New insights from the genetic work-up in early onset nephrotic syndrome: report from a registry in western India.

BACKGROUND: Eighty-five percent of infants with congenital nephrotic syndrome (CNS) and 66% with infantile NS (INS) are likely to have a monogenic etiology. There exists a significant genetic variability between different regions and ethnic groups. This study aimed to determine the genetic defects in children with CNS and INS by establishing a registry in western India. METHODS: In this cross-sectional study, pediatric nephrologists from 13 private and government institutions shared relevant clinical data and details of the genetic evaluation of children presenting with NS within the first year of life. RESULTS: The median age at presentation was 9 months (range 1-23, IQR 3-13 months), history of consanguinity between parents existed in 14 patients (34%), family history of similar illness in 6 (15%), and extra-renal manifestations in 17 (41%). Twenty-five (61%) were confirmed to have a monogenic etiology. NPHS1 gene was the most implicated (9/25) followed by PLCE1 (5/25). There were 12 variants of uncertain significance (VUS) involving 10 genes (10/25, 40%), and no definite genetic abnormality was found in 4 (25%). A re-analysis of these VUS attempted 2-3 years later facilitated reclassification of 7/12 (58%); increasing the diagnostic yield from 61 to 68.2%. CONCLUSIONS: Consistent with worldwide data, variants in NPHS1 gene were the most common cause of NS in infancy; however, PLCE1 was implicated more frequently in our cohort. NUP93 and COL4A3 were reported in early onset NS for the first time. Reclassification of VUS should be attempted, if feasible, since it may lead to a useful revision of diagnosis.

Survival of Tunneled Double Lumen-Cuffed Catheters in Children on Maintenance Hemodialysis - A Retrospective Cohort Study.

Introduction: Survival of tunneled cuffed catheters (TCC), used widely in children, is complicated by infections and catheter dysfunction. In resource limited settings, where risk of complications could be higher and waiting period for transplantation longer, catheter survival determines patient survival. This study was conducted to determine infection free catheter survival rates, incidence of catheter failure and associated risk factors. Methods: Children <18 years of age receiving maintenance hemodialysis through TCC at nephrology division of a pediatric hospital, over a period of 6 years. Data was collected with consecutive selection by a complete enumeration technique from pre-collected data sheets in the records. Exposure detected were catheter infections, thrombosis, and mechanical complications. Results: Forty-five TCCs in 36 children studied for 12,590 catheter days showed catheter failure in 36%, due to catheter related infections in 75% and mechanical complications in 25%. The incidence of complications per 1000 catheter days was 1.19 infection, 1.03 thrombus, and 0.39 mechanical. Catheter-related blood stream infection (CRBSI) (15/36) was associated with thrombus in nine and led to mortality in three. The mean infection free catheter survival was 449 ± 42 days for cohort with 388 ± 38 days in Group A (premature catheter removal) and 593 ± 43 days in Group B (elective removal) (P = 0.03). Catheterization duration of 267 days predicted CRBSI (sensitivity 93%, specificity 66.7%) with area under the curve of 0.808. Conclusions: Median infection free catheter survival was 449 days with catheter failure in 36%. CRBSI was the main cause of failure. Duration of catheterization greater than 267 days was a predictor of CRBSI.

Clinical features and outcomes of patients with diacylglycerol kinase epsilon nephropathy: a nationwide experience.

BACKGROUND: Thrombotic microangiopathy (TMA) is usually caused due to dysregulation of the alternative complement pathway. Rarely, thrombotic microangiopathy is caused by non-complement mediated mutations in diacylglycerol kinase epsilon (DGKE); information about therapy and outcome of these patients is limited. METHODS: Medical records of patients, younger than 18 years, diagnosed with TMA and variants in DGKE were reviewed to include 12 patients from seven centers. Genetic studies included targeted exome sequencing and multiplex-ligation dependent probe amplification of CFH-CFHR5. RESULTS: Patients presented at a median age of 11 (7.5, 12.3) months; all were younger than 2 years. All patients had an infectious prodrome; enteroinvasive, enteropathogenic, and enterotoxigenic Escherichia coli were detected in two patients with diarrhea. Chief features included those of microangiopathic hemolysis (n = 11), microscopic hematuria (n = 10), nephrotic range proteinuria (n = 10), hypoalbuminemia (n = 6), elevated total cholesterol (n = 6), and hypocomplementemia (n = 4). Histopathology showed thrombotic microangiopathy (n = 4), overlapping with membranoproliferative pattern of injury (n = 1). At median 3.3 years of follow-up, significant hypertension and/or proteinuria (40%), relapses (66.7%), and death or progression to CKD (60%) were common. Genetic sequencing showed 13 homozygous and compound heterozygous variants (7 pathogenic, 3 likely pathogenic) located throughout DGKE; 11 variants were novel. CONCLUSIONS: This case series highlights the need to suspect DGKE nephropathy in young patients with TMA, especially those with severe proteinuria. Medium-term outcomes are unsatisfactory with risk of relapses, progressive kidney failure, and death. A higher resolution version of the Graphical abstract is available as Supplementary information.

Intestinal Pseudo-Obstruction - An Under-Recognized Presentation of Systemic Lupus Erythematosus.

Intestinal pseudo-obstruction (IPO), characterized by obstruction without an identifiable anatomic cause, is a rare and poorly understood entity that may occur as a primary condition or secondary to other autoimmune disorders such as systemic lupus erythematosus (SLE). A12-year-old female child was brought with abdominal distension, vomiting, and fever for 15 days. Examination showed height and weight less than the third centile for age, tachypnea, tachycardia, and hypertension with severe abdominal distension, copious bilious aspirate, and very sluggish bowel sounds. Abdominal X-ray showed multiple air fluid levels. Ultrasound abdomen and unenhanced computed tomography (CT) scan revealed thickened dilated bowel loops, ascites, and pleural effusion. In view of multisystem nature of the disease, Koch's abdomen or autoimmune disease was suspected and emergency laparotomy procedure was deferred. She was evaluated and diagnosed to have SLE with lupus nephritis class V as per the International Society of Nephrology/Royal Pathology Society. She was managed conservatively with nasogastric decompression, immunosuppressive therapy and supportive hemodialysis.

Role of Cinacalcet in Treating Cardiac Dysfunction Secondary to Hyperparathyroidism: A Case Series.

Cardiovascular disease is a leading cause of death in children with chronic kidney disease (CKD). A strong correlation exists between disturbed calcium-phosphate metabolism and cardiac dysfunction. Studies with use of cinacalcet in CKD are few and limited to older children and adults and in improving growth and bone deformities. We present three children with CKD on CAPD with cardiac dysfunction with refractory hyperparathyroidism. Patients were initiated on lowest adult weight-adjusted dose of 0.2 mg/kg/day. Dose was titrated every 30 days to achieve decline in iPTH to a goal of 200- 300 pg/ml. Serum calcium, phosphorus and iPTH levels were checked monthly. Complications of therapy related to cinacalcet monitored. Monthly echocardiography done to monitor cardiac dysfunction. None of them experienced significant adverse effects of cinacalcet therapy.

Clinico-pathological Profile and Outcome of C-3 Glomerulopathy in Indian Children.

INTRODUCTION: There is paucity of data of C3 glomerulopathy in Indian children. METHODS: First Indian pediatric case series where consecutive renal biopsies done over a period of ten years were reviewed to identify those patients who had isolated or predominant C3 deposits on immunofluorescent microscopy, fulfilling the criteria for C-3 glomerulopathy. The clinical, biochemical, serological, histopathological profile, eGFR and the need for renal replacement therapy was analyzed. RESULTS: Eighteen patients, comprising 5.3% (18/298) of all renal biopsies, had C3 glomerulopathy, four with Dense Deposit Disease (DDD) and fourteen with C3 Glomerulonephritis (C3GN) with a median follow-up of 38.2 months. Median age of presentation was 7.45±3.03 years (2.5yrs- 13.5yrs) with nine boys and nine girls. Presentation was nephrotic syndrome in seven (39%), acute nephritic syndrome in three (16.7%), hematuria in five (27.7%) and acute kidney injury in three (16.7%). Median eGFR was 69 ml/min/1.73m2 (8.2-107 ml/min/1.73m2). Hematuria was seen in 16 (88%), proteinuria in 18 (100%) and low C3 in 16 (88%) at the time of presentation. Mesangioproliferative glomerulonephritis was the predominant pattern in DDD while C3GN showed a mix of mesangioproliferative, membranoproliferative, endocapillary and crescentic GN (p = 0.43).Complete or partial remission was seen in seven patients who received long term alternate day steroids alone or with added mycophenolate mofetil. The cumulative patient survival was 70.8%. Kaplan Meir analyses for renal survival without progression to ESRD was 60.2% at one year and 48.1% at five and ten years. CONCLUSION: Interstitial fibrosis and tubular atrophy on renal biopsy was an independent predictor of adverse renal outcome in the cohort (p = 0.013, HR8.1;95% CI -1.6-42).

Methicillin resistant Staphylococcus aureus meningitis.

Methicillin resistant Staphylococcus aureus (MRSA) meningitis is rarely known to occur in children. We report an 11-year-old girl with fever, headache and vomiting, right hemiparesis with left-sided upper motor neuron facial nerve palsy and bladder incontinence. On investigation, she was found to have MRSA meningitis with an acute left thalamo-corpuscular infarct. She was treated with vancomycin, linezolid and rifampicin. She recovered successfully with residual right-sided lower limb monoparesis. MRSA meningitis is rare but can occur in children.

Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children.

Antibodies to complement factor H are an uncommon cause of hemolytic uremic syndrome (HUS). Information on clinical features and outcomes in children is limited. In order to explore this we studied a multicenter cohort of 138 Indian children with anti-complement factor H antibody associated HUS, constituting 56% of patients with HUS. Antibody titers were high (mean 7054 AU/ml) and correlated inversely with levels of complement C3, but not complement factor H. Homozygous deletion of the CFHR1 gene was found in 60 of 68 patients. Therapies included dialysis in 119 children, 105 receiving plasma exchanges and 26 intravenous immunoglobulin. Induction immunosuppression consisted of 87 children receiving prednisolone with or without intravenous cyclophosphamide or rituximab. Antibody titers fell significantly following plasma exchanges and increased during relapses. Adverse outcome (stage 4-5 CKD or death) was seen in 36 at 3 months and 41 by last follow up, with relapse in 14 of 122 available children. Significant independent risk factors for adverse outcome were an antibody titer over 8000 AU/ml, low C3 and delay in plasma exchange. Combined plasma exchanges and induction immunosuppression resulted in significantly improved renal survival: one adverse outcome prevented for every 2.6 patients treated. Maintenance immunosuppressive therapy, of prednisolone with either mycophenolate mofetil or azathioprine, significantly reduced the risk of relapses. Thus, prompt use of immunosuppressive agents and plasma exchanges are useful for improving outcomes in pediatric patients with anti-complement factor H-associated HUS.

Smith-Lemli-Opitz-syndrome.

Smith-Lemli-Opitz syndrome is an autosomal recessively inherited disorder. A severe defect in cholesterol biosynthesis has been identified leading to abnormally low plasma cholesterol levels and elevated levels of the cholesterol precursor 7-dehydrocholesterol, the result of deficiency of 7-dehydrocholesterol reductase. We describe one such child with Smith-Lemli-Opitz syndrome. This child had clinical features similar to Smith-Lemli-Opitz syndrome like facial dysmorphism and cardiac and renal anomalies with failure to thrive.