Lethal neonatal respiratory failure due to biallelic variants in BBS1 and monoallelic variant in TTC21B.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive ciliopathy characterized by early onset retinal dystrophy, renal anomalies, postaxial polydactyly, and cognitive impairment with considerable phenotypic heterogeneity. BBS results from biallelic pathogenic variants in over 20 genes that encode key proteins required for the assembly or primary ciliary functions of the BBSome, a heterooctameric protein complex critical for homeostasis of primary cilia. While variants in BBS1 are most frequently identified in affected individuals, the renal and pulmonary phenotypes associated with BBS1 variants are reportedly less severe than those seen in affected individuals with pathogenic variants in the other BBS-associated genes. CASE-DIAGNOSIS: We report an infant with severe renal dysplasia and lethal pulmonary hypoplasia who was homozygous for the most common BBS1 pathogenic variant (c.1169 T > G; p.M390R) and also carried a predicted pathogenic variant in TTC21B (c.1846C > T; p.R616C), a genetic modifier of disease severity of ciliopathies associated with renal dysplasia and pulmonary hypoplasia. CONCLUSIONS: This report expands the phenotypic spectrum of BBS with the first infant with lethal neonatal respiratory failure associated with biallelic, pathogenic variants in BBS1 and a monoallelic, predicted pathogenic variant in TTC21B. BBS should be considered among the ciliopathies in the differential diagnosis of neonates with renal dysplasia and severe respiratory failure.

Characteristics, risk factors, and outcomes of neutropenia after liver or kidney transplantation in children.

BACKGROUND: While prior adult studies have shown that approximately 20%-38% of subjects undergoing solid-organ transplant develop neutropenia, similar analyses in pediatric subjects are scarce. METHODS: We conducted a retrospective chart review of liver transplant (LT) and kidney transplant (KT) recipients at our center during the period 2008-2018. All of the KT and none of the LT subjects during this time period had induction with either anti-thymocyte globulin (ATG) or basiliximab at time of transplant. Neutropenia was defined as absolute neutrophil count (ANC) value ≤1000/mm3 . RESULTS: One hundred subjects with LT and 82 subjects with KT were included. The incidence of neutropenia within the first year of transplant in KT was higher compared to LT (54.8% vs 39%, p = .01). The median number of hospitalizations (p = .001) and infectious complications (p = .04) was significantly higher only in the KT subjects who developed neutropenia (compared to those who did not). Multivariate analysis identified factors associated with severity of liver disease at transplant, namely h/o upper gastrointestinal bleeding (p = .02), weight deficit (p = .01), and pre-LT ANC (p = .01), along with high or moderate risk cytomegalovirus status (p = .05) as predictors of neutropenia in LT subjects. Female gender (p = .03) predicted neutropenia, while BK virus infection was protective for neutropenia (p = .04) in KT subjects. CONCLUSIONS: The incidence of and morbidity associated with neutropenia within 1 year post-transplant is higher in KT subjects compared to LT subjects. The likely reason for this is the use of induction therapy (ATG, basiliximab) at the time of transplant in KT subjects.

Performance of the various serum creatinine-based GFR estimating equations in pediatric kidney transplant recipients, stratified by age and CKD staging.

BACKGROUND: Numerous equations are used to estimate glomerular filtration rate (eGFR), based on serum creatinine (SCr), demographic and anthropometric data, none established in pediatric kidney transplant recipients. This study aimed to validate the available SCr-based eGFR equations in comparison with a measured (mGFR), stratified by chronic kidney disease (CKD) stage and age at the time of testing. METHODS: One hundred twenty-seven pediatric kidney transplant recipients with 411 mGFR values (plasma clearance of iothalamate) were enrolled in this retrospective study. The bias, precision, and accuracy (percentage of estimates within 10% and 30% of mGFR) of five SCr eGFR equations (original Schwartz, CKiDSCr equation, Pottel, Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) were assessed. RESULTS: Height-independent Pottel equation performed well across all the categories of age and CKD staging. CKiDSCr equation performed well in CKD stages II-V. The CKiDSCr equation had a lower bias in children < 15 years of age, while MDRD and CKD-EPI equations had less bias in children > 15 years. Overall, both the Pottel and CKiDSCr equations had high accuracy (80%) and low bias (< 5 ml/min/1.73 m2). In contrast, the original Schwartz, MDRD, and CKD-EPI equations displayed high bias and low precision/accuracy. CONCLUSIONS: Given their low bias and high accuracy across ages and CKD stages, the Pottel or the CKiDSCr equation is better to assess eGFR in pediatric kidney transplant recipients. The Pottel equation outperformed other eGFR equations in adolescents.

Late first acute rejection in pediatric kidney transplantation: A North American Pediatric Renal Trials and Collaborative Studies special study.

Rates of early AR in pediatric kidney transplantation have declined in every era but the most recent NAPRTCS cohort has shown an increase in late first AR rates. We hypothesized this was due to an increased proportion of deceased donor utilization and early steroid taper utilization. Using the NAPRTCS database, we compared the most recent three cohorts of patients transplanted between 2002-2006, 2007-2011, and 2012-2017. To determine variables that predict late first AR, we used two multivariable models: a standard Cox regression model and LASSO model. From the LASSO model, deceased donor source (P = .002), higher recipient age (P = .019), black race (P = .010), and transplant cohort 2012-17 (P = .014) were all significant predictors of more late first AR. On standard Cox regression analysis, those same variables, minus donor source, were significant, in addition to mycophenolates usage (P = .007) and lower eGFR at 12 months (P = .02). The most recent 2012-2017 cohort remains an independently significant risk factor for late first AR, suggesting unmeasured variables. Further research is needed to determine whether these higher late first AR rates will impact long-term graft survival in the most recent cohort.

The light at the end of the tunnel: an unusual case of acute kidney injury in a pediatric patient: Answers.

Monoclonal gammopathies are a rare diagnosis in pediatric patients. A 19-year-old female patient with past medical history of hypogammaglobulinemia and natural killer cell deficiency and stage III follicular lymphoma, in remission, presented with a right-sided pneumonia, noted to have acute kidney injury and proteinuria. Complement C3 and C4 levels were normal. Anti-double-stranded DNA antibodies, antinuclear antibodies, anti-extractable nuclear antigen antibodies, and antineutrophil cytoplasmic antibodies were negative. A renal biopsy showed numerous fractured tubular casts that were periodic acid-Schiff and silver-stain negative and fuchsinophilic on trichrome stain, with associated giant cells, tubulitis, acute tubular injury, and tubular rupture. The tubular casts had 3+ staining for lambda light chains and 0-1+ staining for kappa light chains. These findings were consistent with light chain cast nephropathy (LCCN). Serum free light chains, serum immunofixation, urine protein electrophoresis, and urine immunofixation studies supported the renal biopsy diagnosis of LCCN. A bone marrow biopsy showed normal trilineage hematopoiesis and also revealed an atypical B cell population detected by flow cytometry. Pathology specimens from lesions in the distal small bowel were characteristic of diffuse large B cell lymphoma (DLBCL). Chemoreduction therapy followed by chemotherapy was initiated for the DLBCL. Three months after initiation of chemotherapy, the patient's creatinine has improved by > 50%. The likely cause of her LCCN was the new diagnosis of a DLBCL. Other risk factors include her history of hypogammaglobulinemia, natural killer (NK) cell deficiency, community-acquired pneumonia, and prior follicular lymphoma. Our patient may be the youngest reported case of LCCN. Treatment of LCCN is based on treating the underlying clonal plasma cell or B cell proliferation, typically with chemotherapy.

Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations.

Signaling by the glial cell line-derived neurotrophic factor (GDNF)-RET receptor tyrosine kinase and SPRY1, a RET repressor, is essential for early urinary tract development. Individual or a combination of GDNF, RET and SPRY1 mutant alleles in mice cause renal malformations reminiscent of congenital anomalies of the kidney or urinary tract (CAKUT) in humans and distinct from renal agenesis phenotype in complete GDNF or RET-null mice. We sequenced GDNF, SPRY1 and RET in 122 unrelated living CAKUT patients to discover deleterious mutations that cause CAKUT. Novel or rare deleterious mutations in GDNF or RET were found in six unrelated patients. A family with duplicated collecting system had a novel mutation, RET-R831Q, which showed markedly decreased GDNF-dependent MAPK activity. Two patients with RET-G691S polymorphism harbored additional rare non-synonymous variants GDNF-R93W and RET-R982C. The patient with double RET-G691S/R982C genotype had multiple defects including renal dysplasia, megaureters and cryptorchidism. Presence of both mutations was necessary to affect RET activity. Targeted whole-exome and next-generation sequencing revealed a novel deleterious mutation G443D in GFRα1, the co-receptor for RET, in this patient. Pedigree analysis indicated that the GFRα1 mutation was inherited from the unaffected mother and the RET mutations from the unaffected father. Our studies indicate that 5% of living CAKUT patients harbor deleterious rare variants or novel mutations in GDNF-GFRα1-RET pathway. We provide evidence for the coexistence of deleterious rare and common variants in genes in the same pathway as a cause of CAKUT and discovered novel phenotypes associated with the RET pathway.

Amino acid clearance during acute metabolic decompensation in maple syrup urine disease treated with continuous venovenous hemodialysis with filtration.

OBJECTIVE: Assessment of amino acid clearances by continuous venovenous hemodialysis with filtration in treatment of a metabolic decompensation in acute maple syrup urine disease. DESIGN: Single patient assessment. SETTING: Pediatric intensive care unit. PATIENTS: A 10-yr-old male with known maple syrup urine disease (branched chain alpha-ketoacid dehydrogenase deficiency) with metabolic decompensation due to an acute viral illness, characterized by altered mental status, progressive obtundation, and severe acidosis. INTERVENTIONS: Continuous venovenous hemodialysis with filtration. MEASUREMENTS AND MAIN RESULTS: Continuous venovenous hemodialysis with filtration was instituted with both filtration (500 mL/m(2)/hr) and dialysis (1000 mL/m(2)/hr) utilized, allowing rapid correction of systemic ketoacidosis while providing amino acid clearance. Amino acid clearance was measured at initiation and at 24 hrs into therapy. The procedure was well tolerated, with near normal mental status within 12 hrs and resumption of enteral feedings. During the 24-hr period of continuous venovenous hemodialysis with filtration, serum leucine levels fell from 2352 to 381 micromoles/L, isoleucine fell from 626 to 164, and valine fell from 1117 to 228. Leucine, isoleucine, and valine clearance rates averaged 13.1, 12.8, and 13.2 mL/min, respectively, and were constant during the 24 hrs of treatment. Clearance of other amino acids during this period did not vary significantly between cationic, anionic, neutral, or hydrophobic amino acids. CONCLUSIONS: Continuous venovenous hemodialysis with filtration provides an effective therapeutic alternative to intermittent hemodialysis during acute metabolic decompensation in maple syrup urine disease.