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.
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.
Equity factors in pediatric transplant listing.
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.
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.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
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.
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.
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.
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.
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 (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.
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.
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.
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.
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