Clinical characteristics, genetic profile and short-term outcomes of children with primary hyperoxaluria type 2: a nationwide experience.

BACKGROUND: Three types of primary hyperoxaluria (PH) are recognized. However, data on PH type 2 (PH2), caused by defects in the GRHPR gene, are limited. METHODS: We reviewed the medical records of patients < 18 years of age with genetically-proven PH2 from seven centres across India to identify the age of onset, patterns of clinical presentation, short-term outcomes and genetic profile, and to determine if genotype-phenotype correlation exists. RESULTS: We report 20 patients (all with nephrolithiasis or nephrocalcinosis) diagnosed to have PH2 at a median (IQR) age of 21.5 (7, 60) months. Consanguinity and family history of kidney stones were elicited in nine (45%) and eight (40%) patients, respectively. The median (IQR) serum creatinine at PH2 diagnosis was 0.45 (0.29, 0.56) mg/dL with the corresponding estimated glomerular filtration rate being 83 (60, 96) mL/1.73 m2/min. A mutational hotspot (c.494 G > A), rare in Caucasians, was identified in 12 (60%) patients. An intronic splice site variant (c.735-1G > A) was noted in five (25%) patients. Four (20%) patients required surgical intervention for stone removal. Major adverse kidney events (mortality or chronic kidney disease (CKD) stages 3-5) were noted in six (30%) patients at a median (IQR) follow-up of 12 (6, 27) months. Risk factors for CKD progression and genotype-phenotype correlation could not be established. CONCLUSIONS: PH2 should no longer be considered an innocuous disease, but rather a potentially aggressive disease with early age of presentation, and possible rapid progression to CKD stages 3-5 in childhood in some patients. A mutational hotspot (c.494 G > A variant) was identified in 60% of cases, but needs further exploration to decipher the genotype-phenotype correlation.

A Cross-sectional Study on Fibroblast Growth Factor 23 and Other Markers of Mineral Metabolism in Healthy Children in India.

Fibroblast growth factor 23 (FGF23) plays a significant role in phosphate homeostasis but data on children are limited. We aimed to detect FGF23 levels in 107 healthy children aged 6-16 years and evaluate its correlation with markers of phosphate and calcium metabolism, and the dietary intake of calcium, phosphate, and proteins. Height, weight, and Tanner stages were measured, and dietary intake was calculated. Biochemical analyses of hemoglobin, serum calcium, phosphate, creatinine, Vitamin D, and plasma parathyroid hormone (PTH) and FGF23 levels were performed, alongside their associations with FGF23. Of the children, 65.4% were males. Their mean body mass index was 15.79 ± 2.96 for males and 16.5 ± SD 2.72 for females. The mean Vitamin D and PTH levels were 29.7 ± 1.1 ng/mL and 29.2 ± 1.2 pg/mL, respectively. The mean FGF23 levels were 159 ± 15.2 reference units (RU)/mL. The mean FGF23 levels were significantly higher in females (209.3 ± 31 RU/mL) than in males (132.3 ± 15.1 RU/mL). All biochemical parameters were within the normal range. FGF23 correlated with age, weight, and height, but not Vitamin D, PTH, or dietary calcium and phosphate. FGF23 showed a negative correlation with hemoglobin levels (r = -0.23). Since most children had a nonvegetarian diet, the FGF23 levels were not assessed in vegetarians. These observations were attributed to the rural lifestyle favoring adequate exposure to sunlight and physical activity. The increased FGF23 levels in females, the trends in urban settings, and the levels in strictly vegetarian diets need further study.

Improving Transplant-free Survival With Low-volume Plasma Exchange to Treat Children With Rodenticide Induced Hepatotoxicity.

Background: In a prior report, no patient with rodenticidal hepatotoxicity who met Kochi criteria (MELD score ≥36 or baseline INR ≥6 with hepatic encephalopathy) (PMID: 26310868) for urgent liver transplantation survived with medical management alone. Plasma exchange (PLEX) may improve survival in these patients. Objectives: We describe our experience with low-volume PLEX (PLEX-LV) in treating rodenticide ingestion induced hepatotoxicity in children. Methods: From prospectively collected database of rodenticidal hepatotoxicity patients managed as in-patient with department of Hepatology from December 2017 to August 2021, we retrospectively studied outcomes in children (≤18 years). Hepatotoxicity was categorized as acute liver injury (ALI, coagulopathy alone) or acute liver failure (ALF, coagulopathy and encephalopathy). Kochi criteria was used to assess need for urgent liver transplantation. The primary study outcome was one-month survival. Results: Of the 110 rodenticidal hepatotoxicity patients, 32 children (females: 56%; age: 16 [4.7-18] years; median, range) constituted the study patients. The study patients presented 4 (1-8) days after poison consumption (impulsive suicidal intent:31, accidental:1). Twenty children (62%) had ALI [MELD: 18 (8-36)] and 12 (38%) had ALF [MELD: 37 (24-45)].All children received standard medical care, including N-acetyl cysteine; ALF patients also received anti-cerebral edema measures. None of the patient families opted for liver transplantation. Seventeen children (ALI: 6, ALF: 11) were treated with PLEX-LV (3 [1-5] sessions, volume of plasma exchanged per session: 26 [13-38] ml/kg body weight) and peri-procedure low dose prednisolone.At 1 month, 28 of the 32 children (87.5%) were alive (4 ALF patients died). Of 10 children who met Kochi listing criteria for urgent liver transplantation, two children were ineligible for PLEX-LV (due to hemodynamic instability) and of the remaining 8 children treated by PLEX-LV, 6 (75%) survived. Conclusions: PLEX-LV shows promise as an effective non-liver transplant treatment in children with rodenticidal hepatotoxicity.

Usefulness of urinary calprotectin as a novel marker differentiating functional from structural acute kidney injury in the critical care setting.

BACKGROUND: Biomarkers are fundamental tools for differentiating between types of acute kidney injury (AKI) and may thus be crucial in management and prognosis. We report on a recently described biomarker, calprotectin, that appears to be a promising candidate in differentiating hypovolemic/functional AKI from intrinsic/structural AKI, whose acknowledgement may play a role in improving outcomes. We aimed to study the efficacy of urinary calprotectin in differentiating these two forms of AKI. The effect of fluid administration on the subsequent clinical course of AKI, its severity and the outcomes were also studied. METHODOLOGY: Children who presented with conditions predisposing to AKI or with diagnosis of AKI were included. Urine samples for calprotectin analysis were collected and stored at - 20 ºC for analysis at the end of the study. Fluids were administered as per clinical conditions, followed by intravenous furosemide 1 mg/kg, and patients were observed closely for at least 72 h. Children with serum creatinine normalization and clinical improvement were classified as with functional AKI, while those with no response were classified as with structural AKI. Urine calprotectin levels between these two groups were compared. Statistical analysis was performed with SPSS 21.0 software. RESULTS: Of the 56 children enrolled, 26 were classified as with functional AKI and 30 as with structural AKI. Stage 3 AKI was observed in 48.2% of patients and stage 2 AKI in 33.8%. Mean urine output, creatinine and stage of AKI improved with fluid and furosemide or furosemide alone (OR 6.08, 95% CI 1.65-27.23) (p < 0.01). A positive response to fluid challenge was in favor of functional AKI (OR 6.08, 95% CI 1.65-27.23) (p = 0.008). Presence of edema, sepsis and need for dialysis were hallmarks of structural AKI (p < 0.05). Urine calprotectin/creatinine values were 6 times higher in structural AKI compared to functional AKI. Urine calprotectin/creatinine ratio showed the best sensitivity (63.3%) and specificity (80.7%) at a cut-off value of 1 mcg/mL in differentiating the two types of AKI. CONCLUSION: Urinary calprotectin is a promising biomarker that may help differentiating structural from functional AKI in children.

Epidemiology and outcomes of pneumococcal sepsis in children with nephrotic syndrome in a developing country.

BACKGROUND: Pneumococcal infections are common in children with nephrotic syndrome. Knowledge of the commonly available serotypes and antibiotic susceptibility will help in prevention and appropriate management of pneumococcal sepsis, especially in resource-limited countries. METHODS: Demographic, clinical, and laboratory data on children with nephrotic syndrome and pneumococcal infections were extracted from the electronic medical records. RESULTS: Sixty-three isolates of pneumococci obtained from 60 children with nephrotic syndrome, over a period of 14 years, were included in the study. This represented 18% of all pneumococcal infections occurring in children during the same period. Commonly available vaccines covered up to 58% of all the serotypes causing infection. Severe disease, with shock, intensive care admission and/or meningitis, was observed in 38% children and mortality was observed in 10%. Resistance to commonly used antibiotics was not observed, except for erythromycin. CONCLUSIONS: Pneumococcal sepsis was observed to be common in children with nephrotic syndrome and results in significant morbidity and mortality. Commonly used antibiotics were observed to be effective in management of the infections.

The Clinical Profile and Long-Term Outcome of Children with Membranous Nephropathy, and the Evaluation of Anti-Phospholipase A2 Receptor Antibody Immunohistochemistry in Kidney Biopsy.

Introduction: Idiopathic membranous nephropathy (iMN) is a rare cause of nephrotic syndrome in children (1%-7%). Anti-phospholipase A2 receptor (PLA2R) antibody positivity in kidney biopsy is observed in 52%-78% of adults and 45% of children with iMN. The objectives of the study are to analyze the clinical profile and outcome of membranous nephropathy in children, to assess the prevalence of anti-PLA2R immunohistochemistry (IHC) in kidney biopsy, and to correlate their presence with disease characteristics. Methods: We are reporting a single-center retrospective study conducted in pediatric nephrology division. Clinical data and outcome parameters of children with membranous nephropathy were analyzed. PLA2R IHC was performed in kidney biopsy specimens retrospectively. Results: We analyzed 43 children with membranous nephropathy (MN) from a single center. 18 (42%) had idiopathic MN (iMN). PLA2R IHC was performed in kidney biopsy specimens in 14/18 (78%) patients with iMN and 7/9 (78%) non-lupus secondary membranous nephropathy (SMN) patients. The most common cause of SMN was lupus nephritis in 16 patients (64%). The mean estimated glomerular filtration rate (eGFR) at onset was 156 ± 81 ml/min/1.73m2. The sensitivity and specificity of PLA2R IHC in diagnosing pediatric MN was 50% and 57%, respectively; positive and negative predictive values were 70% and 36%, respectively. At the final follow-up, chronic kidney disease stage 5 (CKD 5) developed in 2/14 (14.3%) iMN patients. Conclusions: IHC PLA2R staining of glomerular tissue is a useful diagnostic marker of IMN. Though PLA2R prevalence is lower in children, its role in guiding treatment needs further exploration.

Steroid Sensitive Nephrotic Syndrome: Revised Guidelines.

JUSTIFICATION: Steroid sensitive nephrotic syndrome (SSNS) is one of the most common chronic kidney diseases in children. These guidelines update the existing Indian Society of Pediatric Nephrology recommendations on its management. OBJECTIVE: To frame revised guidelines on diagnosis, evaluation, management and supportive care of patients with the illness. PROCESS: The guidelines combine evidence-based recommendations and expert opinion. Formulation of key questions was followed by review of literature and evaluation of evidence by experts in two face-to-face meetings. RECOMMENDATIONS: The initial statements provide advice for evaluation at onset and follow up and indications for kidney biopsy. Subsequent statements provide recommendations for management of the first episode of illness and of disease relapses. Recommendations on the use of immunosuppressive strategies in patients with frequent relapses and steroid dependence are accompanied by suggestions for step-wise approach and plan of monitoring. Guidance is also provided regarding the management of common complications including edema, hypovolemia and serious infections. Advice on immunization and transition of care is given. The revised guideline is intended to improve the management and outcomes of patients with SSNS, and provide directions for future research.

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.

Pediatric Continuous Renal Replacement Therapy (PCRRT) expert committee recommendation on prescribing prolonged intermittent renal replacement therapy (PIRRT) in critically ill children.

INTRODUCTION: Recently, prolonged intermittent renal replacement therapies (PIRRT) have emerged as cost-effective alternatives to conventional CRRT and their use in the pediatric population has started to become more prominent. However, there is a lack of consensus guidelines on the use of PIRRT in pediatric patients in an intensive care setting. METHODS: A literature search was performed on PubMed/Medline, Embase, and Google Scholar in conjunction with medical librarians from both India and the Cleveland Clinic hospital system to find relevant articles. The Pediatric Continuous Renal Replacement Therapy workgroup analyzed all articles for relevancy, proposed recommendations, and graded each recommendation for their strength of evidence. RESULTS: Of the 60 studies eligible for review, the workgroup considered data from 37 studies to formulate guidelines for the use of PIRRT in children. The guidelines focused on the definition, indications, machines, and prescription of PIRRT. CONCLUSION: Although the literature on the use of PIRRT in children is limited, the current studies give credence to their benefits and these expert recommendations are a valuable first step in the continued study of PIRRT in the pediatric population.

Congenital Nephrotic Syndrome in India in the Current Era: A Multicenter Case Series.

BACKGROUND: There is a paucity of information on epidemiology, diagnosis, and treatment outcomes of congenital nephrotic syndrome (CNS) in developing countries. METHODS: Retrospective (2012-2017) review of case records undertaken across 12 Indian pediatric nephrology centers. RESULTS: Sixty-five children (58% male, median birth weight 2.4 kg [interquartile range (IQR) 2.1-2.86]) were identified with CNS. Nearly half (45%) were preterm with previous history of fetal loss/sibling death in 22% and history of consanguinity in a third. No infective etiology was confirmed. Genetic reports available for 15 (23%) children identified causal mutations in 10 (8 in NPHS1 [1 novel variant], 1 in WT 1 [novel variant], and 1 in PLCE-1 gene). In addition, 1 child was clinically diagnosed as Galloway Mowat syndrome. Next-generation sequencing showed 80% yield and Sanger sequencing 20%. Albumin infusion and angiotensin-converting enzyme inhibitors were used initially in around two-third of cohort, while only 12% of children received indomethacin. Totally, 22 (34%) children were lost to follow-up after initial visit, and among the rest median follow-up was 69 days (IQR 20-180) with 18 (42%) deaths. Eight children showed partial response (including 2 with NPHS1 compound mutation), 1 complete response, and all of them were alive at last follow-up in contrast to 53% mortality among nonresponders, p = 0.004. CONCLUSION: This largest reported series on CNS from India revealed suboptimal management with poor outcome as well as low number of CNS being subjected to genetic evaluation.

Urinary Neutrophil Gelatinase Associated Lipocalin - A Sensitive Marker for Urinary Tract Infection in Children.

Early antibiotic treatment for urinary tract infection (UTI) in young children can prevent renal scarring. Sensitivity of pyuria and positive urine nitrite test as indicators of UTI are low, whereas results of urine culture, the gold standard for diagnosing UTI, may not be available for 48--72 h. Novel markers for rapid and accurate diagnosis of UTI would help in the early initiation of treatment in children with suspected UTI. We studied the utility of urinary neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of UTI. This study included 100 children between 3 months and 5 years with suspected UTI. After parental consent, a midstream clean catch or suprapubic aspirate urine specimen was sent for culture and NGAL analysis. Sensitivity and specificity of urine NGAL as a marker of UTI were estimated. Of the 100 children evaluated, urine culture was positive in 34%. Median urine NGAL values were higher in culture-positive children than in culture-negative children (223.20 vs 13.65, P = 0.0001). Receiver operating curve analysis showed an optimal cutoff level of 27 ng/ml for urine NGAL (odds ratio, 8.2, 95% confidence interval, 3.1--22.1) correlating best with culture positivity. Sensitivity and specificity of urine NGAL estimation were significantly better (79.4% and 68.2%) when compared with urine white blood cell estimation (70.6% and 53%). Urine NGAL is a sensitive and specific marker to predict UTI in children with a cutoff level of 27 ng/ml. It may serve as a screening test for detecting simple, uncomplicated UTI in young children.

Clinical and Immunological Profile of Anti-factor H Antibody Associated Atypical Hemolytic Uremic Syndrome: A Nationwide Database.

Background: Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury (AKI), is characterized by dysregulation of the alternative complement pathway. Autoantibodies to factor H (FH), a chief regulator of this pathway, account for a distinct subgroup. While high anti-FH titers predict relapse, they do not correlate well with disease activity and their functional characterization is required. Methods: Of 781 patients <18-year-old of aHUS in the nationwide database from 2007 to 2018, 436 (55.8%) had anti-FH antibodies. Clinical features and outcome of patients managed in the last 6-year (n = 317) were compared to before (n = 119). In plasma samples of 44 patients, levels of serial circulating FH immune complexes (CIC), free FH, soluble terminal complement complex (sC5b-9), sheep red blood cell (SRBC) lysis and epitope specificity (n = 8) were examined. Functional renal reserve, ambulatory hypertension, left ventricular hypertrophy (LVH), and proteinuria were evaluated in a subset. Results: Patients presented with markedly elevated anti-FH titers (10,633.2 ± 998.5 AU/ml). Management varied by center, comprising plasma exchange (PEX; 77.5%) and immunosuppression (73.9%). Patients managed in the last 6-year showed better renal survival at mean 28.5 ± 27.3 months (log rank P = 0.022). Mean anti-FH titers stayed 700-1,164 AU/ml during prolonged follow-up, correlating with CIC. Patients with relapse had lower free-FH during remission [Generalized estimating equations (GEE), P = 0.001]; anti-FH levels ≥1,330 AU/ml and free FH ≤440 mg/l predicted relapse (hazards ratio, HR 6.3; P = 0.018). Epitope specificity was similar during onset, remission and relapse. Antibody titer ≥8,000 AU/ml (HR 2.23; P = 0.024), time to PEX ≥14 days (HR 2.09; P = 0.071) and PEX for <14 days (HR 2.60; P = 0.017) predicted adverse renal outcomes. Combined PEX and immunosuppression improved long-term outcomes (HR 0.37; P = 0.026); maintenance therapy reduced risk of relapses (HR 0.11; P < 0.001). At 4.4±2.5 year, median renal reserve was 15.9%; severe ambulatory, masked and pre-hypertension were found in 38, 30, and 18%, respectively. Proteinuria and LVH occurred in 58 and 28% patients, respectively. Conclusion: Prompt recognition and therapy with PEX and immunosuppression, is associated with satisfactory outcomes. Free-FH predicts early relapses in patients with high anti-FH titers. A significant proportion of impaired functional reserve, ambulatory hypertension, proteinuria and LVH highlight the need for vigilant long-term follow-up.

Does severe ADAMTS13 deficiency in thrombotic microangiopathy rule out complement-mediated atypical hemolytic uremic syndrome.

In evaluating a patient with thrombotic microangiopathy (TMA), it is necessary to rule out thrombotic thrombocytopenic purpura before a diagnosis of atypical hemolytic uremic syndrome (aHUS) is made. There have been reports that mutations of complement factors can coexist with partial A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 deficiency. Here, we report the case of a 6-year-old girl who was initially diagnosed as nephrotic syndrome and developed TMA after five years of onset of illness. She had poor response to treatment and had multiple relapses due to associated complement factor mutation. Hence, genetic evaluation has to be considered in all children presenting with aHUS.

Renal Mucormycosis: A Rare Cause of Urinary Tract Infection Leading to End-stage Renal Disease (ESRD).

Mucormycosis is a rare fungal infection often seen in immunocompromised hosts. Isolated renal mucormycosis may however present in immunocompetent children as renal failure and has a uniformly poor prognosis if not detected and treated early into the course of illness. We present a 3-year-old boy with unrelenting pyelonephritis in whom serial urine cultures done were negative. A final diagnosis of isolated renal mucormycosis was made by magnetic resonance imaging and renal biopsy.

A retrospective study on non-drug related poisoning in the community among children from south India.

OBJECTIVES: This retrospective study was performed to determine the incidence, demographic distribution, types and outcomes across various non-drug related poisonings among children attending a tertiary care center in south India. METHODS: All children from 0-16 years who presented to the Paediatric Emergency Department, Christian Medical College, Vellore with non-drug related poisoning from October 2004 to September 2013 were included. RESULTS: Out of the total 997 cases of poisoning, 629 (63.1%) cases were contributed by chemicals and plants: mainly hydrocarbons (kerosene) 309 (49.1%); organophosphates 72 (11.5%); corrosive acids and alkalis 57 (9.1%); insecticides 51 (8.1%); and plant poisons 20 (3.2%). Males (62.79%) and children < 5 years (77.42%) were mostly affected. Although many children developed complications requiring intensive care unit admissions, the total mortality was only 9 (1.4%). The incidence of poisoning showed a decreasing trend over the last 4 years. CONCLUSION: This study for the first time gives an elaborative insight on non-drug related pediatric poisoning from a tertiary care center in south India for almost a decade.

Anti-glomerular basement membrane: A rare cause of renal failure in children.

Anti-glomerular basement membrane (GBM) disease is a rare cause of acute renal failure and known to have bad prognosis regarding renal functions recovery and patient survival specially when diagnosed late and presents with severe renal failure that requires dialysis. We report a case of 11-year-old child with acute renal failure secondary to anti-GBM disease and associated with antineutrophil cytoplasmic antibody-positive vasculitis. He was treated with plasmapheresis, steroids, and cyclophosphamide with recovery of his kidney functions.

Drug poisoning in the community among children: a nine years' experience from a tertiary care center in south India.

OBJECTIVES: This study was performed to determine the incidence, demographic distribution, types and outcomes across various drug poisonings among children from south India. METHODS: This retrospective study included children less than 16 years who presented to the Pediatric Emergency Department with drug poisoning from the 1st of October 2004 to the 30th of September 2013. RESULTS: Out of the total 997 poisoning cases, 366 (36.71%) were contributed by drugs; mainly antiepileptics, central nervous system depressants, psychotropics, analgesic-antipyretics and natural drugs. Males and children of < 5 years were mostly affected. Although many children developed complications and required intensive care unit admissions, the total mortality rate was less than 1%. The incidence of drug poisoning showed a decreasing trend over the last 4 years. CONCLUSION: This study for the first time gives an elaborative insight into pediatric drug poisoning over a nine-year period from a Pediatric Emergency Department tertiary care center in south India.