Shashi Nagaraj

Management of Childhood Onset Nephrotic Syndrome

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Childrens Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a childrens primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

Efficacy, Safety, and Pharmacokinetics of Candesartan Cilexetil in Hypertensive Children Aged 6 to 17 Years

This 4‐week randomized, double blind, placebo‐controlled study (N=240), 1‐year open label trial (N=233), and single‐dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy‐one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8–11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P<.01 compared to placebo for SBP and for the mid and high doses for DBP; placebo‐corrected 4.9/3.0–7.5/6.2 mm Hg). The slopes for dose were not, however, different from zero (P>.05). The response rate (SBP and DBP <95th percentile) after 1 year was 53%. The pharmacokinetic profiles in 6‐ to 12‐ and 12‐ to 17‐year‐olds were similar and were comparable to adults. Eight candesartan patients discontinued treatment because of an adverse event. Candesartan is an effective, well‐tolerated antihypertensive agent for children aged 6 to 17 years and has a pharmacokinetic profile that is similar to that in adults.

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

Efficacy of Antibiotic Prophylaxis in Children with Vesicoureteral Reflux: Systematic Review and Meta-Analysis

PURPOSE Controversy exists regarding the use of continuous antibiotic prophylaxis vs observation in the management of children with vesicoureteral reflux. The reported effectiveness of continuous antibiotic prophylaxis in children with reflux varies widely. We determined whether the aggregated evidence supports use of continuous antibiotic prophylaxis in children with vesicoureteral reflux. MATERIALS AND METHODS We searched the Cochrane Controlled Trials Register, clinicaltrials.gov, MEDLINE(®), EMBASE(®), Google Scholar and recently presented meeting abstracts for reports in any language. Bibliographies of included studies were then hand searched for any missed articles. The study protocol was prospectively registered at PROSPERO (No. CRD42014009639). Reports were assessed and data abstracted in duplicate, with differences resolved by consensus. Risk of bias was assessed using standardized instruments. RESULTS We identified 1,547 studies, of which 8 are included in the meta-analysis. Pooled results demonstrated that continuous antibiotic prophylaxis significantly reduced the risk of recurrent febrile or symptomatic urinary tract infection (pooled OR 0.63, 95% CI 0.42-0.96) but, if urinary tract infection occurred, increased the risk of antibiotic resistant organism (pooled OR 8.75, 95% CI 3.52-21.73). A decrease in new renal scarring was not associated with continuous antibiotic prophylaxis use. Adverse events were similar between the 2 groups. Significant heterogeneity existed between studies (I(2) 50%, p = 0.03), specifically between those trials with significant risk of bias (eg unclear protocol descriptions and/or lack of blinding). CONCLUSIONS Compared to no treatment, continuous antibiotic prophylaxis significantly reduced the risk of febrile and symptomatic urinary tract infections in children with vesicoureteral reflux, although it increased the risk of infection due to antibiotic resistant bacteria. Continuous antibiotic prophylaxis did not significantly impact the occurrence of new renal scarring or reported adverse events.

Water intoxication in a patient with the Prader-Willi syndrome treated with desmopressin for nocturnal enuresis.

PURPOSE We report on a girl with the Prader-Willi syndrome who received desmopressin for nocturnal enuresis, and water intoxication developed after she ingested a large amount of fluid. MATERIALS AND METHODS The patient received 10 mg. desmopressin at bedtime for enuresis. She was hospitalized when a major motor seizure and coma (Glasgow coma scale 8) occurred after ingesting 48 ounces of fluid. Treatment included 3% saline, followed by 5% dextrose in water and sodium chloride given intravenously. RESULTS Serum sodium increased to 128 mEq./l. and serum glucose remained normal. Computerized tomography and magnetic resonance imaging of the head were normal and revealed no evidence of cerebral pontine myelinosis. Patient consciousness returned to normal by day 5 after the seizure. CONCLUSIONS In patients treated with desmopressin the risk of a seizure or altered level of consciousness can be minimized by not ingesting large quantities of fluid. We recommend that patients drink no more than 8 ounces of fluid on any evening that desmopressin is administered.

Potential donor-recipient MYH9 genotype interactions in posttransplant nephrotic syndrome after pediatric kidney transplantation.

Recurrence of focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome is relatively common after kidney transplantation in young recipients whose predialysis course consists of heavy proteinuria, hypertension and subacute loss of kidney function. The gene(s) mediating this effect remain unknown. We report an unusual circumstance where kidneys recovered from a deceased African American male donor with MYH9‐related occult FSGS (risk variants in seven of eight MYH9 E1 haplotype single nucleotide polymorphisms) were transplanted into an African American male child with risk variants in four MYH9 E1 risk variants and a European American female teenager with two MYH9 E1 risk variants. Fulminant nephrotic syndrome rapidly developed in the African American recipient, whereas the European American had an uneventful posttransplant course. The kidney donor lacked significant proteinuria at the time of organ procurement. This scenario suggests that donor–recipient interactions in MYH9, as well as other gene–gene and gene–environment interactions, may lead to recurrent nephrotic syndrome after renal transplantation. The impact of transplanting kidneys from donors with multiple MYH9 risk alleles into recipients with similar genetic background at high risk for recurrent kidney disease needs to be determined.

Hyperimmune human IgG or recombinant human granulocyte-macrophage colony-stimulating factor as adjunctive therapy for group B streptococcal sepsis in newborn rats***

Group B streptococcus (GBS) continues to cause considerable morbidity and death in newborn infants despite the use of antibiotics. We investigated the use of adjunctive therapies to be used with antibiotics in the treatment of neonatal sepsis, using a neonatal rat model of established GBS disease. After the development of GBS bacteremia, a human IgG preparation hyperimmune for GBS, administered with penicillin, decreased the mortality rate compared with the use of penicillin alone (14% vs 57%; p = 0.02). Similarly, recombinant human granulocyte-macrophage colony-stimulating factor, administered in a range of doses to animals with bacteremia, decreased mortality rates. The greatest effect was noted at a dose of 0.05 micrograms/kg (mortality rate 39% in combination with penicillin vs 76% for penicillin alone; p < 0.0001). Thus adjunctive therapies such as those studied here may have the potential to improve the outcome of neonatal sepsis.

Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation

Background Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroid-resistant nephrotic syndrome (SRNS). The disease is characterized by early-onset proteinuria, resistance to immunosuppressive therapy and rapid progression to end-stage renal disease. Compound heterozygous changes involving the podocin variant R229Q combined with another pathogenic mutation have been associated with a mild phenotype with disease onset often in adulthood. Methods We screened 19 families with early-onset SRNS for mutations in NPHS2 and WT1 and identified four disease-causing mutations (three in NPHS2 and one in WT1) prior to planned whole-exome sequencing. Results We describe two families with three individuals presenting in childhood who are compound heterozygous for R229Q and one other pathogenic NPHS2 mutation, either L327F or A297V. One child presented at age 4 years (A297V plus R229Q) and the other two at age 13 (L327F plus R229Q), one with steadily deteriorating renal function. Conclusions These cases highlight the phenotypic variability associated with the NPHS2 R229Q variant plus pathogenic mutation. Individuals may present with early aggressive disease.

Pediatric biopsy of a single native kidney.

Abstract Technological improvements have reduced the frequency of complications in children receiving a percutaneous renal biopsy. No study has systematically compared the safety of open and percutaneous kidney biopsy. Yet many nephrologists consider a single native kidney an absolute contraindication to percutaneous biopsy. We have established an international registry of single native kidney biopsies in children and we now report our early results. Eight biopsies are included. Seven patients had percutaneous biopsies and one an open biopsy. None of the patients had major complications, and adequate tissue was obtained from all. Our limited experience indicates that the presence of a single native kidney is not an absolute indication for an open approach. We encourage our colleagues to report to the international registry in order to further document the safety of percutaneous biopsy of the single native kidney in children.

Recurrence of nephrotic syndrome following kidney transplantation is associated with initial native kidney biopsy findings

Background and objectivesSteroid-resistant nephrotic syndrome (SRNS) due to focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is a leading cause of end-stage kidney disease in children. Recurrence of primary disease following transplantation is a major cause of allograft loss. The clinical determinants of disease recurrence are not completely known. Our objectives were to determine risk factors for recurrence of FSGS/MCD following kidney transplantation and factors that predict response to immunosuppression following recurrence.MethodsMulticenter study of pediatric patients with kidney transplants performed for ESKD due to SRNS between 1/2006 and 12/2015. Demographics, clinical course, and biopsy data were collected. Patients with primary-SRNS (PSRNS) were defined as those initially resistant to corticosteroid therapy at diagnosis, and patients with late-SRNS (LSRNS) as those initially responsive to steroids who subsequently developed steroid resistance. We performed logistic regression to determine risk factors associated with nephrotic syndrome (NS) recurrence.ResultsWe analyzed 158 patients; 64 (41%) had recurrence of NS in their renal allograft. Disease recurrence occurred in 78% of patients with LSRNS compared to 39% of those with PSRNS. Patients with MCD on initial native kidney biopsy had a 76% recurrence rate compared with a 40% recurrence rate in those with FSGS. Multivariable analysis showed that MCD histology (OR; 95% CI 5.6; 1.3–23.7) compared to FSGS predicted disease recurrence.ConclusionsPediatric patients with MCD and LSRNS are at higher risk of disease recurrence following kidney transplantation. These findings may be useful for designing studies to test strategies for preventing recurrence.