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.

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.

Native nephrectomy in advanced pediatric kidney disease: indications, timing, and surgical approaches.

In pediatric kidney failure, native kidneys may pose a risk to successful transplant outcomes. The indications and timing of native nephrectomy represent a controversial management decision. A lack of high-quality, outcomes-based data has prevented development of evidence-based guidelines for intervention. In this article, we review the published literature on medical indications for native nephrectomy and current knowledge gaps. In addition, we provide a surgical perspective regarding timing and approach.

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.

Post-transplant recurrence of focal segmental glomerular sclerosis: consensus statements.

Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.

The effects of COVID-19 on pediatric and adult solid organ transplant recipients and the emergence of telehealth.

BACKGROUND: The SARS-CoV-2 pandemic and corresponding acute respiratory syndrome have affected all populations and led to millions of deaths worldwide. The pandemic disproportionately affected immunocompromised and immunosuppressed adult patients who had received solid organ transplants (SOTs). With the onset of the pandemic, transplant societies across the world recommended reducing SOT activities to avoid exposing immunosuppressed recipients. Due to the risk of COVID-19-related outcomes, SOT providers adapted the way they deliver care to their patients, leading to a reliance on telehealth. Telehealth has helped organ transplant programs continue treatment regimens while protecting patients and physicians from COVID-19 transmission. This review highlights the adverse effects of COVID-19 on transplant activities and summarizes the increased role of telehealth in the management of solid organ transplant recipients (SOTRs) in both pediatric and adult populations. METHODS: A comprehensive systematic review and meta-analysis were conducted to accentuate the outcomes of COVID-19 and analyze the efficacy of telehealth on transplant activities. This in-depth examination summarizes extensive data on the clinical detriments of COVID-19 in transplant recipients, advantages, disadvantages, patient/physician perspectives, and effectiveness in transplant treatment plans via telehealth. RESULTS: COVID-19 has caused an increase in mortality, morbidity, hospitalization, and ICU admission in SOTRs. Telehealth efficacy and benefits to both patients and physicians have increasingly been reported. CONCLUSIONS: Developing effective systems of telehealth delivery has become a top priority for healthcare providers during the COVID-19 pandemic. Further research is necessary to validate the effectiveness of telehealth in other settings.

Impact of multiorgan and kidney-pancreas allocation policies on pediatric kidney-alone transplant candidates in the United States.

BACKGROUND: The United States organ allocation policies prioritize kidney-pancreas and other multiorgan candidates above pediatric kidney-alone candidates, but the effects of these policies are unclear. METHODS: We used OPTN data to describe trends in multiorgan and kidney-pancreas transplantation and identify 377 next-sequential pediatric kidney-alone candidates between 4/1/2015 and 10/31/2019 for individual-level analysis. RESULTS: Eleven percent of all kidneys were allocated as part of a multiorgan or kidney-pancreas transplant and 6% of pediatric kidney candidates were impacted. Pediatric next-sequential candidates accrued a median of 118 days (IQR 97-135 days) of additional wait time, and this was significantly longer for children who were Hispanic (p = .02), blood type B or O (p = .01), or had a cPRA ≥20% (p < .01). Eight pediatric next-sequential candidates (2%) were removed from the waitlist due to death or "too sick to transplant." 63% were transplanted with a kidney with a higher KDPI than the original multiorgan match (p < .01). Donor service areas with higher volumes of kidney-pancreas transplants had significantly longer additional wait times for pediatric next-sequential candidates (p = .01). CONCLUSIONS: Current allocation policy results in longer waiting times and higher KDPI kidneys for pediatric kidney candidates. As multiorgan transplant volume is increasing, further consideration of allocation policy is necessary to maximize equality and utility.

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.

Overview of the findings and advances in the neurocognitive and psychosocial functioning of mild to moderate pediatric CKD: perspectives from the Chronic Kidney Disease in Children (CKiD) cohort study.

The Chronic Kidney Disease in Children (CKiD) prospective cohort study was designed to address the neurocognitive, growth, cardiovascular, and disease progression of children and adolescents with mild to moderate CKD. The study has had continuous funding from NIDDK for 17 years and has contributed significant advances in pediatric CKD. The goals of this educational review are threefold: (1) to provide an overview of the neurocognitive and psychosocial studies from CKiD to date; (2) to provide best practice recommendations for those working with the neurocognitive and psychosocial aspects of pediatric CKD based on CKiD findings; and (3) to help chart future goals and directives for both research and clinical practice. This collection of 22 empirical studies has produced a number of key findings for children and adolescents with mild to moderate CKD. While various studies suggest a relatively positive presentation for this population as a whole, without evidence of significant impairment or deterioration, findings do indicate the presence of neurocognitive dysfunction, emotional-behavioral difficulties, and lower quality of life for many children with CKD. These findings support the promotion of best practices that are accompanied by additional future clinical and research initiatives with this patient population.

Survey of Telemedicine by Pediatric Nephrologists During the COVID-19 Pandemic.

INTRODUCTION: The slow increase in use of telemedicine began to expand rapidly, along with reimbursement changes, during the coronavirus disease-2019 (COVID-19) pandemic. Standardized protocols for these services are lacking but are needed for effective and equitable health care. In this study, we queried pediatric nephrologists and their patients about their telemedicine experiences during the pandemic. METHODS: Surveys that were in compliance with the Health Insurance Portability and Accountability Act were deployed online to patients and physicians. RESULTS: We collected survey responses from 400 patients and 197 pediatric nephrologists. Patients reported positive experiences with telemedicine visits as it was logistically easier than in-person visits. Patients also felt that the quality of their visits were equivalent to what they would receive in person. Physicians used a wide variety of online systems to conduct synchronous telemedicine with Zoom (23%), EPIC (9%), Doxy.me (7%), services not specified (37%), or a mix of local or smaller services (24%). Most physicians' concerns were related to technological issues and the ability to procure physical exams and/or laboratory results. CONCLUSIONS: There is a paucity of published trials on telemedicine services in pediatric nephrology. Virtual care was feasible and acceptable for patients, caregivers, and providers during the COVID-19 pandemic.

Practice patterns and influence of allograft nephrectomy in pediatric kidney re-transplantation: A pediatric nephrology research consortium study.

INTRODUCTION: There are no guidelines regarding management of failed pediatric renal transplants. MATERIALS & METHODS: We performed a first of its kind multicenter study assessing prevalence of transplant nephrectomy, patient characteristics, and outcomes in pediatric renal transplant recipients with graft failure from January 1, 2006, to December 31, 2016. RESULTS: Fourteen centers contributed data on 186 pediatric recipients with failed transplants. The 76 recipients that underwent transplant nephrectomy were not significantly different from the 110 without nephrectomy in donor or recipient demographics. Fifty-three percent of graft nephrectomies were within a year of transplant. Graft tenderness prompted transplant nephrectomy in 91% (P < .001). Patients that underwent nephrectomy were more likely to have a prior diagnosis of rejection within 3 months (43% vs 29%; P = .04). Nephrectomy of allografts did not affect time to re-listing, donor source at re-transplant but significantly decreased time to (P = .009) and incidence (P = .0002) of complete cessation of immunosuppression post-graft failure. Following transplant nephrectomy, recipients were significantly more likely to have rejection after re-transplant (18% vs 7%; P = .03) and multiple rejections in first year after re-transplant (7% vs 1%; P = .03). CONCLUSIONS: Practices pertaining to failed renal allografts are inconsistent-40% of failed pediatric renal allografts underwent nephrectomy. Graft tenderness frequently prompted transplant nephrectomy. There is no apparent benefit to graft nephrectomy related to sensitization; but timing / frequency of immunosuppression withdrawal is significantly different with slightly increased risk for rejection following re-transplant.

Longitudinal Changes in Health-Related Quality of Life in Primary Glomerular Disease: Results From the CureGN Study.

INTRODUCTION: Prior cross-sectional studies suggest that health-related quality of life (HRQOL) worsens with more severe glomerular disease. This longitudinal analysis was conducted to assess changes in HRQOL with changing disease status. METHODS: Cure Glomerulonephropathy (CureGN) is a cohort of patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA vasculitis, or IgA nephropathy. HRQOL was assessed at enrollment and follow-up visits 1 to 3 times annually for up to 5 years with the Patient-Reported Outcomes Measurement Information System (PROMIS). Global health, anxiety, and fatigue domains were measured in all; mobility was measured in children; and sleep-related impairment was measured in adults. Linear mixed effects models were used to evaluate HRQOL responsiveness to changes in disease status. RESULTS: A total of 469 children and 1146 adults with PROMIS scores were included in the analysis. HRQOL improved over time in nearly all domains, though group-level changes were modest. Edema was most consistently associated with worse HRQOL across domains among children and adults. A greater number of symptoms also predicted worse HRQOL in all domains. Sex, age, obesity, and serum albumin were associated with some HRQOL domains. The estimated glomerular filtration rate (eGFR) was only associated with fatigue and adult physical health; proteinuria was not associated with any HRQOL domain in adjusted models. CONCLUSION: HRQOL measures were responsive to changes in disease activity, as indicated by edema. HRQOL over time was not predicted by laboratory-based markers of disease. Patient-reported edema and number of symptoms were the strongest predictors of HRQOL, highlighting the importance of the patient experience in glomerular disease. HRQOL outcomes inform understanding of the patient experience for children and adults with glomerular diseases.

Treatment of infant formula with patiromer dose dependently decreases potassium concentration.

BACKGROUND: Hyperkalemia is a potentially life-threatening complication of chronic kidney disease (CKD). Dietary potassium restriction is challenging in infants despite low-potassium formulas. Decreasing potassium in formula using patiromer, a new calcium-based cation exchange polymer may be one option to accomplish this; however, data confirming efficacy is lacking. METHODS: Varying doses of patiromer were added to prepared Similac Advance and Similac PM 60/40. Measurements of potassium, calcium, sodium, magnesium, and phosphorus were obtained at baseline and at 30 min, 60 min, and 24 h following patiromer administration. RESULTS: Following pre-treatment with patiromer, the potassium concentration of both formulas decreased. This effect was mild with the lowest dose but increased in a dose-dependent fashion. Treating for 60 min or 24 h did not yield substantially greater effects than treating for 30 min. Calcium levels increased in both formula groups, mostly in a dose-dependent fashion. Changes in magnesium, sodium, and phosphorus were also seen after patiromer pre-treatment. CONCLUSIONS: Pre-treatment with patiromer decreases the potassium concentration of infant formula. Calcium levels increased after treatment as expected with the majority of ion exchange occurring in 30 min. Treatment of formula with patiromer shows promise as a unique option for managing hyperkalemia.

Health-related quality of life in glomerular disease.

There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted ß [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.

Cytokine kinetics profiling in pediatric renal transplant recipients.

Pediatric renal transplant recipients experience side effects of immunosuppression. Few immunoassays exist which can assess the adequacy of immunosuppression. We developed a CKT, whereby cytokine levels are measured in a five-day mixed lymphocyte reaction. We describe the in vitro cytokine responses to donor and third-party antigen in a pilot study of nine children after living-donor renal transplantation. The CKT identified five patterns of IFN-gamma secretion relative to donor and third-party alloantigen: no response to alloantigen (n = 2), hypo-response to donor (n = 3), equal response (n = 1), hyper-response to donor (n = 1), and intermediate response (n = 2). IL-2 and IL-13 patterning correlated with IFN-gamma expression. Two of nine subjects had acute rejection, which correlated with intermediate and hyper-responsive profiles. No rejection occurred during immunosuppression or donor-specific hypo-responsiveness. Significant immunosuppression was universal early after transplantation. Two of four children showed strong pretransplant responses to donor, which were regained three months post-transplant, and associated with rejection in one subject. The CKT reflects the level of immunosuppression and may offer a method to assess the adequacy of immunosuppression. A pattern of complete non-responsiveness or hypo-responsiveness correlated with lack of acute rejection. The CKT may prove useful in titrating immunosuppression and in improving live donor selection.

A national conference to determine research priorities in pediatric solid organ transplantation.

The need for evidence-based practice guidelines requires high quality, carefully controlled clinical research trials. This multidisciplinary conference attempted to: identify urgent clinical and research issues, identify obstacles to performing clinical trials, develop concepts for organ-specific and all-organ research and generate a report that would serve as a blueprint for future research initiatives. A few themes became evident. First, young children present a unique immunologic environment which may lead to tolerance, therefore, including young children in immunosuppression withdrawal and tolerance trials may increase the potential benefits of these studies. Second, adolescence poses significant barriers to successful transplantation. Non-adherence may be insufficient to explain poorer outcomes. More studies focused on identification and prevention of non-adherence, and the potential effects of puberty are required. Third, the relatively naive immune system of the child presents a unique opportunity to study primary infections and alloimmune responses. Finally, relatively small numbers of transplants performed in pediatric centers mandate multicenter collaboration. Investment in registries, tissue and DNA repositories will enhance productivity. The past decade has proven that outcomes after pediatric transplantation can be comparable to adults. The pediatric community now has the opportunity to design and complete studies that enhance outcomes for all transplant recipients.

IgA nephropathy in children and adults: comparison of histologic features and clinical outcomes.

BACKGROUND: While some studies have reported that IgA nephropathy has a relatively benign clinical course in children, others have shown that renal outcomes of paediatric patients with IgA nephropathy followed into adulthood are similar to those of patients diagnosed as adults. Some of this variability may be related to differences in histologic severity of cohorts of patients diagnosed as children versus adults. METHODS: We retrospectively examined correlations between renal biopsy findings, clinical features at presentation and renal survival in 99 children and adolescents (

Pharmacokinetics of enteric-coated mycophenolate sodium in stable pediatric renal transplant recipients.

This study aims to characterize the pharmacokinetics of mycophenolic acid (MPA) and its glucuronide metabolite (mycophenolic acid 7-O-glucuronide, MPAG) following single oral administration of enteric-coated mycophenolate sodium (EC-MPS, myfortic) at an approximate dose level of 450 mg/m(2) body surface area (BSA) to 25 stable renal transplant recipients (aged 5-16 yr), and to evaluate the safety and tolerability of EC-MPS in this pediatric population. Patients had been maintained on a cyclosporine emulsion, Neoral-based immunosuppressive regimen for at least 3 months and had received their first or second renal transplant more than 6 months prior to entry into the study. After a brief lag phase (t(lag) 0.75 h), MPA was rapidly absorbed (t(max) 2.5 h) and rapidly converted to MPAG (t(max) 3.25 h), with relatively high plasma concentrations of MPAG (C(max) 67.7 microg/mL) compared with MPA (C(max) 36.3 microg/mL). The elimination half-life for MPAG was slightly longer than for MPA (approximately 13 h vs. 8.5 h), and the apparent oral clearance of MPA was approximately 0.2 L/h/kg. The pharmacokinetics of MPA or MPAG were not affected by age, body weight or BSA, within the study population. The pharmacokinetic results for pediatric patients are comparable with those obtained previously in adults, although exposure based on AUC(0-infinity) was approximately 23% higher, and this finding may be a result of dosing on the basis of BSA, rather than body weight. The recommended dose of EC-MPS in pediatric patients is 400-450 mg/m(2) twice daily or, alternatively, approximately 10-14 mg/kg twice daily when used in combination with cyclosporine microemulsion.