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.

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.

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.

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 (

Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: The North American Pediatric Renal Transplant Cooperative Study experience.

Membranoproliferative glomerulonephritis type II (MPGN II) is an uncommon form of complement-dependent acquired renal disease. Although it has been recognized since the 1970s that MPGN II recurs almost universally in renal transplants, data regarding the long-term consequences of disease recurrence are limited. Therefore, a retrospective comparative analysis of 75 patients with MPGN II contained in the North American Pediatric Renal Transplant Cooperative Study transplantation database was performed. Five-year graft survival for patients with MPGN II was significantly worse (50.0 +/- 7.5%) compared with the database as a whole (74.3 +/- 0.6%; P < 0.001). Living related donor organs had a significantly better 5-yr survival (65.9 +/- 10.7%) compared with cadaveric donor organs (34.1 +/- 9.8%; P = 0.004). The primary cause of graft failure in 11 (14.7%) patients was recurrent disease. Supplemental surveys were obtained on 29 (38%) of 75 patients. Analysis of these data indicated that recurrent disease occurred in 12 (67%) of the 18 patients with posttransplantation biopsies. Although there was no correlation between pretransplantation presentation, pre- or posttransplantation C3 levels, and either disease recurrence or graft failure, there was a strong association between heavy proteinuria and disease recurrence. The presence of glomerular crescents in allograft biopsies had a significant negative correlation with graft survival. At last follow-up, patients with recurrent disease had significantly higher serum creatinine and qualitatively more proteinuria than patients without biopsy-proven disease. These data indicate that recurrent MPGN II has a significant negative impact on renal allograft function and survival.

Campath-1H use in pediatric renal transplantation.

Campath-1H is a humanized, monoclonal antibody directed against CD52 determinants on the surface of human B- and T-cells and monocytes. Reports of Campath-1H use as induction in adult renal transplantation have been encouraging with low rejection rates and minimal adverse events. We report four high risk pediatric kidney transplant patients who received Campath-1H for unique indications with variable results. Children ranged in age from 20 months to 16 years. Immunosuppression regimens varied. Three of four patients experienced acute rejection, two of which were C4d positive. Serial flow cytometry was performed on all four patients. The patient who received only Campath-1H has an absolute lymphocyte count that remains less than 50% of baseline at 12-months post-transplant. In addition, in this patient CD3, CD4, CD8 and CD20 remain less than 50% of baseline. From this initial experience using Campath-1H in pediatric renal transplantation we conclude that; (1) the use of Campath-1H does not prevent recurrence of FSGS, (2) as seen in adults, lack of calcineurin inhibition when using Campath-1H may increase the risk of antibody-mediated rejection and (3) prolonged lymphocyte depletion remains even after a single dose of Campath-1H in children.

Medical management of pediatric stone disease.

Childhood urolithiasis remains endemic in certain parts of the world, namely, Turkey and the Far East. The prevalence of nephrolithiasis in North American children varies widely among geographic regions and accounts for 1 per 1000 to 1 per 7600 pediatric hospital admissions. Stones occur in children of all ages. The clinical manifestations of stone disease are often more subtle in children when compared with the dramatic adult presentation. This article discusses the evaluation and medical management of pediatric stone disease.

Long-term outcomes in pediatric renal transplant recipients who survive into adulthood.

BACKGROUND: Long-term results in renal transplant recipients who underwent transplantation as children are often buried within the outcomes of adult centers, leaving a void in our knowledge regarding this unique cohort. The authors aim to describe the long-term outcomes of children who experienced renal failure and subsequently underwent transplantation during childhood and who have now reached adulthood, with an emphasis on social and economic rehabilitation. METHODS: Two hundred seventeen children were identified who underwent transplantation between 1967 and 1999. Of those 217174 who were born before October 1982 and who would therefore have reached adulthood were selected for study. A questionnaire and consent form were sent to the surviving 132 patients of this subpopulation. RESULTS: Fifty-seven adult survivors answered the questionnaire. No significant differences were found comparing the respondents to the nonrespondents. Nearly half of all respondents were severely short and 27% were obese. Questionnaire respondents had high rates of hypertension, bone and joint symptoms, fractures, hypercholesterolemia, and cataracts. Despite significant remaining health issues, 82% of respondents were employed, 95% reported their health as "fair" or "good," 61% reported "no" or "minor" physical limitations, and 82% described themselves as "just as" or "more content than others." Nearly 50% of the respondents were married, and the overwhelming majority reported satisfaction in their sexual lives. CONCLUSIONS: Despite a high retransplantation rate and the presence of significant morbidity, renal transplantation in children can lead to attainment of a productive and satisfying life, with a high degree of rehabilitation in adulthood.