44% of cases. The most common diagnoses were aHUS (47.4%), Shiga toxin-producing Escherichia coli HUS (12%), unspecified thrombotic microangiopathies (9%), and glomerulonephritis (9%). Genetic testing was available for 60% of patients; 20% had gene variants. Dosing regimens were variable. Kidney outcomes tended to vary according to diagnosis. Infectious adverse events were the most common adverse event (33.5%). No cases of meningitis were reported. Nine patients died of noninfectious causes while on therapy. CONCLUSIONS: This multi-center retrospective cohort analysis indicates that a significant number of children and young adults are being exposed to C5 blockade for off-label indications. Dosing schedules were highly variable, limiting outcome conclusions. Attributable adverse events appeared to be low. Cohort mortality (6.6%) was not insignificant. Prospective studies in homogenous disease cohorts are needed to support the role of C5 blockade in kidney outcomes.

Substituting imputation of HLA antigens for high-resolution HLA typing: Evaluation of a multiethnic population and implications for clinical decision making in transplantation.

Molecular mismatch analysis for assessment of histocompatibility in transplantation requires high-resolution HLA typing. Algorithms to "guesstimate" high-resolution from low-resolution typing exist, but their accuracy remains unknown. We converted high-resolution, sequence-based, HLA typing of 310 subjects from an ethnically heterogeneous population to low-resolution equivalents and tested the ability of the NMDP HaploStats and HLA Matchmaker programs to impute/reproduce the measured high-resolution HLA type, using the more common "winner-takes-all" approach. Only 35.6% of the HaploStats imputed HLA-A, -B, -C, -DRB1, and -DQB1 haplotypes had no mistakes, and the accuracy was significantly lower for non-Caucasians (29.1%) compared to Caucasians (45.2%) (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.3-0.8; P = .004). HLA Matchmaker was not able to provide high-resolution haplotypes for 45.2% of Caucasian subjects and 63.5% of non-Caucasian subjects (P = .002). Of those with an imputed result, only 10.3% of Caucasians and 4.8% of non-Caucasians had accurate 10-allele high-resolution output. Eplet analysis revealed additional, inaccurate eplets in 37% of individuals, with 22.5% showing at least 2 additional, inaccurate eplets; incorrect eplets were more common among non-Caucasians (OR, 1.8; 95% CI, 1.1-2.9; P = .018). Given this high error rate, caution should be taken before using imputation tools for clinical or research purposes, especially for non-Caucasian individuals.

Donor-specific Antibody Surveillance and Graft Outcomes in Pediatric Kidney Transplant Recipients.

BACKGROUND: The development of de novo donor-specific antibodies (dnDSA) has been associated with rejection and graft loss in kidney transplantation, and DSA screening is now recommended in all kidney transplant recipients. However, the clinical significance of dnDSA detected by screening patients with a stable creatinine remains unclear. METHODS: One hundred three patients younger than 18years receiving a first, kidney alone transplant between December 1, 2007, and December 31, 2013, underwent DSA screening every 3months for 2years posttransplant, with additional testing as clinically indicated. No treatment was given for DSAs in the absence of biopsy-proven rejection. RESULTS: Twenty (19%) patients had dnDSA first detected on a screening test, and 13 (13%) patients had dnDSA first detected on a for-cause test. Mean follow-up time posttransplant was 4.4years. Screening-detected dnDSA was associated with an increased risk of rejection within 3years, microvascular inflammation, and C4d staining on a 2-year protocol biopsy. In a Cox proportional hazards regression, screening-detected dnDSA was not associated with time to 30% decline in estimated glomerular filtration rate (adjusted hazard ratio, 0.88; 95% confidence interval [CI], 0.30-2.00; P=0.598) or graft loss. dnDSA first detected on for-cause testing was associated with a 2.8 times increased risk of decline in graft function (95% CI, 1.08-7.27; P=0.034) and a 7.34 times increased risk of graft loss (95% CI, 1.37-39.23 P=0.020) compared with those who did not develop dnDSA. CONCLUSIONS: The clinical setting in which dnDSA is first detected impacts the association between dnDSA and graft function. Further research is needed to clarify the role of dnDSA screening in pediatric kidney transplantation.