Equity factors in pediatric transplant listing: Initial findings from a single center review.

BACKGROUND: In order to improve transparency within the patient selection process, a transplant listing advisory committee was formed within the Boston Children's Hospital Pediatric Transplant Center. Its mission is to promote equity in access to organ transplantation by ensuring that the institutional transplant selection criteria are fair, unbiased, and nondiscriminatory. The committee conducts comprehensive case and data review of individual characteristics and reviews in aggregate to identify potential systems bias. METHODS: Charts for 256 patients evaluated for transplant from 3/2016 to 3/2019 were reviewed. Among these, 64 (25%) patients were declined for transplant. Univariate logistic regression analysis was used to identify demographic variables and vulnerable status factors associated with being declined. Odds ratios (OR) are reported. RESULTS: Among all patients, median age was 8.5 years and 58% were male. Asian patients were more likely to be declined than White patients (OR = 5.3, Wald p = .007). Socioeconomic factors that affected likelihood of listing decline included concerns for caregivers' ability to manage and understand care requirements (OR = 3.8, p = .011), caregiver employment status (OR = 1.9, p = .042), and use of public assistance programs (OR = 2.2, p = .05). Patients with severe neurodevelopmental delay were more likely to be declined for listing (OR = 3.7, p = .019). CONCLUSION: This analysis identified areas of potential bias related to race, socioeconomic status, and neurodevelopmental delay where initiatives can be targeted. Advisory committees are an important aspect of evaluating equity in transplant center selection policy and practice.

Survival of neonates born with kidney failure during the initial hospitalization.

BACKGROUND: Survival to hospital discharge in neonates born with kidney failure has not been previously described. METHODS: This was a retrospective, observational analysis of the Pediatric Health Information System (PHIS) database from 2005 to 2019. Primary outcome was survival at discharge; secondary outcomes were hospital and ICU length of stay (LOS). Univariate analysis was performed to describe the population by birth weight (BW) and characterize survival; multivariable generalized liner mixed modeling assuming a binomial distribution and logit link was performed to identify mortality risk factors. RESULTS: Of 213 neonates born with kidney failure (median BW 2714 g; GA 35 weeks; 68% male), 4 (1.9%) did not receive dialysis or peritoneal dialysis (PD) catheter placement, 152 (72.9%) received PD only, 49 (23.4%) received PD plus extracorporeal dialysis (ECD), and 8 (3.4%) were treated with an undocumented dialysis modality. Median age at dialysis initiation was 7 days; median hospital LOS and ICU LOS were 84 and 69 days, respectively. One-hundred and sixty-two patients (76%) survived to discharge. Non-survivors (n = 51) were more likely to have received ECD and mechanical ventilation, and had a longer duration of mechanical ventilation. Every day of mechanical ventilation increased the mortality odds by 2% (n = 189; adjusted OR 1.02; 1.01, 1.03); in addition, the odds of mortality were 2 times higher in those who received ECD vs. only PD (adjusted OR 2.25; 1.04, 4.86). CONCLUSIONS: Survival to initial hospital discharge occurs in the majority of neonates born with kidney failure. Predictors of increased mortality included longer duration of mechanical ventilation, as well as the requirement for ECD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT.

PURPOSE: Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES. METHODS: We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping. RESULTS: In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype-phenotype correlation. CONCLUSION: We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.

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.

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients.

BACKGROUND: Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. METHODS: To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children's Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. RESULTS: By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients. CONCLUSIONS: Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis.

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

Bilateral native nephrectomy reduces systemic oxalate level after combined liver-kidney transplant: A case report.

Primary hyperoxaluria type 1 (PH1) is a rare liver enzymatic defect that causes overproduction of plasma oxalate. Accumulation of oxalate in the kidney and subsequent renal failure are fatal to PH1 patients often in pediatric age. Combined liver and kidney transplantation is the therapy of choice for end-stage renal disease due to PH1. Levels of plasma oxalate remain elevated for several months after liver transplantation, as the residual body oxalate is slowly excreted. Patients with persistent hyperoxaluria after transplant often require hemodialysis, and accumulation of residual oxalate in the kidney can induce graft dysfunction. As the native kidneys are the main target of calcium oxalate accumulation, we postulated that removal of native kidneys could drastically decrease total body oxalate levels after transplantation. Here, we report a case of bilateral nephrectomy at the time of combined liver-kidney transplantation in a pediatric PH1 patient. Bilateral nephrectomy induced a rapid decrease in plasma oxalate to normal levels in less than 20 days, compared to the several months reported in the literature. Our results suggest that removal of native kidneys could be an effective strategy to decrease the need for hemodialysis and the risk of renal dysfunction after combined liver-kidney transplantation in patients with PH1.

Derivation and Validation of an Optimal Neutrophil Gelatinase-Associated Lipocalin Cutoff to Predict Stage 2/3 Acute Kidney Injury (AKI) in Critically Ill Children.

Introduction: Acute kidney injury (AKI) defined by changes in serum creatinine (SCr), or oliguria is associated with increased morbidity and mortality in children who are critically ill. We derived and validated a clinical cutoff value for urine neutrophil gelatinase-associated lipocalin (NGAL), in a prospective multicenter study of children who were critically ill. We report the clinical performance of urine NGAL (uNGAL) to aid in pediatric AKI risk assessment. Methods: Eligible subjects were aged ≥ 90 days to < 22 years, admitted to an intensive care unit (ICU), and had 1 or more of the following: mechanical ventilation, vasoactive medication administration, solid organ or bone marrow transplantation, or hypotension within 24-hours of admission. uNGAL was assessed within 24-hours of admission. The primary outcome was SCr-based stage 2/3 AKI presence at 48- to 72-hours. Results: Twenty-five (12.3%) derivation study patients had stage 2/3 AKI at 48- to 72-hours. uNGAL concentration of 125 ng/ml was the optimal cutoff. Forty-seven (9.1%) validation study patients had stage 2/3 AKI at 48- to 72-hours. The area under the curve of a receiver operator characteristics curve (AUC-ROC) for uNGAL performance was 0.83 (95% confidence interval [CI]: 0.77-0.90). Performance characteristics were sensitivity 72.3% (95% CI: 57.4%-84.4%), specificity 86.3% (95% CI: 82.8%-89.3%), positive predictive value 34.7% (95% CI: 28.5%-41.5%), and negative predictive value 96.9% (95% CI: 95.1%-98.0%). Conclusion: These prospective, pediatric, multicenter studies demonstrate that uNGAL in the first 24-hours performs very well to predict Kidney Disease Improving Global Outcomes (KDIGO) stage 2/3 AKI at 48- to 72-hours into an ICU course. We suggest that a uNGAL cut point of 125 ng/ml can aid in the risk assessment for stage 2/3 AKI persistence or development.

Sensenbrenner syndrome (Cranioectodermal dysplasia): clinical and molecular analyses of 39 patients including two new patients.

Sensenbrenner syndrome, also known as cranioectodermal dysplasia, is a rare multiple anomaly syndrome with distinctive craniofacial appearance, skeletal, ectodermal, connective tissue, renal, and liver anomalies. Dramatic advances with next-generation sequencing have expanded its phenotypic variability and molecular heterogeneity. We review 39 patients including two new patients, one with compound heterozygous novel mutations in WDR35 and a previously unreported multisutural craniosynostosis that may be a part of Sensenbrenner syndrome. In 14 of 25 (56.0%) patients pathogenic mutations have been identified in 4 different genes that regulate (intraflagellar) cilia transport. We compared Sensenbrenner syndrome to asphyxiating thoracic dystrophy-Jeune syndrome (ATD-JS) and other ciliopathies. Our analyses showed that the high anterior hairline, forehead bossing and dolichocephaly (accompanied by sagittal craniosynostosis in more than half of the patients) occur in almost all patients with Sensenbrenner syndrome. Metaphyseal dysplasia with narrow thorax, proximal limb shortness, and short fingers are typical of Sensenbrenner syndrome and ATD-JS. Respiratory complications have been reported in both syndromes, usually less severe with Sensenbrenner syndrome. Proposed diagnostic criteria for Sensenbrenner syndrome include the distinctive craniofacial appearance, ubiquitous brachydactyly and ectodermal anomalies, and sagittal craniosynostosis. Mild heart defects have been noted, but there have been no atrioventricular canal or heterotaxy defects that are common in Ellis-Van Creveld syndrome. We anticipate that the steady identification of molecularly defined patients may allow correlation of phenotype and genotype. Additional natural history data will improve genetic counseling and current guidelines.

A severely immunocompromised child with uncomplicated oseltamivir-resistant 2009 H1N1 pandemic influenza infection.

2009 H1N1 pandemic influenza was associated with increased risk for severe disease in children and the immunosuppressed. We report a case of uncomplicated pneumonia because of infection with oseltamivir-resistant 2009 H1N1 virus in an immunosuppressed pediatric renal transplant patient. Innate immunity and/or altered viral fitness may be responsible for the mild clinical phenotype of the case.

Promoting Emotional Well-Being Through an Innovative Personal and Professional Development Curriculum for Pediatric Residents.

Burnout and attenuation of empathy during training are significant problems facing pediatric residency programs. To proactively address these issues, a curriculum of Personal and Professional Development was created to build skills of reflection and exploring emotions. Data on 3 years of this program suggests that it prevents erosion of empathy.

Clinical significance of incidentally discovered renal cysts in pediatric patients.

PURPOSE: To determine the clinical significance of incidentally discovered renal cysts in pediatric patients and identify imaging predictors of autosomal dominant polycystic kidney disease (ADPKD). METHODS: A retrospective search of radiology reports from 2000 to 2016 was performed to identify patients < 18 years old with an imaging exam identifying at least one renal cyst and a ≥ 1-year follow-up renal imaging exam for cyst evaluation and/or diagnosis of ADPKD. Cysts with clear solid mass components were excluded. RESULTS: 84 pediatric patients with renal cysts were identified (mean age, 9.5 years), including 76 patients with incidentally discovered cysts and 8 patients with cysts identified from screening for ADPKD family history. Among the incidentally discovered cyst group, 7.9% were found to have ADPKD compared with 100% of patients with cysts and ADPKD family history. Maximum cyst diameter was significantly increased in patients with ADPKD compared to patients without ADPKD (22.0 mm vs 12.7 mm; P < 0.001, Fisher's Exact test). Multiple cysts or bilateral cysts were imaging features associated with a significantly higher (P < 0.01) incidence of ADPKD, both for the entire study population and the incidentally discovered cyst group. An increase in cyst size on the follow-up study was associated with higher incidence of ADPKD (P < 0.05). No malignancies were identified. CONCLUSIONS: Incidentally discovered renal cysts in pediatric patients are associated with a small but non-zero risk of ADPKD. Among cyst characteristics, bilaterality, multiplicity, large size, and increased size on follow-up imaging were associated with a statistically significant elevation of ADPKD risk, and should prompt diagnostic evaluation.

Urine proteomic profiling to identify biomarkers of steroid resistance in pediatric nephrotic syndrome.

Long-term prognosis for children with nephrotic syndrome (NS) is directly related to steroid responsiveness. There are currently no diagnostic tests that accurately predict steroid responsiveness in pediatric NS. The initial prolonged course of daily, high-dose corticosteroid therapy thus serves both as a diagnostic and therapeutic maneuver. Urine proteomics is emerging as a potentially rich source of noninvasive biomarkers of drug responsiveness in NS. In this article, we discuss some of the initial studies of the urinary proteome in NS as well as ongoing and future challenges, define the normal urinary proteome and address the overwhelming abundance of urinary albumin and its impact on biomarker discovery.

Outcome of management strategies for BK virus replication in pediatric renal transplant recipients.

Management of BKV infection is not well defined. Eighteen pediatric renal transplant patients with BKV-PCR (+) were divided into three groups; Group 1: Viruria only (6), Group 2: Viremia with stable GFR (4), Group 3: Viremia with >25% decline in GFR and BKVAN on biopsy (8). With initial BKV-PCR(+), Group 1 received no treatment; Group 2 had MMF reduced 30%; Group 3: 6/8 had CNI discontinuation, 2/8 had reduced MMF and cidofovir. BKV, GFR and histology were compared pre- and post-treatment. In Group 1 viruria decreased in all patients; GFR remained stable. Group 2 showed reduced viremia with no GFR change. Group 3 showed reduced viremia in 8/8 patients. Patients with >50% decline in GFR from baseline (6/8) showed worse histology: 2/6 lost grafts despite no BKV on follow-up biopsy. Our results show that with viruria alone no treatment is necessary; with viremia and stable GFR, reduced immunosuppression decreases viremia and maintains GFR. With viremia and reduced GFR, immunosuppression reduction with or without cidofovir decreases viremia and stabilizes GFR in most patients. Greater than 50% reduction in GFR at BKVAN diagnosis correlates with risk for graft loss. Serial monitoring of BKV viremia with early intervention may prevent BKVAN graft loss in children.

The potential for tolerance in pediatric renal transplantation.

PURPOSE OF REVIEW: Immune tolerance has remained the Holy Grail in transplantation since the first kidney transplantation was performed over 50 years ago. Children present unique challenges in renal transplantation because of increased infectious risks and adolescent nonadherence to the intensive medication regimen necessary for allograft function. The current review presents recent studies and approaches toward achieving tolerance in renal transplantation and the prospects for pediatric patients. RECENT FINDINGS: A number of approaches have been used toward minimization of immunosuppression in pediatric patients, but none has yet achieved true operational tolerance with maintenance of allograft function of all immunosuppression. Recent work in adult renal transplant recipients using combined kidney-bone marrow transplantation by the induction of transient mixed chimerism has allowed for full withdrawal of immunosuppression with stable long-term renal function. SUMMARY: On the basis of recent adult studies, the prospect of immune tolerance in pediatric renal transplantation remains hopeful and may be ready for extension to the adolescent population.