Genetic Studies in Infants with Congenital Nephrotic Syndrome: A Case Series.

Information on the genetic profile of congenital nephrotic syndrome (CNS) from India is scarce. The management of CNS is largely supportive of the setting of developing countries, mainly via the administration of intravenous albumin infusions, angiotensin-converting enzyme inhibitors, and levothyroxine. Inadequate infrastructure and management facilities, including genetic analyses, further hamper the outcome. These infants may progress to end-stage renal disease, and mortality is high in infancy. Here, we report a case series of four infants (aged 14-60 days) with CNS from our center with genetic mutations (including mutations in the NPHS1 and LAMB2 genes) that were not described in previous reports from India. Although responsiveness to enalapril has been documented in anecdotal reports of NPHS1 mutations, our case series of four infants did not exhibit any response to enalapril. Our case series adds to the existing literature regarding the genetic profile of CNS in India.

An Unusual Presentation of Hemorrhagic Disease in an Infant: A Probable Case of Abetalipoproteinemia.

We report a probable case of abetalipoproteinemia in an infant who presented with unusual symptoms of late-onset vitamin K deficiency. Abetalipoproteinemia is a rare autosomal recessive disease caused by mutation of the microsomal triglyceride transfer protein gene, resulting in the absence of microsomal triglyceride transfer protein function in the small bowel. It is characterized by the absence of plasma apolipoprotein B-containing lipoproteins, fat malabsorption, hypocholesterolemia, retinitis pigmentosa, progressive neuropathy, myopathy, and acanthocytosis. A biopsy of the small intestine characteristically shows marked lipid accumulation in the villi of enterocytes. Large supplements of fat-soluble vitamins A, D, E, and K have been shown to limit neurologic and ocular manifestations. Dietary fat intake is limited to medium-chain triglycerides.

Diagnostic Accuracy of Point-of-care Nitrite and Leukocyte Esterase Dipstick Test for the Screening of Pediatric Urinary Tract Infections.

Our study aimed to evaluate the diagnostic performance of point-of-care nitrite and leukocyte esterase (LE) dipsticks in the diagnosis of suspected urinary tract infection (UTI) in infants <6 months (young infants) versus older children. The secondary objectives were to study the dipstick efficacy in children with congenital anomalies of the kidney and urinary tract (CAKUT) versus those without CAKUT; in children with simple UTI versus complicated UTI; and to evaluate the clinico-microbiological profile of children presenting with UTI. In this prospective observational study, cases with suspected UTI were enrolled from pediatric emergency or outpatient departments. Urine was collected for performing the urine dipstick and culture. Descriptive data regarding CAKUT, age, gender, etc., were recorded in a predesigned pro forma. We screened 506 children with suspected UTI, of whom 221 had urine culture positive. Approximately 38.4% of the children with UTI had underlying CAKUT, while 7.6% had renal scars. The most common CAKUT was vesicoureteric reflux (VUR). About 12 patients (2.3%) were known to have CAKUT at the time of enrollment in the study. In infants <6 months, LE dipstick had sensitivity 92%, specificity 89.7%, positive predictive value (PPV) 86.7%, negative predictive value (NPV) 93.8%, likelihood ratio (LR) + 8.9, LR- 0.09. In infants <6 months, nitrite dipstick had sensitivity 38%, specificity 97%, PPV 90.4%, NPV 68%, LR+ 12.6 and LR-0.63. In the age group 6 months to 12 years, the efficacy was better for both dipsticks. In age group more than 6 months to 12 years, LE dipstick had sensitivity 96.4%, specificity 95.8%, PPV 94.8 %, NPV 97.2%, LR+ 22.9, LR- 0.04. In age group more than six months to 12 years, nitrite dipstick had sensitivity 94.7%, specificity 99.5%, PPV 99.3%, NPV 96%, LR+ 189.4, and LR-0.05.

Metabolic and Clinical Characteristics of Children with Urolithiasis from Southern India.

OBJECTIVE: To study the etiological profile and patterns of clinical presentations of urolithiasis (UL) in children. METHODS: This observational study included patients <18 y with UL, who were referred to the pediatric nephrology clinic. Clinical features, family history, consanguinity and estimated glomerular filtration rate (eGFR) at presentation and follow-up were recorded. The children were evaluated using relevant blood and urine investigations. RESULTS: A total of 72 children with UL were evaluated for the study. The etiology of UL (n = 72) included hyperoxaluria (n = 25; 34.7%), idiopathic hypercalciuria (n = 21; 29.2%), idiopathic hyperuricosuria (n = 3; 4.2%), cystinuria (n = 3; 4.2%), urate transporter defect (n = 2; 2.8%) and mixed stones (predominant component calcium oxalate) (n = 9; 12.5%). No etiology was detected in 4 cases (5.5%). Common presenting complaints included flank pain (n = 41; 56.7%), hematuria (n = 29; 40.3%), urinary tract infection (UTI) (n = 29; 40.3%) and vomiting (n = 11; 15.3%). The median age of presentation was 60 (36, 96) mo. Family history and consanguinity were present in 30 cases (41.7%) and 28 cases (38.9%) respectively. Stone analysis was done in 20 cases, of which 9 cases were mixed stones (predominant calcium oxalate) and 6 were calcium oxalate stones. CONCLUSIONS: Among children with urolithiasis, hyperoxaluria, idiopathic hypercalciuria, idiopathic hyperuricosuria, and cystinuria were the predominant identifiable entities, together accounting for 72% of cases; and renal colic, hematuria and UTI were the commonest clinical complaints.

Screening for Renal and Urinary Tract Anomalies in Asymptomatic First Degree Relatives of Children with Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).

OBJECTIVE: To estimate the frequency of renal and urinary tract anomalies in first-degree relatives of children with Congenital anomalies of kidney and urinary tract (CAKUT). METHODS: This descriptive study was conducted on parents and siblings of 138 children with CAKUT. Renal ultrasonogram, radionuclide diuretic renogram and micturating cysturethrogram were the tools used for screening these family members. RESULTS: Asymptomatic first-degree relatives of 138 children [total of 270 first-degree relatives (95 fathers, 97 mothers and 78 siblings)] were screened, with new anomalies detected in 11 first-degree relatives (4% out of 270 first-degree relatives screened) from 11 families (7.9% out of 138 families screened). The anomalies detected were vesicoureteric reflux (VUR) (n = 2), non-obstructive non-refluxing hydronephrosis (n = 2), pelviureteral junction obstruction (PUJO) (n = 3), Duplex collecting system (n = 1), hypodysplastic kidney (n = 1), single kidney (n = 1) and horseshoe kidney (n = 1). Most of the anomalies were discordant to the index anomaly (66.6%). Among 95 fathers screened, 5 (5.2%) had renal anomalies. Among 97 mothers screened, 2 (2.1%) had renal anomalies. Among the 78 siblings screened, 4 (5.1%) had renal anomalies. CONCLUSIONS: Familial clustering was noted in 7.9% of the 138 families (of the index cases) screened. The anomalies detected were mostly discordant to the index anomaly.

Etiological Profile of Nephrocalcinosis in Children from Southern India.

OBJECTIVE: To study the etiological profile and patterns of clinical presentation of nephrocalcinosis. METHODS: In this observational study, patients 18 years or younger, referred to the pediatric nephrology clinic with nephrocalcinosis were evaluated for etiology. Symptoms/signs at presentation, estimated glomerular filtration rate (eGFR) at presentation and follow-up, and growth parameters were recorded. RESULTS: The etiology of nephrocalcinosis (n=54) included distal renal tubular acidosis (n=18; 33.3%), primary hyperoxaluria (n=9; 16.7%), Bartter syndrome (n=7; 13%), Dent disease (n=4; 7.4%), cystinosis, familial hypomagnesemia with hypercalciuria and idiopathic hypercalcemia of infancy (2 each). Idiopathic nephrocalcinosis was seen in 5 (9.3%) children. Clinical features included failure to thrive (53.7%), polyuria (44.4%), bony deformities (31.5%) and hypokalemic paralysis (11.1%). At a median (IQR) follow-up of 24 (8, 56) months, the mean (SD) eGFR had improved from 59 (25.5) to 77 (31.48) mL/min/1.73m2 (P<0.01). Consanguinity was present in 50% (27/54). Genetic analysis in 5 primary hyperoxaluria cases confirmed AGXT mutations in 4; and GRHPR mutation in 1 child. CONCLUSIONS: Distal RTA, primary hyperoxaluria and Bartter syndrome were the common etiologies of nephrocalcinosis in our patient population.

Three-monthly bolus vitamin D supplements (1000 vs 400 IU/day) for prevention of bone loss in children with difficult-to-treat nephrotic syndrome: a randomised clinical trial.

BACKGROUND: Nephrotic syndrome (NS) in children is one of the most common chronic diseases with a remitting and relapsing course. Glucocorticoids (prednisolone) are considered to be the treatment of choice but are associated with osteoporosis. There are no uniform consensus guidelines regarding the optimum dose of calcium and vitamin D for osteoprotection. Some authorities suggest a daily dose of 1000 IU vitamin D for children for osteoprotection, while others suggest a daily dose of 400 IU. OBJECTIVES: To compare the efficacy of three-monthly bolus vitamin D supplementation (1000 vs 400 IU/day) to prevent bone loss in children with difficult-to-treat NS (DTNS). METHODS: In this parallel-group, open-label, randomised clinical trial, 60 children aged 1-18 years with DTNS [37 with frequently relapsing NS (FRNS), 13 steroid-dependent NS (SDNS) and 10 steroid-resistant NS (SRNS)] were enrolled and block randomised in a 1:1 allocation ratio to receive 1000 IU/day vitamin D (Group A, n = 30) or 400 IU/day (Group B, n = 30), administered as three-monthly bolus supplemental doses. In Group A, vitamin D (cholecalciferol, Calcirol®sachet) was administered as a stat dose of 90,000 IU every three months (calculated for a period of three months at 1000 IU/day). In Group B, vitamin D (cholecalciferol) was administered as a stat dose of 36,000 IU every three months (calculated for a period of three months at 400 IU/day). The proportionate change in bone mineral content (BMC) was studied by dual energy X-ray absorptiometry (DEXA) scan in both groups after vitamin D supplementation by analysing the values of BMC obtained 12 months apart (baseline vs. after 12 months). RESULTS: Sixty children were randomised to receive vitamin D at a dose of either 1000 IU/day (Group A) or 400 IU/day (Group B). The two groups were comparable in their baseline clinical and laboratory parameters (including BMC and bone mineral density (BMD)). The distribution of the three types of NS (FRNS, SDNS and SRNS) was also comparable in both groups. In Group A, there were 19, 6 and 5 children with FRNS, SDNS and SRNS, respectively, and in Group B there were 18, 7 and 5 children with FRNS, SDNS and SRNS, respectively. The proportionate change in BMC was not significantly different between the two groups (median proportionate change in BMC in Group A 13.36% vs 11.59% in Group B, p = 0.22). Overall, BMC increased in both groups (96.7% in each). Only one (3.3%) patient in each group exhibited bone loss. None of the patients had a urinary calcium:creatinine ratio >0.2 at the end of the study. CONCLUSION: Three-monthly bolus vitamin D dosing regimens administered either as 1000 or 400 IU/day prevent bone loss in children with DTNS who require long-term steroids. Overall, three-monthly bolus supplemental prophylactic vitamin D, either 1000 or 400 IU/day, would seem to be an effective strategy for preventing bone loss in children with DTNS, as evidenced by the extremely low rates of bone loss (3.3% in each group), and is useful for delivering optimal care to children with DTNS. However, since this study was designed as an equivalence trial and not a superiority trial, further studies are required to demonstrate the superiority of the former regimen over the latter. ABBREVIATIONS: BMC, bone mineral content; BMD, bone mineral density; DEXA, dual energy X-ray absorptiometry; DTNS, difficult-to-treat nephrotic syndrome; FRNS, frequently relapsing nephrotic syndrome; IFRNS, infrequently relapsing nephrotic syndrome; iPTH, intact parathyroid hormone; NS, nephrotic syndrome; SDNS, steroid-dependent nephrotic syndrome; SRNS steroid-resistant nephrotic syndrome.

Effect of two prophylactic bolus vitamin D dosing regimens (1000 IU/day vs. 400 IU/day) on bone mineral content in new-onset and infrequently-relapsing nephrotic syndrome: a randomised clinical trial.

OBJECTIVES: To examine the efficacy of two vitamin D dosages (1000 vs. 400 IU/day) for osteoprotection in children with new-onset and infrequently-relapsing nephrotic syndrome (IFRNS) receiving corticosteroids. METHODS: This parallel-group, open label, randomised clinical trial enrolled 92 children with new-onset nephrotic syndrome (NS) (n = 28) or IFRNS (n = 64) to receive 1000 IU/day (Group A, n = 46) or 400 IU/day (Group B, n = 46) vitamin D (administered as a single bolus initial supplemental dose) by block randomisation in a 1:1 allocation ratio. In Group A, vitamin D (cholecalciferol in a Calcirol® sachet) was administered in a single stat dose of 84,000 IU on Day 1 of steroid therapy (for new-onset NS), calculated for a period of 12 weeks@1000 IU/day) and 42,000 IU on Day 1 of steroid therapy (for IFRNS, calculated for a period of 6 weeks@1000 IU/day). In Group B, vitamin D (cholecalciferol in a Calcirol® sachet) was administered as a single stat dose of 33,600 IU on Day 1 of steroid therapy (for new-onset NS, calculated for a period of 12 weeks@400 IU/day) and 16,800 IU on Day 1 of steroid therapy (for IFRNS, calculated for a period of 6 weeks@400 IU/day). The proportionate change in bone mineral content (BMC) was analysed in both groups after vitamin D supplementation. RESULTS: Of the 92 children enrolled, 84 (n = 42 new onset, n = 42 IFRNS) completed the study and were included in the final analysis. Baseline characteristics including initial BMC, bone mineral density, cumulative prednisolone dosage and serum 25-hydroxycholecalciferol levels were comparable in the two groups. There was a greater median proportionate change in BMC in the children who received 1000 IU/day vitamin D (3.25%, IQR -1.2 to 12.4) than in those who received 400 IU/day vitamin D (1.2%, IQR -2.5 to 3.8, p = 0.048). The difference in proportionate change in BMC was only statistically significant in the combined new-onset and IFRNS, but not for IFRNS alone. There was a greater median proportionate change in serum 25-hydroxycholecalciferol, in the children who received 1000 IU/day vitamin D (20.6%, IQR 14.9-36.75) than in those who received 400 IU/day vitamin D (7.7%, IQR 3.5-18.5, p < 0.01). There was a greater median proportionate change in serum calcium in the children who received 1000 IU/day vitamin D (20%, IQR 13.1-29.0) than in those who received 400 IU/day vitamin D (11.3%, IQR 2.8-25.0, p = 0.03). Despite vitamin D therapy, BMC decreased from the baseline in 15 (32.6%) children receiving 1000 IU/day vitamin D and in 17 (36.9%) children receiving 400 IU/day vitamin D. There were no adverse effects attributable to vitamin D. CONCLUSION: The 1000 IU/day dose is marginally more effective than 400 IU/day and it is likely than an even larger dose is required. Further research is required to assess the efficacy and safety of vitamin D doses higher than 1000 IU/day.