Clinical characteristics and genetic profile of children with WDR72-associated distal renal tubular acidosis: a nationwide experience.

BACKGROUND: Limited data, primarily from small case series, exist regarding the clinical profile, genetic variants, and outcomes of WDR72-associated distal renal tubular acidosis (WDR72-dRTA). METHODS: Our study enrolled children diagnosed with WDR72-dRTA below 18 years of age from 9 Indian centers and analyzed their clinical characteristics, genetic profiles, and outcomes. Potential genotype-phenotype correlations were explored. RESULTS: We report 22 patients (59% female) with WDR72-dRTA who were diagnosed at a median age of 5.3 (3, 8) years with polyuria (n = 17; 77.3%), poor growth (16; 72.7%), and rickets (9; 40.9%). Amelogenesis imperfecta was present in 21 (95.5%) cases. At presentation, all patients had normal anion gap metabolic acidosis; hypokalemia and nephrocalcinosis were seen in 17 (77.3%) patients each. Seven (31.8%) patients had concomitant proximal tubular dysfunction. Genetic analysis identified biallelic nonsense variants in 18 (81.8%) patients, including novel variants in 6 cases. A previously reported variant, c.88C > T, and a novel variant, c.655C > T, were the most frequent variants, accounting for 10 (45.5%) cases. Over a median follow-up of 1.3 (1, 8) years, the height velocity improved by 0.74 (0.2, 1.2) standard deviation scores, while 3 children (13.6%) progressed to chronic kidney disease (CKD) stage 2, with eGFR ranging from 67 to 76 mL/min/1.73 m2, respectively, after 11.3-16 years of follow-up. No specific genotype-phenotype correlation could be established. CONCLUSIONS: WDR72-dRTA should be considered in children with typical features of amelogenesis imperfecta and dRTA. Biallelic nonsense variants are common in Asians. While most patients respond well to treatment with improved growth and preserved eGFR, on long-term follow-up, a decline in eGFR may occur.

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.

Exposure to Mycophenolic Acid and Its Clinical Response in an Indian Pediatric Population with Nephrotic Syndrome.

Background: Children with nephrotic syndrome experience many side effects and frequent relapses when treated with steroids and other drugs. Mycophenolic acid (MPA) is one of the effective and least toxic drug for the treatment of nephrotic syndrome. This drug needs to be monitored for maximal efficacy and minimal toxicity. The therapeutic reference range for this drug is not established for the aforementioned patient population of Indian origin. Materials and Methods: In this observational study, children with nephrotic syndrome on mycophenolate mofetil were followed up for a minimum duration of three months. Following this, their clinical status (relapse/remission) was determined and the mycophenolate exposure was measured for over 12 hours. Results: A total of 34 participants were included, with 17 (50%) in relapse. Median MPA Area under the curve over 12 hours (AUC0-12h) (36.5 µg·h/ml) in the remission group differed significantly compared to that in the relapse group (17.2 µg·h/ml). Conclusion: Higher exposure to MPA AUC0-12h is associated with clinical remission of pediatric nephrotic syndrome.

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.

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.