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.
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.
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%).
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.
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.
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.
Fecal microbiota transplant (FMT) is an effective treatment for recurrent Clostridioides difficile infection (CDI). Safety concerns around FMT are increased in immunocompromised populations, such as ...solid organ transplant (SOT) recipients. Outcomes among adult SOT recipients suggest FMT is efficacious and safe; however, pediatric SOT data are lacking.
We describe the efficacy and safety of FMT among pediatric SOT recipients in a single-center retrospective study from March 2016 to December 2019. Successful FMT was defined as no recurrence of CDI within 2 mo of FMT. We identified 6 SOT recipients ages 4-18 y who received FMT a median of 5.3 y post-SOT.
Success after a single FMT was 83.3%. One liver recipient did not achieve cure after 3 FMTs and remains on low-dose vancomycin. One serious adverse event (SAE) occurred; cecal perforation and bacterial peritonitis occurred following colonoscopic FMT coordinated with intestinal biopsy in a kidney transplant recipient. He achieved full recovery and CDI cure. There were no other SAEs. There were no adverse events related to immunosuppression or transplantation status including: bacteremia, cytomegalovirus activation or reactivation, allograft rejection, or allograft loss.
In this limited series, efficacy of FMT in pediatric SOT is comparable to efficacy in the general pediatric recurrent CDI population. There may be an increased risk of procedure-related SAE in SOT patients and larger cohort studies are needed.
Background
Growth failure is common among children with chronic kidney disease (CKD). We examined the relationship of growth parameters with glomerular filtration rate (GFR), CKD diagnosis, sex and ...laboratory results in children with CKD.
Methods
Baseline data from 799 children (median age 11.0 years, median GFR 49.9 mL/min/1.73 m
2
) participating in the Chronic Kidney Disease in Children Study were examined. Growth was quantified by age–sex-specific height, weight, body mass index (BMI–age), and height–age–sex-specific BMI (BMI-height-age) standard deviation scores (SDS).
Results
Median height and weight SDS were −0.55 interquartile range (IQR) −1.35 to 0.19 and 0.03 (IQR −0.82 to 0.97), respectively. Girls with non-glomerular CKD were the shortest (median height SDS −0.83; IQR −1.62 to −0.02). Compared to those with a serum bicarbonate (CO
2
) level of ≥22 mEq/L, children with CO
2
of <18 mEq/L had a height SDS that was on average 0.67 lower 95 % confidence interval (CI) −0.31 to −1.03. Only 23 % of children with a height SDS of ≤−1.88 were prescribed growth hormone therapy. Forty-six percent of children with glomerular CKD were overweight or obese (BMI-height-age ≥85th percentile).
Conclusions
Growth outcomes in a contemporary cohort of children with CKD remain suboptimal. Interventions targeting metabolic acidosis and overcoming barriers to recombinant human growth hormone usage may improve growth in this population.
Programmed cell death ligand 1 (PD-L1) expression on tumor cells engages the PD-1 receptor on T cells, inhibiting anti-tumor responses. PD-L1 has been detected in cases of post-transplant ...lymphoproliferative disorder (PTLD) but reports are limited. Here we examine PD-L1 expression and evaluate for clinical correlations.
Twenty-one cases of PTLD were identified among pediatric kidney transplant recipients at our institution from February 1996 to April 2017. Using paraffin-embedded tissue biopsies, we examined 21 primary tumors for expression using PD-L1 monoclonal antibody performed with PAX5 as a double stain. We scored expression of PD-L1 on lesional B-cells as a percentage of positive cells. Clinical course and outcome were obtained from retrospective chart review.
Applying revised 2017 WHO PTLD classification showed five non-destructive, nine polymorphic, and seven monomorphic cases. Average PD-L1 expression based upon PTLD subtype was: non-destructive 11%, polymorphic 43%, and monomorphic 73% (p = .01). Two patients transferred shortly after diagnosis, five received chemotherapy, and three died from PTLD. Among the fatalities, all showed monomorphic PTLD and 90% of lesional B-cells expressed PD-L1.
In this case series, significant differences in PD-L1 expression were seen among different subtypes, and monomorphic PTLD demonstrated the highest expression. Study of a larger cohort is needed, and if the correlation of PD-L1 expression and PTLD subtype is confirmed, this may highlight the potential utility of checkpoint inhibitor therapy in cases of severe or refractory disease among kidney transplant recipient in whom the risk of allograft loss is acceptable given the option of chronic dialysis.
Background
Obesity is prevalent among children with chronic kidney disease (CKD) and is associated with cardiovascular disease and reduced quality of life. Its relationship with pediatric CKD ...progression has not been described.
Methods
We evaluated relationships between both body mass index (BMI) category (normal, overweight, obese) and BMI z-score (BMIz) change on CKD progression among participants of the Chronic Kidney Disease in Children study. Kaplan–Meier survival curves and multivariable parametric failure time models depict the association of baseline BMI category on time to kidney replacement therapy (KRT). Additionally, the annualized percentage change in estimated glomerular filtration rate (eGFR) was modeled against concurrent change in BMIz using multivariable linear regression with generalized estimating equations which allowed for quantification of the effect of BMIz change on annualized eGFR change.
Results
Participants had median age of 10.9 years IQR: 6.5, 14.6, median eGFR of 50 ml/1.73 m
2
IQR: 37, 64 and 63% were male. 160 (27%) of 600 children with non-glomerular and 77 (31%) of 247 children with glomerular CKD progressed to KRT over a median of 5 years IQR: 2, 8. Times to KRT were not significantly associated with baseline BMI category. Children with non-glomerular CKD who were obese experienced significant improvement in eGFR (+ 0.62%; 95% CI: + 0.17%, + 1.08%) for every 0.1 standard deviation concurrent decrease in BMI. In participants with glomerular CKD who were obese, BMIz change was not significantly associated with annualized eGFR change.
Conclusion
Obesity may represent a target of intervention to improve kidney function in children with non-glomerular CKD.
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.
We report two patients with PMM2‐CDG who developed end stage renal disease (ESRD). Renal abnormalities of clinical significance have only been reported in about 6% of patients with PMM2‐CDG and have ...rarely been reported as the cause of death. Given the recurrent episodes of acute kidney injury associated with hospital admissions and the accelerated development of ESRD thereafter in our two patients, we recommend proactively involving Nephrology early in the care of these patients.
Background
Longitudinal changes in body mass index (BMI) among overweight and obese children with chronic kidney disease (CKD) are not well characterized. We studied longitudinal trajectories and ...correlates of these trajectories, as results may identify opportunities to optimize health outcomes.
Methods
Longitudinal changes in age-sex-specific BMI z-scores over 1851 person-years of follow-up were assessed in 524 participants of the Chronic Kidney Disease in Children Study. A total of 353 participants were categorized as normal (BMI > 5th to < 85th percentile), 56 overweight (BMI ≥ 85th to 95th percentile) and 115 obese (BMI ≥ 95th percentile) based on the average of three BMI measurements during the first year of follow-up. Studied covariates included age, sex, race, CKD etiology, corticosteroid usage, household income, and maternal education.
Results
In unadjusted analysis, BMI z-scores decreased over time in elevated BMI groups (overweight: mean = − 0.06 standard deviations (SD) per year, 95% CI: − 0.11, − 0.01; obese: mean = − 0.04 SD per year, 95% CI: − 0.07, − 0.01). Among obese children, only age was associated with change in BMI z-score; children < 6 years had a mean decrease of 0.19 SD during follow-up (95% CI: − 0.30, − 0.09). Socioeconomic factors were not associated with change in BMI.
Conclusion
Overweight and obese children with CKD demonstrated a significant annual decline in BMI, though the absolute change was modest. Among obese children, only age < 6 years was associated with significant decline in BMI. Persistence of elevated BMI in older children and adolescents with CKD underscores the need for early prevention and effective intervention.
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