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.

Bioavailable Vitamin D Levels in Children With First Episode Nephrotic Syndrome: A Longitudinal Study.

OBJECTIVE: To estimate the levels of serum bioavailable vitamin D in children presenting with first episode nephrotic syndrome (FENS) at diagnosis and after 4 weeks of standard steroid therapy while the child is in remission, and compare the same with age-sex matched healthy controls. METHODS: We included children aged 1 month to 12 years presenting as FENS and estimated the serum calcium, phosphorus, alkaline phosphatase, 25-hydroxy vitamin D (25(OH)D), parathormone, serum and urine Vitamin D binding protein (VDBP) at diagnosis and after 4 weeks of standard steroid therapy while the child is in remission. We also included age-sex matched healthy controls for comparison. Bioavailable and free 25(OH)D were estimated at enrolment and at 4 weeks of therapy. RESULTS: The mean 25(OH)D level (ng/mL) in children with FENS was 11.3 (6.1) at diagnosis and 13.6 (6.2) at 4 weeks follow-up, while corresponding values in healthy controls was 16 (7) ng/mL. The median (IQR) serum VDBP level in FENS at enrolment was 223.0 (144, 305.5) µg/mL. There was significant correlation of serum VDBP with serum albumin levels (P = 0.04). At 4 weeks (remission), the VDBP levels increased to 554.5 (383, 644.75) µg/mL (P < 0.001). The median (IQR) free 25(OH)D levels (pg/mL) in children with FENS was 1.07 (0.8, 1.6) at enrolment and 0.53 (0.37, 0.86) at 4 weeks follow-up. The median (IQR) bioavailable vitamin D in FENS during proteinuria was 0.58 (0.4, 0.83) ng/ml, much lower as compared to controls 0.97(0.85, 1.08) ng/ml (P < 0.001). On follow-up at 4 weeks of remission the median (IQR) bioavailable vitamin D levels increased to 0.87 (0.59, 1.42) ng/ml (P = 0.015). There was a very strong positive correlation between free vitamin D and bioavailable vitamin D (r = 0.9, P < 0.001); a strong negative correlation between serum VDBP and bioavailable vitamin D (r = - 0.69, P < 0.001). There was a positive correlation between 25-hroxy vitamin D and bioavailable vitamin D (r = 0.63, P < 0.001). A positive correlation was seen between urine UP/UC and urine VDBP (r = 0.51, P = 0.004). Serum VDBP and serum albumin showed statistically significant positive correlation (r = 0.37, P < 0.05). CONCLUSION: Children with FENS are deficient in vitamin D. The free and bioavailable vitamin D levels are reduced in children with FENS during the proteinuric phase. Further studies to assess the association between bioavailable vitamin D and 25(OH)D with bone mineral density are needed in children with nephrotic syndrome to validate the utility of bioavailable vitamin D in clinical practice.

Activin A: a marker of mineral bone disorder in children with chronic kidney disease?

BACKGROUND: Activin A has been shown to enhance osteoclast activity and its inhibition results in bone growth. The potential role of activin A as a marker of chronic kidney disease-mineral bone disease (CKD-MBD) and its relationship with other markers has not been studied in children with CKD. METHODS: A cross sectional study was conducted among 40 children aged 2 to 18 years with CKD (Stage 2 to 5; 10 in each stage) and 40 matched controls. Activin A, cathepsin K, FGF-23, PTH, serum calcium, phosphorous and alkaline phosphatase in both groups were measured and compared. The correlation of activin A and markers of CKD-MBD was studied. A p value of < 0.05 was considered significant. RESULTS: The mean age of children with CKD was 9.30 ± 3.64 years. Mean levels of activin A in cases were 485.55 pg/ml compared to 76.19 pg/ml in controls (p < 0.001). FGF-23 levels in cases were 133.18 pg/ml while in controls it was 6.93 pg/ml (p < 0.001). Mean levels of cathepsin K were also significantly higher in cases as compared to controls. There was a progressive increase in activin A and cathepsin K levels with increasing stage of CKD. Activin A had a significant positive correlation with serum creatinine (r = 0.51; p < 0.001). CONCLUSIONS: Activin A levels progressively rise with advancing CKD stage. These findings suggest that activin A can be a potential early marker of CKD-MBD in children.

Urinary Apolipoprotein A1 and Neutrophil Gelatinase-associated Lipocalin in Children with Idiopathic Nephrotic Syndrome.

Urinary biomarkers are a promising diagnostic modality whose role was explored in nephrotic syndrome (NS). We estimated urinary apolipoprotein A1 (Apo A1) and neutrophil gelatinase-associated lipocalin (NGAL) in children with first-episode NS (FENS) and controls with a longitudinal follow-up to see the serial changes during remission. The study groups comprised 35 children with FENS and an equal number of age- and sex-matched controls. Patients were followed up at regular intervals, and 32 patients were classified as having steroid-sensitive NS (SSNS) and 3 as having steroid-resistant NS (SRNS). The mean follow-up period was 8.7 ± 4.2 months. Three patients in the SSNS group were labeled as having frequent relapses or steroid-dependent disease during follow-up. Of the three children with SRNS, two had minimal changes in the disease and one had idiopathic membranous nephropathy. The levels of Apo A1:creatinine, NGAL:creatinine, and spot urinary protein:urinary creatinine ratios were significantly higher in children with FENS compared with controls. The levels of the urine biomarkers decreased significantly at subsequent follow-up with remission. The Apo A1 and NGAL levels in SSNS patients were significantly high compared with both the controls and FENS patients. Urinary Apo A1 levels in SRNS patients were lower at initial presentation. This longitudinal study revealed changes in the urinary Apo A1 and NGAL in NS over the course of the disease.

SARS-CoV-2 Infection in Children with Idiopathic Nephrotic Syndrome: A Multicentric Study.

A multicenter retrospective study was conducted to assess the clinical spectrum of 30 severe acute respiratory syndrome coronavirus (SARS-CoV-2)-positive children with idiopathic nephrotic syndrome. Difficult to treat nephrotic syndrome was found to be a high-risk group with a high incidence of acute kidney injury and mortality.

Factors Associated With Hypertension and Cardiovascular Parameters in Children With Infrequently Relapsing Nephrotic Syndrome.

OBJECTIVES: To assess the prevalence of hypertension in children with infrequently relapsing nephrotic syndrome (IRNS) and its association with dyslipidemia, and end organ damage including left ventricular hypertrophy (LVH), at relapse and after steroid induced remission. METHODS: Prospective observational study conducted in 83 children aged 1-12 years with IRNS, presenting in relapse. Blood pressure, fundus examination, blood and urine investigations were done at relapse and then at 4 weeks of therapy. Echocardiography at 4 weeks was performed for assessment of LVH and relative wall thickness (RWT) for concentric geo-metry (CG). RESULTS: 27 patients (32.5%) developed hypertension, out of which 21 patients (25.3%) had stage I hypertension. Hypertension in first episode (63.0%, P<0.01) and in previous relapses (87.5%, P<0.001) was significantly associated with hypertension in the current episode. 12 patients had a positive family history of hypertension, of which 8 (66.7%) were classified under the hypertensive group (P=0.016). Concentric geometry (CG) was found in 28% of hypertensive and 5.5% of non-hypertensive children (P=0.011). On regression analysis, a lower Up:Uc at the time of relapse was found to have a protective role for development of hypertension. CONCLUSION: One third children with IRNS had hypertension at relapse and a high proportion of hypertensive patients had CG pattern on echocardiography.

Integration of Urinary Neutrophil Gelatinase-associated Lipocalin with the Renal Angina Index to Predict Subsequent Severe Acute Kidney Injury in Critically Ill Children: A Diagnostic Accuracy Study.

The primary objective of this study was to determine the performance of the renal angina index (RAI) in predicting subsequent severe acute kidney injury (AKI) on day 3 of admission and whether integrating urinary neutrophil gelatinase-associated lipocalin (NGAL) with RAI would lead to improved prediction of AKI. This was a prospective observational study conducted in the pediatric intensive care unit (PICU) of a tertiary care hospital involving 170 children meeting the inclusion criteria. The RAI was assessed within 24 h of admission to the PICU. Positivity for renal angina was considered RAI ≥8. Urine samples were collected for all enrolled patients within the first 24 h and on day 3 of the PICU stay. NGAL was assayed using human-specific enzyme-linked immunosorbent assay. The overall incidence of AKI was 18.2%. Out of 170 children, 31 (18.2%) were RAI-positive on day 0. A higher proportion of patients in the RAI-positive group developed AKI on day 3 compared with the RAI-negative group (83.9% vs. 3.6%, P <0.001). Those who were RAI-positive on day 0 had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value of 83.8%, 96.4%, 83.8%, and 96.4%, respectively, for predicting severe AKI on day 3. Incorporating urinary NGAL improved the specificity and PPV to 97.8% and 85.7%, respectively. Assessing the RAI is simple and useful for predicting severe AKI in critically ill children. The addition of urinary NGAL to the RAI optimizes its use for identifying patients at risk of subsequent severe AKI.

Comparison of clinical and laboratory profile of survivors and non-survivors of SARS-CoV-2-related multisystem inflammatory syndrome of childhood in India: An observational study.

AIM: The SARS-CoV-2 pandemic is characterised by multiple reports of paediatric multisystem inflammatory disease or multisystem inflammatory syndrome in children (MIS-C) with Kawasaki disease-like features often complicated by myocarditis, shock and macrophage activation syndrome. Certain clinical and laboratory markers may be used to identify high risk cases. METHODS: All sequentially admitted patients hospitalised between April 2020 and October 2020, who met the WHO case definition for MIS-C were included. Data included patient demographic information, presenting symptoms, organ dysfunction and laboratory parameters. SARS-CoV-2 infection was diagnosed by nasopharyngeal swab real-time reverse transcription-polymerase chain reaction and/or rapid antibody test for SARS-CoV-2 as recommended. The clinical and laboratory criteria were compared in the survival and non-survival groups. RESULTS: A total of 29 patients with MIS-C were treated during the study period. There were 21 survivors and 8 non-survivors. The non-survivors had more neurocognitive and respiratory symptoms along with increased incidence of myocarditis compared with survivors. The serum levels of CPK-MB, D-dimer, ferritin and triglyceride were significantly raised in non-survivors as compared to survivors. CONCLUSION: The non-survivor group had higher CPK and greater proportion of children with troponin-T elevation indicating higher incidence of myocardial injury and necrosis. The D-dimer, ferritin and triglyceride were also higher in the mortality group, indicating the greater extent of inflammatory damage in this group.

Predictors of mortality in children admitted with SARS-CoV-2 infection to a tertiary care hospital in North India.

AIM: To compare the demographic, clinical, laboratory and radiological parameters of patients with different clinical outcomes (death or discharge) and analyse them to find out the potential predictors for mortality in children hospitalised with SARS-CoV-2 infection. METHODS: Retrospective chart review of all patients less than 18 years of age with laboratory-confirmed SARS-CoV-2 infection and requiring hospital admission between 16 April 2020 and 31 October 2020. RESULTS: Of 255 children with SARS-CoV-2 infection, 100 patients (median age 62.5 months, 59% males, 70% with moderate to severe disease) were hospitalised, of whom 27 died (median age 72 months, 59% males and 30% severely underweight). The subgroup with comorbidities (n = 14) was older (median age 126 months) and had longer duration of stay (median 10 days). Fever and respiratory symptoms were comparable while gastrointestinal symptoms were more common among non-survivors. Hypoxia at admission (odds ratio (OR) 5.48, P = 0.001), multiorgan dysfunction (OR 75.42, P = 0.001), presence of acute kidney injury (OR 11.66, P = 0.001), thrombocytopenia (OR 4.40, P = 0.003) and raised serum C-reactive protein (CRP) (OR 4.69, P = 0.02) were independently associated with mortality. The median time from hospitalisation to death was 3 days. The deceased group had significantly higher median levels of inflammatory parameters and a higher incidence of complications (myocarditis, encephalitis, acute respiratory distress syndrome and shock). CONCLUSIONS: Hypoxia at admission, involvement of three or more organ systems, presence of acute kidney injury, thrombocytopenia and raised serum C-reactive protein were found to be independently associated with increased odds of in-hospital mortality in children admitted with SARS-CoV-2 infection.

The 2021 Toolkit for Emergency Preparedness and Mitigation to Combat Surge of Pediatric COVID-19 Patients in India: The World Health Organization Collaborating Center for Emergency and Trauma in South East Asia Recommendations.

The authors of this toolkit focus on children under the age of 18 comprising approximately 41% of the total population in India. This toolkit has been created with an objective to prepare, mitigate the effects of any surge of COVID-19 in our communities, and help to optimally utilize the scarce resources. The toolkit design suggests the manpower, equipment, laboratory support, training, consumables, and drugs for a 10-bedded pediatric emergency room, 25-bedded COVID pediatric intensive care unit, and 75-bedded COVID pediatric high dependency unit/ward as defined for a 100-bedded facility. A dedicated and detailed chapter is included to address the psychological needs of the children. These data can be modified for other department sizes based on the facilities, needs, local environment, and resources available.

Clinical and Histopathological Profile of Adolescent onset Idiopathic Nephrotic Syndrome in North Indian Children.

Adolescent onset idiopathic nephrotic syndrome (INS) is marked by increased incidence atypical features and non-minimal change disease in histopathology. The objective of the study was to analyze the clinical features and histopathological spectrum of adolescent-onset INS. It was conducted in a Pediatric nephrology clinic of a tertiary care hospital in North India. We retrospectively evaluated clinical features, biochemical investigations and histopathology of 33 adolescents with idiopathic NS registered in pediatric nephrology clinic. Twenty-three (70.0%) adolescents had steroid resistant nephrotic syndrome. Hematuria was present in 39%, hypertension 36% and acute kidney injury (AKI) in 27%. Three-fourth of adolescents who underwent biopsy had non-minimal change disease in histopathology. Adolescent onset INS have increased incidence of AKI, hypertension, and non-minimal change disease.

Acute Kidney Injury in Hospitalized Children with COVID19.

BACKGROUND: Acute kidney injury (AKI) has been recognized as a significant risk factor for mortality among adults with severe acute respiratory syndrome coronavirus infection. AIM: The aim of this study is to assess the prevalence and risk factors for AKI and mortality in children with coronavirus disease 2019 (COVID19) from a resource-limited setting. METHODS: Cross-sectional analysis of laboratory confirmed COVID19 children admitted from 1 March to 30 November 2020 in a tertiary care hospital in New Delhi, India was done. Clinical features and associated comorbidities of COVID19 were noted. Baseline serum creatinine (height-independent Hoste's equation) and peak serum creatinine were used for staging of AKI by the 2012 Kidney Disease Improving Global Outcomes serum creatinine criteria. Univariate analysis and Kaplan-Meier survival analysis were used to compare the overall outcome in the AKI vs. the non-AKI group. RESULTS: A total of 64 810 children between 1 month and 18 years visited the hospital; 3412 were tested for suspected COVID19, 295 tested positive and 105 (54% boys) were hospitalized. Twenty-four hospitalized children (22.8%) developed AKI; 8 in Stage 1 (33.3%), 7 in Stage 2 (29.2%) and 9 in Stage 3 (37.5%) respectively. Overall, three patients received KRT. Highest reported mortality was (66.6%) in AKI Stage 3. Risk factors for AKI included associated sepsis (OR 95% CI, 1.22-9.43, p < 0.01), nephrotic syndrome (OR 95% CI, 1.13-115.5, p < 0.01), vasopressor support (OR 3.59, 95% CI, 1.37-9.40, p value< 0.007), shock at presentation (OR 2.98, 95% CI, 1.16-7.60, p value 0.01) and mechanical ventilation (OR 2.64, 95% CI, 1.04-6.71, p value< 0.03). Mortality (25.71%) was higher in the AKI group (OR 95% CI, 1.14-8.35, p < 0.023) with shock (OR 45.92; 95% CI, 3.44-612.0, p value <0.004) and ventilation (OR 46.24; 95% CI, 1.6-1333.0 p value< 0.02) as significant risk factors for mortality. CONCLUSION: AKI is an important modifiable risk factor for mortality in children with COVID19 in a resource-limited setting. Our study supports the strengthening of kidney replacement therapy and its timely initiation to reduce the progression of AKI and thus mortality in children.

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.