Publications by authors named "Pankaj Hari"

114 Publications

Metabolic and Genetic Evaluation in Children with Nephrolithiasis.

Indian J Pediatr 2022 Jul 11. Epub 2022 Jul 11.

Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Kidney Diseases, All India Institute of Medical Sciences, New Delhi, 110029, India.

Objective: To evaluate metabolic and genetic abnormalities in children with nephrolithiasis attending a referral center in North India.

Methods: The patients aged 1-18 y old with nephrolithiasis underwent biochemical evaluation and whole-exome sequencing. The authors evaluated for monogenic variants in 56 genes and compared allele frequency of 39 reported polymorphisms between patients and 1739 controls from the GenomeAsia 100 K database.

Results: Fifty-four patients, aged 9.1 ± 3.7 y were included. Stones were bilateral in 42.6%, familial in 33.3%, and recurrent in 25.9%. The most common metabolic abnormalities were hypercalciuria (35.2%), hyperoxaluria (24.1%), or both (11.1%), while xanthinuria (n = 3), cystinuria (n = 1), and hyperuricosuria (n = 1) were rare. Exome sequencing identified an etiology in 6 (11.1%) patients with pathogenic/likely pathogenic causative variants. Three variants in MOCOS and one in ATP7B were pathogenic; likely pathogenic variants included MOCOS (n = 2), AGXT, and SLC7A9 (n = 1, each). Causality was not attributed to two SLC34A1 likely pathogenic variants, due to lack of matching phenotype and dominant family history. Compared to controls, allele frequency of the polymorphism TRPV5 rs4252402 was significantly higher in familial stone disease (allele frequency 0.47 versus 0.53; OR 3.2, p = 0.0001).

Conclusion: The chief metabolic abnormalities were hypercalciuria and hyperoxaluria. A monogenic etiology was identified in 11% with pathogenic or likely pathogenic variants using a gene panel for nephrolithiasis. Heterozygous missense variants in the sodium-phosphate cotransporter SLC34A1 were common and required evaluation for attributing pathogenicity. Rare polymorphisms in TRPV5 might increase the risk of familial stones. These findings suggest that a combination of metabolic and genetic evaluation is useful for determining the etiology of nephrolithiasis.
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http://dx.doi.org/10.1007/s12098-022-04234-9DOI Listing
July 2022

Feasibility and Efficacy of Sustained Low-Efficiency Dialysis in Critically Ill Children with Severe Acute Kidney Injury.

Indian J Pediatr 2022 Jul 4. Epub 2022 Jul 4.

Division of Nephrology, ICMR Center for Advanced Research in Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

Objectives: To examine the feasibility, efficacy, and safety of sustained low-efficiency dialysis (SLED) in hemodynamically unstable, critically ill children.

Methods: Critically ill patients, 1-18 y old with hemodynamic instability (≥ 1 vasoactive drugs) and severe acute kidney injury (AKI) requiring kidney replacement therapy (KRT) in a tertiary care pediatric intensive care unit were prospectively enrolled. Patients weighing ≤ 8 kg or with mean arterial pressure < 5 percentile despite > 3 vasoactive drugs, were excluded. Patients underwent SLED until hemodynamically stable and off vasoactive drugs, or lack of need for dialysis. The primary outcome was the proportion of patients in whom the first session of SLED was initiated within 12 h of its indication and completed without premature (< 6 h) termination. Efficacy was estimated by ultrafiltration, urea reduction ratio (URR), and equilibrated Kt/V. Other outcomes included: changes in hemodynamic scores, circuit clotting, adverse events, and changes in indices on point-of-care ultrasonography and echocardiography.

Results: Between November 2018 and March 2020, 18 patients with median age 8.6 y and vasopressor dependency index of 83.2, underwent 41 sessions of SLED. In 16 patients, SLED was feasible within 12 h of indication. No session was terminated prematurely. Ultrafiltration achieved was 4.0 ± 2.2 mL/kg/h, while URR was 57.7 ± 16.2% and eKt/V 1.17 ± 0.56. Hemodynamic scores did not change significantly. Asymptomatic hypokalemia was the chief adverse effect. Sessions were associated with a significant improvement in indices on ultrasound and left ventricular function. Fourteen patients died.

Conclusions: SLED is feasible, safe, and effective in enabling KRT in hemodynamically unstable children with severe AKI.
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http://dx.doi.org/10.1007/s12098-022-04214-zDOI Listing
July 2022

Short-Term Effects of Cholecalciferol Supplementation on cFGF23 Levels in Children with Chronic Kidney Disease and Vitamin D Insufficiency.

Indian J Pediatr 2022 Jun 30. Epub 2022 Jun 30.

Division of Nephrology, ICMR Center for Advanced Research in Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

Data on the effect of vitamin D supplementation on fibroblast growth factor 23 (FGF23), in chronic kidney disease (CKD) are scarce. In a prospective interventional study, the effect of vitamin D supplementation on cFGF23 (C-terminal FGF23) levels in children with CKD stages 2-4 was examined. Forty-one children with CKD and vitamin D insufficiency were administered 600,000 units of cholecalciferol over 3 d; 88% of patients achieved sufficiency at 8 wk. Significant increase in serum cFGF23 and phosphate levels was observed in CKD stage 2 after supplementation, but not in CKD stages 3 and 4. There was no correlation of the change in cFGF23 level with baseline or change in bone health parameters (calcium, phosphate, parathormone or alkaline phosphatase) or with change in flow-mediated dilatation (FMD) of the brachial artery. It is concluded that cholecalciferol supplementation increases serum calcium and reduces PTH, but does not adversely affect FGF23 levels in CKD.
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http://dx.doi.org/10.1007/s12098-022-04247-4DOI Listing
June 2022

Genetic and clinical profile of patients with hypophosphatemic rickets.

Eur J Med Genet 2022 Aug 21;65(8):104540. Epub 2022 Jun 21.

Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, India. Electronic address:

Nutritional vitamin D deficiency is the most frequent cause of rickets followed by genetic causes, that include entities like classic hypophosphatemic rickets (FGF23 related), Dent disease, Fanconi syndrome, renal tubular acidosis, and vitamin D dependent rickets. Hypophosphatemia is a feature in all these forms. The diagnosis relies on a combination of clinical, biochemical and radiological features, but genetic testing is required to confirm the diagnosis. We screened 66 patients with hypophosphatemic rickets referred to this center between May 2015 and July 2019 using whole exome sequencing (WES) in addition to the measurement of their intact serum fibroblast growth factor 23 (FGF23) levels. WES revealed 36 pathogenic and 28 likely pathogenic variants in 16 different genes (PHEX, FGF23, DMP1, ENPP1, CLCN5, CTNS, SLC2A2, GATM, SLC34A1, EHHADH, SLC4A1, ATP6V1B1, ATP6V0A4, CYP27B1, VDR and FGFR1) in 63 patients which helped differentiate between the various forms of hypophosphatemic rickets. Intact serum FGF23 levels were significantly higher in patients with variations in PHEX, FGF23, DMP1 or ENPP1 genes. The major genetic causes of rickets were classic hypophosphatemic rickets with elevated FGF23 levels, distal renal tubular acidosis, and vitamin D dependent rickets. Based on the present results, we propose a customized gene panel for targeted exome sequencing, which will be useful for confirming the diagnosis in most patients with hypophosphatemic rickets.
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http://dx.doi.org/10.1016/j.ejmg.2022.104540DOI Listing
August 2022

Virulence gene mutations as a differentiator of clinical phenotypes: insights from community-acquired uropathogenic .

Microbiology (Reading) 2022 04;168(4)

Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.

Uropathogenic (UPEC) remains an important cause of urinary tract infection during pregnancy. Multiple molecular virulence determinants and antibiotic resistant genes facilitate its pathogenesis and virulence phenotype. Hence it is hypothesized that there will be considerable variation in genes among the isolates from symptomatic as well as asymptomatic bacteriuria (ABU) during pregnancy. The aim of this study was to decipher the genetic variation among the two phenotypes. Six different UPEC isolates collected from urine specimens of consecutive pregnant females (five, symptomatic bacteriuria and one, ABU) were tested for their growth kinetics, and biofilm formation. A total of 87 virulence determinants and 56 antibiotic resistance genes were investigated using whole-genome sequencing, to identify putative drives of virulence phenotype. In this analysis, we identified eight different types of fully functional toxin antitoxin (TA) systems [HipAB, YefM-YoeB, YeeU-YeeV (CbtA), YhaV-PrlF, ChpBS, HigAB, YgiUT and HicAB] in the isolates from symptomatic bacteriuria; whereas partially functional TA system with mutations were observed in the asymptomatic one. Isolates of both the groups showed equivalent growth characteristics and biofilm-formation ability. Genes for an iron transport system (Efe UOB system, Fhu system except FhuA) were observed functional among all symptomatic and asymptomatic isolates, however functional mutations were observed in the latter group. Gene YidE was observed predominantly associated with the biofilm formation along with few other genes (BssR, BssS, YjgK, etc.). This study outlines putative critical relevance of specific variations in the genes for the TA system, biofilm formation, cell adhesion and colonization among UPEC isolates from symptomatic and asymptomatic bacteriuria among pregnant women. Further functional genomic study in the same cohort is warranted to establish the pathogenic role of these genes.
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http://dx.doi.org/10.1099/mic.0.001161DOI Listing
April 2022

Prevalence and resistance pattern of uropathogens from community settings of different regions: an experience from India.

Access Microbiol 2022 9;4(2):000321. Epub 2022 Feb 9.

Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India.

Introduction: Urinary tract infection (UTI) is one of the most common infections in clinical practice worldwide in both healthcare and community settings causing significant morbidity and mortality. It is one of the major conditions at the community level treated empirically and regarded as a potential cause of emergence of antimicrobial resistance (AMR). Limited information is available regarding community-acquired UTI (CA-UTI) from India.

Methodology: This is a first of its kind, multicentric-cross-sectional study at the community level targeting patients attending the out-patient department (OPD) of the community health centre (CHC) from four geographical regions (North, South, West and East) of India. The study had been designed to determine the epidemiology, antibiogram profile and identification of extended-spectrum beta-lactamase (ESBL) producer and carbapenem resistant (CR) uropathogens. Samples were collected prospectively from UTI suspected patients coming at CHC and processed at the tertiary healthcare centres using a common standard operating procedure. Clinical history of all the patients exhibiting significant bacteriuria was collected and data was analysed.

Result: Overall, 250 out of a total of 2459 (10.1 %) urine samples were positive for bacteria with significant bacteriuria (adult: paediatrics, 6.7 : 1). Females were predominantly affected (male: female, 1 : 2.9). History of recent episode of UTI was observed as the commonest risk factor followed by diabetes mellitus. Altogether, 86 % of total cases were caused by (68 %) and (17.6 %) together. Among the commonly used oral antibiotics for the Gram-negative bacilli (GNB), the highest resistance was observed against beta-lactams, first- and second-generation cephalosporins, fluoroquinolones and co-trimoxazole. Overall, the prevalence of ESBL producer and CR isolates were 44.8, and 4.3 %, respectively. However, the ESBL production, CR and nitrofurantoin resistance among the uropathogenic (UPEC) isolates was 52.8, 5.1 and 14 %, respectively. No resistance was found against fosfomycin among the UPEC isolates.

Conclusion: The current study highlights the increasing incidence of AMR among uropathogens at the community-settings of India. A significant percentage of ESBL producers among the isolated UPEC and were observed. The currently available evidence supports the clinical recommendation of fosfomycin and nitrofurantoin for empiric therapy in CA-UTI in India.
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http://dx.doi.org/10.1099/acmi.0.000321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8941965PMC
February 2022

Efficacy of rituximab versus tacrolimus in difficult-to-treat steroid-sensitive nephrotic syndrome: an open-label pilot randomized controlled trial.

Pediatr Nephrol 2022 Mar 14. Epub 2022 Mar 14.

Division of Nephrology, ICMR Center for Advanced Research in Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

Background: Rituximab and tacrolimus are therapies reserved for patients with frequently relapsing or steroid-dependent nephrotic syndrome who have failed conventional steroid-sparing agents. Given their toxicities, demonstrating non-inferiority of rituximab to tacrolimus may enable choice between these medications.

Methods: This investigator-initiated, single-center, open-label, pilot randomized controlled trial examined the non-inferiority of two doses of intravenous (IV) rituximab given one-week apart to oral therapy with tacrolimus (1:1 allocation), in maintaining sustained remission over 12 months follow-up, in patients with difficult-to-treat steroid-sensitive nephrotic syndrome, defined as frequently relapsing or steroid-dependent disease that had failed ≥ 2 steroid-sparing strategies. Secondary outcomes included frequency of relapses, proportion with frequent relapses, time to relapse and frequent relapses, and adverse events (CTRI/2018/11/016342).

Results: Baseline characteristics were comparable for 41 patients randomized to receive rituximab (n = 21) or tacrolimus (n = 20). While 55% of patients in each limb were in sustained remission at 1 year, non-inferiority of rituximab to tacrolimus was not demonstrated (mean difference 0%; 95% CI - 30.8%, 30.8%; non-inferiority limit - 20%; P = 0.50). Frequent relapses were more common in patients administered rituximab compared to tacrolimus (risk difference 30%, 95% CI 7.0, 53.0, P = 0.023). Both groups showed similar reductions in relapse rates and prednisolone use. Common adverse events were infusion-related with rituximab and gastrointestinal symptoms with tacrolimus.

Conclusions: Therapy with rituximab was not shown to be non-inferior to 12-months treatment with tacrolimus in maintaining remission in patients with difficult-to-treat steroid-sensitive nephrotic syndrome. Frequent relapses were more common with rituximab. While effective, both agents require close monitoring for adverse events. A higher resolution version of the Graphical abstract is available as Supplementary information.
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http://dx.doi.org/10.1007/s00467-022-05475-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919684PMC
March 2022

Anti-factor H antibody associated hemolytic uremic syndrome following SARS-CoV-2 infection.

Pediatr Nephrol 2022 Sep 28;37(9):2151-2156. Epub 2022 Jan 28.

Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Background: The pathogenesis of autoantibody generation in anti-factor H (FH) antibody associated atypical hemolytic uremic syndrome (aHUS) is unknown and is perhaps triggered by an infectious or environmental agent. We observed an unusual increase of patients with anti-FH antibody associated aHUS coinciding with the second pandemic wave in New Delhi and suspected that SARS-CoV-2 infection might be a potential trigger.

Methods: We screened for SARS-CoV-2 infection using reverse transcriptase polymerase chain reaction (RT-PCR) and serology in 13 consecutive patients with anti-FH antibody associated aHUS during the past year in New Delhi.

Results: We report 5 patients, 4-13 years old, who presented with a febrile illness without respiratory symptoms during the second pandemic wave. Of these, 3 patients presented with a relapse 25-85 months following the initial episode of aHUS. SARS-CoV-2 was detected by RT-PCR in 1 patient and by serology in 4 patients (median titer 47.1 cut-off index). Patients had high titers of anti-FH antibodies (median 2,300 AU/ml). Genetic studies, done in 3 of the 5 patients, showed homozygous CFHR1 deletion without other significant genetic abnormalities. Specific management comprised plasma exchanges and oral prednisolone, combined with either cyclophosphamide or mycophenolate mofetil. At median follow-up of 3.3 months, the estimated glomerular filtration rate in 4 patients ranged from 62 to 110 ml/min/1.73 m; one patient was dialysis-dependent.

Conclusion: Increased vigilance is required during the pandemic, especially in patients with anti-FH associated aHUS, who might relapse despite quiescent disease for a prolonged period. A higher resolution version of the Graphical abstract is available as Supplementary information.
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http://dx.doi.org/10.1007/s00467-021-05390-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8796738PMC
September 2022

Efficacy and Safety of Combination Therapy with Tolvaptan and Furosemide in Children with Nephrotic Syndrome and Refractory Edema: A Prospective Interventional Study.

Indian J Pediatr 2022 07 26;89(7):699-705. Epub 2022 Jan 26.

Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, 110029, India.

Objective: Severe edema in children with nephrotic syndrome is often refractory to conventional diuretics. Tolvaptan has been used satisfactorily for managing edema in patients with heart failure and cirrhosis. The safety and efficacy of combination therapy with oral tolvaptan and intravenous (IV) furosemide was assessed in patients with furosemide refractory edema.

Methods: Patients, aged 5-18 y with nephrotic syndrome and severe edema, were screened for eligibility. After excluding hypovolemia, patients received IV furosemide (3-4 mg/kg/d) for 48 h. Those refractory to IV furosemide (weight loss < 3%) received tolvaptan (0.5-1 mg/kg once daily) and IV furosemide for the next 48 h. Parameters were compared between 48 h of furosemide alone and combination therapy.

Results: A total of 24 patients (18 boys) with mean age of 8.0 ± 3.0 y were enrolled. Urine volume significantly increased with combination therapy as compared to furosemide therapy (mean difference: 1.2 mL/kg/h; 95% CI: 0.8-1.65 mL/kg/h) (p < 0.001). Compared to therapy with furosemide alone, combination therapy resulted in significant reduction in body weight from 26.9 ± 10.3 kg to 24.8 ± 9.7 kg (p < 0.001). Estimated glomerular filtration rate did not change (p = 0.81) but serum sodium increased from 135.7 ± 3.3 mEq/L to 140.4 ± 4.8 mEq/L (p < 0.001) with combination therapy; 2 patients showed asymptomatic hypernatremia.

Conclusion: The combination of oral tolvaptan and IV furosemide is effective in augmenting diuresis and reducing weight in patients with furosemide refractory edema but requires monitoring of electrolytes and volume status.
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http://dx.doi.org/10.1007/s12098-021-03988-yDOI Listing
July 2022

SARS-CoV-2 infection in children with chronic kidney disease.

Pediatr Nephrol 2022 04 14;37(4):849-857. Epub 2021 Sep 14.

Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.

Background: Information on the course of SARS-CoV-2 infection in children with chronic kidney disease (CKD) is limited.

Methods: We retrospectively reviewed the presentation and outcomes of SARS-CoV-2 infection in patients with CKD followed at any of the four pediatric nephrology centers in New Delhi from April 2020 to June 2021. Outcomes, including cardiopulmonary and renal complications, were reported in relation to underlying disease category and illness severity at presentation.

Results: Underlying illness in 88 patients included nephrotic syndrome (50%), other CKD stages 1-4 (18.2%), CKD 5D (17%), and CKD 5T (14.8%). Thirty-two of 61 patients with symptomatic COVID-19 and 9/27 asymptomatic patients were admitted for median 10 (interquartile range 7-15) days. Seventeen (19.3%) patients developed moderate or severe COVID-19. Systemic complications, observed in 30 (34.1%), included acute kidney injury (AKI, 34.2%), COVID-19 pneumonia (15.9%), unrelated pulmonary disease (2.3%), and shock (4.5%). Nineteen (21.6%) had severe complications (AKI stage 2-3, encephalopathy, respiratory failure, shock). Eight (11%) of twelve (16.4%) patients with severe AKI required dialysis. Three (3.4%) patients, two with steroid-resistant nephrotic syndrome in relapse and one with CKD 1-4, died due to respiratory failure. Univariate logistic regression indicated that patients presenting with nephrotic syndrome in relapse or moderate to severe COVID-19 were at risk of AKI (respective odds ratio, 95%CI: 3.62, 1.01-12.99; 4.58, 1.06-19.86) and/or severe complications (respective odds ratio, 95%CI: 5.92, 1.99-17.66; 61.2, 6.99-536.01).

Conclusions: Children with CKD presenting with moderate-to-severe COVID-19 or in nephrotic syndrome relapse are at risk of severe complications, including severe AKI and mortality. A higher resolution version of the Graphical abstract is available as Supplementary information.
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http://dx.doi.org/10.1007/s00467-021-05218-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438908PMC
April 2022

Survey of Telemedicine by Pediatric Nephrologists During the COVID-19 Pandemic.

Kidney Int Rep 2021 Sep 7;6(9):2316-2322. Epub 2021 Jul 7.

Department of Hematology and Oncology, Akron Children's Hospital, Akron, Ohio, USA.

Introduction: The slow increase in use of telemedicine began to expand rapidly, along with reimbursement changes, during the coronavirus disease-2019 (COVID-19) pandemic. Standardized protocols for these services are lacking but are needed for effective and equitable health care. In this study, we queried pediatric nephrologists and their patients about their telemedicine experiences during the pandemic.

Methods: Surveys that were in compliance with the Health Insurance Portability and Accountability Act were deployed online to patients and physicians.

Results: We collected survey responses from 400 patients and 197 pediatric nephrologists. Patients reported positive experiences with telemedicine visits as it was logistically easier than in-person visits. Patients also felt that the quality of their visits were equivalent to what they would receive in person. Physicians used a wide variety of online systems to conduct synchronous telemedicine with Zoom (23%), EPIC (9%), Doxy.me (7%), services not specified (37%), or a mix of local or smaller services (24%). Most physicians' concerns were related to technological issues and the ability to procure physical exams and/or laboratory results.

Conclusions: There is a paucity of published trials on telemedicine services in pediatric nephrology. Virtual care was feasible and acceptable for patients, caregivers, and providers during the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.ekir.2021.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419113PMC
September 2021

Non-antibiotic interventions for prevention of urinary tract infections in children: a systematic review and meta-analysis of randomized controlled trials.

Eur J Pediatr 2021 Dec 22;180(12):3535-3545. Epub 2021 Jun 22.

Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, India.

A considerable proportion of children experience a recurrence of urinary tract infection (UTI) following the first episode. While low-dose antibiotic prophylaxis has been the mainstay for the prevention of UTI, recent evidence raised concerns over their efficacy and safety. Hence, we aim to systematically synthesize evidence on the efficacy and safety of non-antibiotic prophylactic interventions for UTI. Using keywords related to study population (children) and intervention (non-antibiotic), we searched CENTRAL, Embase, PubMed, and Web of Science for randomized controlled trials (RCTs) published until August 2020. RCTs comparing any non-antibiotic interventions with placebo/antibiotics for prevention of UTIs in children were considered eligible. We used a random-effect model to provide pooled estimates. Sixteen trials evaluating 1426 participants were included. Cranberry was as effective as antibiotic prophylaxis (RR: 0.92; 95% CI: 0.56-1.50) but better than placebo/no therapy (RR: 0.48; 95% CI: 0.28-0.80) in reducing UTI recurrence. Probiotic therapy was more effective in reducing UTI recurrence (RR: 0.52; 95% CI: 0.29-0.94) when compared with placebo. While probiotic therapy was not better than antibiotics prophylaxis in preventing UTI (RR: 0.82; 95% CI: 0.56-1.21), they have a lower risk of antibiotic resistance (RR: 0.38; 95% CI: 0.21-0.69).Conclusion: Cranberry products and probiotics are the two non-antibiotic interventions that have been chiefly evaluated, reduce the risk of UTI recurrence when compared with placebo in children with a normal urinary tract. The findings from this systematic review suggest that while cranberry and probiotics may be used, there is a definite need to identify better and more acceptable non-antibiotic interventions. What is Known: • Efficacy of the low-dose antibiotic is controversial in preventing UTI and it is associated with increase in the risk of antimicrobial resistance. • Non-antibiotic interventions such as cranberry products are effective in preventing UTI recurrence in adults. What is New: • Cranberry products are effective in reducing the recurrence of UTI in children with normal urinary tract. • Low-quality evidence suggests that probiotics can be a potential prophylactic measure to reduce recurrence of UTI in the pediatric population.
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http://dx.doi.org/10.1007/s00431-021-04091-2DOI Listing
December 2021

Importance of clinical practice guidelines to practicing pediatric nephrologists and IPNA survey.

Pediatr Nephrol 2021 11 20;36(11):3493-3497. Epub 2021 May 20.

Department of Pediatric Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover Medical School, Carl-Neuberg-Str 1, 30625, Hannover, Germany.

Clinical practice guidelines (CPGs) are systematically developed statements backed by scientific evidence to assist practitioners in management in clinical practice. An international cross-sectional survey was conducted by the IPNA to examine the perceptions of pediatric nephrologists on guidelines and their usage and to identify important diseases for future clinical practice guidelines (CPGs). The survey found that the majority of pediatric nephrologists find CPGs useful in clinical practice and admitted to using them most of the time. Developing CPGs is challenging and there are standards available to develop trustworthy guidelines. While evidence-based global guidelines are ideal, pediatric nephrologists expressed the desire that they address regional differences. Most respondents (89.2%) to the survey agreed that adult guidelines did not cover the pediatric perspective adequately and 71.4% opined that consensus-based pediatric guidelines can be developed when evidence for the pediatric population is lacking. The development of high-quality practice guidelines requires substantial resources and may not be feasible in resource-poor countries. Adaptation of an existing guideline has been suggested as an alternative and the ADAPTE collaboration provides a systematic approach to adapting guidelines. Several diseases where pediatric guidelines are needed as a priority including IgA and C3 glomerulopathy were identified in the survey. Implementation of guideline-based care is challenging and the survey found that lack of availability of guidelines (43%) and resources (22.8%) are important reasons for poor implementation in lower-middle and low-income countries. Perceived complexity of guidelines, physician attitudes, and lack of training also contribute to non-adherence to guidelines.
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http://dx.doi.org/10.1007/s00467-021-05105-9DOI Listing
November 2021

Next-Generation Sequencing for Congenital Nephrotic Syndrome: A Multi-Center Cross-Sectional Study from India.

Indian Pediatr 2021 May;58(5):445-451

Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. Correspondence to: Professor Arvind Bagga, Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Objective: Information on etiology of congenital nephrotic syndrome in non-Caucasian populations is limited. This study aimed to determine the genetic basis of congenital nephrotic syndrome in Indian patients.

Methods: In this observational, cross-sectional study, whole exome sequencing was performed on samples from all children diagnosed with congenital nephrotic syndrome, presenting at centers collaborating in a nationwide registry and biorepository. Analysis was targeted to focus on reported or novel, pathogenic or likely pathogenic variants in 89 genes implicated in etiology of nephrotic syndrome. Sanger sequencing was used to confirm disease-causing variants in patients and allelic segregation of compound heterozygous variants in samples from parents. Inheritance of a shared haplotype was analyzed among ten individuals carrying the most common variant.

Results: During 2017-2019, 34 patients with congenital nephrotic syndrome were screened. Consanguinity and similar illness in siblings were reported in eleven patients each. Homozygous or compound heterozygous, pathogenic or likely pathogenic variants were found in NPHS1 in 24 cases, including two novel variants. One patient each had homozygous pathogenic or likely pathogenic known or novel variant in NPHS2, PLCE1, OSGEP and LAMB2 genes. Patients with OSGEP and LAMB2 mutations had phenotype typical of Galloway Mowat and Pierson syndromes, respectively. Three variants in NPHS1 were common to 16 individuals. One reported variant in exon 19 (c.2600G>A; p.Gly867Asp) appears to share a common founder.

Conclusions: A genetic cause was determined for 82.4% patients with congenital nephrotic syndrome. Variants in NPHS1 are most common in Indian patients and founder mutations might be present.
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May 2021

Short-Duration Prednisolone in Children with Nephrotic Syndrome Relapse: A Noninferiority Randomized Controlled Trial.

Clin J Am Soc Nephrol 2021 02 21;16(2):225-232. Epub 2021 Jan 21.

Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Background And Objectives: In children with nephrotic syndrome, steroids are the cornerstone of therapy for relapse. The adequate duration and dosage of steroids, however, have not been an active area of research, especially in children with infrequently relapsing nephrotic syndrome. This study investigated the efficacy of an abbreviated regimen for treatment of a relapse in this population.

Design, Setting, Participants, & Measurements: In a single-center, open-label, randomized controlled trial, we evaluated the efficacy of prednisolone as a "short regimen" (40 mg/m on alternate days for 2 weeks) compared with "standard regimen" (40 mg/m on alternate days for 4 weeks) for children aged 1-16 years who achieved remission of a relapse. The primary outcome was the proportion of children developing frequent relapses or steroid dependence at 12 months.

Results: A total of 117 patients were enrolled and randomized to short (55) or standard (62) regimen. Fourteen (24%) patients in standard regimen and 12 (23%) in short regimen developed frequent relapses or steroid dependence over a period of 1 year (risk difference, -1%; 95% confidence interval, -15 to 16; =0.90). A large 95% confidence interval crossed the proposed noninferiority margin. In a time to event analysis, there was no significant difference in the proportion of children developing frequent relapses or steroid dependence and time to outcome between the two groups (hazard ratio, 1.01; 95% confidence interval, 0.83 to 1.23; =0.98). Time to relapse, relapse rate, and steroid-related adverse events were similar in both groups. Cumulative steroid exposure was significantly lower in the short regimen (risk difference, -541 mg/m; 95% confidence interval, -917 to -164 mg/m; <0.001).

Conclusions: In children with infrequently relapsing nephrotic syndrome, a short steroid treatment for relapse resulted in a similar proportion of patients developing frequent relapses or steroid dependence; however, noninferiority of a short regimen was not established.

Clinical Trial Registry Name And Registration Number: CTRI/2015/11/006345.
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http://dx.doi.org/10.2215/CJN.06140420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863637PMC
February 2021

Consensus Guidelines on Management of Steroid-Resistant Nephrotic Syndrome.

Indian Pediatr 2021 Jul 4;58(7):650-666. Epub 2021 Jan 4.

Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. Correspondence to:Dr. Arvind Bagga, Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi110029, India.

Justification: The management of steroid resistant nephrotic syndrome (SRNS) is challenging. These guidelines update existing 2009 Indian Society of Pediatric Nephrology recommendations on its management.

Objective: To frame revised guidelines on diagnosis and evaluation, treatment and follow up, 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 systematic review of literature, evaluation of evidence by experts and two face-to-face meetings.

Recommendations: Fourteen statements provide updated advice for managing steroid resistance, and underscore the importance of estimating proteinuria and baseline kidney function, and the need for kidney biopsy and genetic screening. Calcineurin inhibitors are recommended as most effective in inducing remission of proteinuria, the chief factor associated with long-term renal survival. Advice on managing allograft recurrence, congenital nephrotic syndrome, and monitoring and supportive care, including transition of care, are described. This revised practice guideline is intended to improve management and patient outcomes, and provide direction for future research.
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July 2021

Impaired Distal Tubular Acidification, Renal Cysts and Nephrocalcinosis in Monogenic Hypertension.

Indian J Pediatr 2021 06 25;88(6):579-581. Epub 2020 Nov 25.

Division of Nephrology, Department of Pediatrics and ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, 110029, New Delhi, India.

Monogenic defects in tubular sodium handling contribute a small proportion to hypertension in childhood. Presentation varies from severe hypertension manifesting at birth to asymptomatic hypertension and hypokalemic metabolic alkalosis detected incidentally in adulthood. A 12-y-old girl presenting with polyuria, polydipsia, severe hypertension and seizures, was found to have hypokalemia, renal medullary cysts and nephrocalcinosis. Clinical exome revealed a homozygous variation of unknown significance in exon 5 of the HSD11B2 gene, indicating the diagnosis of apparent mineralocorticoid excess. Therapy with spironolactone was associated with resolution of hypokalemia and normal blood pressure during two-year follow up.
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http://dx.doi.org/10.1007/s12098-020-03516-4DOI Listing
June 2021

Phenotypic variability in distal acidification defects associated with WDR72 mutations.

Pediatr Nephrol 2021 04 7;36(4):881-887. Epub 2020 Oct 7.

Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Background: Distal renal tubular acidosis (RTA) is typically caused by defects in ATP6V0A4, ATP6V1B1, and SLC4A1, accounting for 60-80% of patients. Genes recently implicated include FOXI1, ATP6V1C2, and WDR72, of which WDR72 is associated with dental enamel defects.

Methods: We describe 4 patients, from three unrelated consanguineous families, with RTA and amelogenesis imperfecta. Distal tubular acidification was evaluated by furosemide-fludrocortisone test, urine-to-blood PCO2 gradient and fractional excretion of bicarbonate. Exome sequencing was performed using a panel of genes implicated in human disease.

Results: Patients had polyuria, hypokalemia, hypercalciuria, and nephrocalcinosis, but metabolic acidosis varied in severity. Although all patients acidified urine to pH < 5.3 during furosemide-fludrocortisone test, urine-to-blood PCO gradient was < 20 mmHg during bicarbonate loading. All patients had transient proximal tubular dysfunction with urinary losses of phosphate and beta-2-microglobulin, and generalized aminoaciduria. Homozygous pathogenic truncating variants in WDR72 was detected in all probands.

Conclusion: Patients with WDR72 mutations show mild rate-dependent distal RTA with variable metabolic acidosis, and intact ability to acidify the urine on provocative testing. Concomitant proximal tubular dysfunction may be present. Mutations in WDR72 should be considered in patients with suspected distal RTA, especially if associated with dental defects.
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http://dx.doi.org/10.1007/s00467-020-04747-5DOI Listing
April 2021

Therapy and outcomes of C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis.

Pediatr Nephrol 2021 03 4;36(3):591-600. Epub 2020 Sep 4.

Division of Nephrology, ICMR Center for Advanced Research in Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Background: Data on therapy and outcome of dense deposit disease (DDD), C3 glomerulonephritis (C3GN), and immune-complex MPGN (IC-MPGN) in children are limited.

Methods: In this retrospective single-center study from 2007 to 2019, kidney biopsies were reviewed to include patients aged <18-years with C3 glomerulopathy and IC-MPGN. Initial immunosuppression comprised prednisolone, mycophenolate mofetil (n = 51), tacrolimus (n = 11), and/or IV cyclophosphamide (n = 20). Clinicopathological features, response to therapy, and adverse outcome (eGFR < 15 mL/min/1.73 m or death) were evaluated.

Results: A total of 92 patients were classified as DDD (n = 48, 52.2%), C3GN (n = 26, 28.3%), and IC-MPGN (n = 18, 19.6%) by immunohistochemistry and electron microscopy; 8 patients with DDD were misclassified as IC-MPGN on immunofluorescence. At last follow-up (median 4.3 years), complete or partial remission occurred in 28.5, 36.1, and 16.7% patients with DDD, C3GN, and IC-MPGN, respectively. Serum albumin at onset < 2.5 g/dL (HR = 0.29, P = 0.005) and persistently low serum C3 (HR = 0.34, P = 0.02) were associated with lack of remission. The 5-year kidney survival was 62.6, 85.5, and 88.5% in patients with DDD, C3GN, and IC-MPGN, respectively (log-rank, P = 0.006). Presentation as rapidly progressive GN (HR = 11.2, P < 0.001), age > 10 years at onset (HR = 4.0, P = 0.004), and DDD (HR = 4.2, P = 0.02) were independently associated with adverse outcome; achieving remission was protective (HR = 0.04; P < 0.001).

Conclusion: Outcome in patients with C3 glomerulopathy and IC-MPGN was unsatisfactory, and only a small proportion of patients achieved complete or partial remission. Patients with DDD were more likely to present with rapidly progressive GN and were at higher risk of adverse outcomes, including kidney failure.
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http://dx.doi.org/10.1007/s00467-020-04736-8DOI Listing
March 2021

Managing Children With Renal Diseases During the COVID-19 Pandemic.

Indian Pediatr 2020 07;57(7):641-651

Division of Pediatric Nephrology, Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. Correspondence to: Dr Om P Mishra, Professor, Division of Pediatric Nephrology, Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, Uttar Pradesh, India.

The coronavirus outbreak is a rapidly evolving pandemic, placing unprecedented strain on health-care systems. COVID-19 presents challenges for management of children with renal diseases, especially those receiving long-term immunosuppressive medications, including renal transplant recipients and those with chronic kidney disease and acute kidney injury requiring dialysis. Our preparedness for managing this vulnerable group of children is the need of the hour. The purpose of this article is to provide guidance to caregivers and health care personnel involved in management of children with renal diseases and to ensure patient well-being, while protecting staff from infection.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387253PMC
July 2020

Managing Children with Renal Diseases during COVID-19 Pandemic.

Indian Pediatr 2020 May 15. Epub 2020 May 15.

Division of Pediatric Nephrology, Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. Correspondence to: Dr Om P Mishra, Professor, Division of Pediatric Nephrology, Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005.

The coronavirus outbreak is a rapidly evolving pandemic, placing unprecedented strain on health-care systems. COVID-19 presents challenges for management of children with renal diseases especially those receiving long-term immunosuppressive medications, including renal transplant recipients and those with chronic kidney disease and acute kidney injury requiring dialysis. Our preparedness for managing this vulnerable group of children is the need of the hour. The purpose of this article is to provide guidance to caregivers and health care personnel involved in management of children with renal diseases and to ensure patient well-being, while protecting staff from infection.
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May 2020

Prevalence of Bladder and Bowel Dysfunction in Toilet-Trained Children With Urinary Tract Infection and/or Primary Vesicoureteral Reflux: A Systematic Review and Meta-Analysis.

Front Pediatr 2020 31;8:84. Epub 2020 Mar 31.

Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, India.

Urinary tract infection (UTI) in children leads to renal scarring in 10-15% of patients. Urinary tract anomalies and bladder and bowel dysfunction (BBD) are documented risk factors for recurrent UTIs. Estimates of baseline prevalence of BBD in children with UTI will help the clinician in the management strategy. Hence, a systematic review and meta-analysis was conducted to estimate the pooled prevalence of BBD. MEDLINE, EMBASE, and CENTRAL (Cochrane Central Register of Controlled Trials) databases were searched for articles related to UTI, primary vesicoureteral reflux (VUR), and BBD. We included studies that provided prevalence of BBD in toilet-trained patients aged 1-18 years with UTI and/or VUR. BBD was defined based on clinical history or questionnaire or urodynamic studies. Two authors independently reviewed, assessed, and abstracted data from studies. Pooled prevalence was calculated based on a random effects model. Forty-three studies fulfilling the eligibility criteria were selected from a total of 1,731 studies. Among patients presenting with UTI without primary VUR, pooled prevalence of BBD was 41% (95% CI: 26-55; nine studies, 920 patients, = 96.0%), whereas its prevalence in patients with primary VUR was 49% (43-56; 30 studies, 5,060 patients, = 96.0%). Weighting by the study design and quality did not affect the prevalence. In patients with primary VUR, prevalence of BBD was higher in females (53%; 42-65) than in males (44%; 15-73). In studies where urodynamic study was used for the diagnosis of BBD, prevalence was 63%. The presence of BBD in patients with primary VUR increased risk of recurrent UTIs [relative risk (RR): 2.1; 1.7-2.5]. In five studies that reported separate data on constipation, pooled prevalence of constipation was 27% (16-37). Almost half of the patients with primary VUR have BBD, and its presence increases the risk of recurrent UTIs. Trends of high BBD prevalence were also observed in patients presenting with UTI without VUR. These prevalence estimates suggest that all toilet-trained children presenting with UTI with or without VUR should be assessed for BBD, which will help in their further management.
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http://dx.doi.org/10.3389/fped.2020.00084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145391PMC
March 2020

Isolated nephrocalcinosis due to compound heterozygous mutations in renal outer medullary potassium channel.

CEN Case Rep 2020 08 17;9(3):232-236. Epub 2020 Mar 17.

Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Identification of a monogenic etiology is possible in a proportion of patients with childhood-onset nephrolithiasis or nephrocalcinosis. Bartter syndrome (BS), a hereditary tubulopathy characterized by polyuria, hypokalemic alkalosis and growth retardation that rarely presents with isolated nephrocalcinosis. Patients with defect in renal outer medullary potassium channel, encoded by the KCNJ1 gene causing BS type 2, typically present during the neonatal period. We describe a 14-year-old girl with mild late-onset BS type 2 with reported pathogenic compound heterozygous variations in exon 2 of KCNJ1 (c.146G > A and c.657C > G). This patient presented with isolated medullary nephrocalcinosis due to hypercalciuria; absence of hypokalemia and metabolic alkalosis was unique. This case highlights the importance of screening the KCNJ1 gene in patients with hypercalciuria and nephrocalcinosis, even in older children.
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http://dx.doi.org/10.1007/s13730-020-00464-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320131PMC
August 2020

Therapy with the Combination of Tolvaptan and Furosemide for Refractory Edema in Nephrotic Syndrome.

Indian J Nephrol 2020 Jan-Feb;30(1):53-55. Epub 2019 Sep 6.

Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, India.

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http://dx.doi.org/10.4103/ijn.IJN_358_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977386PMC
September 2019

Current Management of Urinary Tract Infection and Vesicoureteral Reflux.

Indian J Pediatr 2020 08 11;87(8):625-632. Epub 2019 Dec 11.

Department of Pediatrics, All India Institiute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Urinary tract infection (UTI) is defined as the growth of a significant number of microorganisms of a single species in the urine, in the presence of symptoms. Symptoms in young children are non-specific such as fever without focus; young infants may manifest with irritability, failure to thrive, jaundice, vomiting and diarrhea. Older children usually have symptoms of cystitis or pyelonephritis. Symptoms of cystitis are dysuria, frequency, new onset incontinence and malodorous urine while symptoms of pyelonephritis are high grade fever, flank pain and vomiting. Rapid urine testing by microscopy for pus cells, dipstick testing for leukocyte esterase and nitrite, and enhanced urinalysis are supportive tests. Urine culture samples should be collected with proper technique and results interpreted for significant growth accordingly. Antibiotic therapy for 7-14 d for complicated UTI and 3-4 d for uncomplicated UTI is adequate. Further evaluation is recommended clinically for bladder-bowel dysfunction and obvious anatomical defects and by imaging for vesicoureteral reflux (VUR), usually by micturating cystourethrography (MCU). Since MCU involves exposure to radiation and urethral catheterization, it is now reserved for children with parenchymal involvement or recurrent UTI. VUR is the backward flow of urine into one or both ureters. Clinical manifestations other than UTI include incidental diagnosis on antenatal ultrasonography. Reflux nephropathy, the renal scarring associated with VUR may manifest clinically as hypertension, proteinuria and renal failure. The management of VUR is primarily with antibiotic prophylaxis. Anatomical correction is indicated in case of breakthrough febrile UTI. No intervention has been shown to reduce renal scarring.
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http://dx.doi.org/10.1007/s12098-019-03099-9DOI Listing
August 2020

Dyslipidemia and cardiovascular health in childhood nephrotic syndrome.

Pediatr Nephrol 2020 09 13;35(9):1601-1619. Epub 2019 Jul 13.

Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA.

Children with steroid-resistant nephrotic syndrome (SRNS) are exposed to multiple cardiovascular risk factors predisposing them to accelerated atherosclerosis. This risk is negligible in steroid-sensitive nephrotic syndrome, but a substantial proportion of children with SRNS progress to chronic kidney disease, exacerbating the already existing cardiovascular risk. While dyslipidemia is an established modifiable risk factor for cardiovascular disease in adults with NS, it is uncertain to what extent analogous risks exist for children. There is increasing evidence of accelerated atherosclerosis in children with persistently high lipid levels, especially in refractory NS. Abnormalities of lipid metabolism in NS include hypertriglyceridemia and hypercholesterolemia due to elevated apolipoprotein B-containing lipoproteins, decreased lipoprotein lipase and hepatic lipase activity, increased hepatic PCSK9 levels, and reduced hepatic uptake of high-density lipoprotein. Existing guidelines for the management of dyslipidemia in children may be adapted to target lower lipid levels in children with NS, but they will most likely require both lifestyle modifications and pharmacological therapy. While there is a lack of data from randomized controlled trials in children with NS demonstrating the benefit of lipid-lowering drugs, therapies including statins, bile acid sequestrants, fibrates, ezetimibe, and LDL apheresis have all been suggested and/or utilized. However, concerns with the use of lipid-lowering drugs in children include unclear side effect profiles and unknown long-term impacts on neurological development and puberty. The recent introduction of anti-PCSK9 monoclonal antibodies and other therapies targeted to the molecular mechanisms of lipid transport disrupted in NS holds promise for the future treatment of dyslipidemia in NS.
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http://dx.doi.org/10.1007/s00467-019-04301-yDOI Listing
September 2020

Successful use of tocilizumab in amyloidosis secondary to systemic juvenile idiopathic arthritis.

Rheumatol Int 2020 Jan 4;40(1):153-159. Epub 2019 Jul 4.

Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Amyloidosis secondary to juvenile idiopathic arthritis is a known complication of poorly controlled systemic juvenile idiopathic arthritis (SJIA), occurring in 1-2% of the patients. The IL-6 inhibitor tocilizumab is effective in controlling systemic signs and symptoms of sJIA and may be of therapeutic benefit in secondary amyloidosis. Herein, we report the clinical timeline of a 10-year boy with sJIA and secondary amyloidosis, who showed a sustained improvement of systemic symptoms and a reduction in proteinuria with tocilizumab. Compared to the data on adult patients affected with the secondary amyloidosis, there are very few reports on therapeutic options for the children affected with SJIA and secondary amyloidosis in the paediatric population. While doing a systematic literature search for writing this review, we could only retrieve nine case reports and one case series of the children affected with SJIA and secondary amyloidosis, including five cases which were treated with tocilizumab. We also looked into the clinical and biochemical response to various agents that have been used in the previous cases, including tocilizumab. The available literature and the present case report suggest that tocilizumab may be considered as a safe and effective option to treat SJIA-related secondary amyloidosis.
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http://dx.doi.org/10.1007/s00296-019-04363-zDOI Listing
January 2020

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

Front Immunol 2019 7;10:1282. Epub 2019 Jun 7.

Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

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. 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 ( = 317) were compared to before ( = 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 ( = 8) were examined. Functional renal reserve, ambulatory hypertension, left ventricular hypertrophy (LVH), and proteinuria were evaluated in a subset. 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 = 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), = 0.001]; anti-FH levels ≥1,330 AU/ml and free FH ≤440 mg/l predicted relapse (hazards ratio, HR 6.3; = 0.018). Epitope specificity was similar during onset, remission and relapse. Antibody titer ≥8,000 AU/ml (HR 2.23; = 0.024), time to PEX ≥14 days (HR 2.09; = 0.071) and PEX for <14 days (HR 2.60; = 0.017) predicted adverse renal outcomes. Combined PEX and immunosuppression improved long-term outcomes (HR 0.37; = 0.026); maintenance therapy reduced risk of relapses (HR 0.11; < 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. 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.
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http://dx.doi.org/10.3389/fimmu.2019.01282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567923PMC
November 2020

Membrane-filtration based plasma exchanges for atypical hemolytic uremic syndrome: Audit of efficacy and safety.

J Clin Apher 2019 Oct 7;34(5):555-562. Epub 2019 Jun 7.

Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Background: While complement blockade with eculizumab is recommended as first-line therapy of atypical hemolytic uremic syndrome (aHUS), plasma exchanges (PEX) remain the chief option for anti-factor H (FH) antibody associated disease and when access to eculizumab is limited.

Methods: We reviewed adverse events (AEs) and adverse outcomes (eGFR <30 mL/min/1.73 m or death), in all patients with aHUS managed with membrane-filtration based PEX at one tertiary care center over 5.5 years.

Results: During January 2013 to June 2018, 109 patients with aHUS (74 with antibodies to FH), aged median (range) 7.6 (0.5-18) year weighing 22.1 (6-90) kg, underwent 2024 sessions of PEX. AE, in 12.1% patients, were usually self-limiting and included chills (5.5%), vomiting/abdominal pain (3.3%), hypotension (1.6%), urticaria (1.5%), seizures (0.2%), hypocalcemia (0.2%), and hemorrhage (0.1%); plasma hypersensitivity and severe reactions were rare. Rate of catheter-related infections was 1.45/1000 catheter-days. Filter reuse (OR 1.69; 95% CI 1.26-2.26; P < .001) and >20 sessions of PEX/patient (OR 1.99; 95% CI 1.27-3.10; P = .002) were independently associated with adverse events; infusion of IV calcium gluconate during PEX was protective (OR 0.26; 95% CI 0.16-0.43; P < .001). Hematological remission was achieved in 96.3% patients after 6 (5-8) PEX sessions; 80.8% and 89.6% patients were dialysis independent by one and 3 months, respectively.

Conclusions: PEX is safe and associated with satisfactory short-term outcomes in children with aHUS. Prolonged PEX and filter-reuse are associated with complications.
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http://dx.doi.org/10.1002/jca.21711DOI Listing
October 2019

Glomerular C4d Staining Does Not Exclude a C3 Glomerulopathy.

Kidney Int Rep 2019 May 13;4(5):698-709. Epub 2019 Feb 13.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.

Introduction: C4d, an early product in the classical/lectin complement pathway has shown potential in the evaluation of C3 glomerulopathy where its absence would support an alternative pathway abnormality. As autoimmune/genetic complement testing is not readily available to most parts of the world, glomerular C4d staining may serve as a useful additional step toward the diagnosis.

Methods: To test this hypothesis, C4d staining was performed on a large cohort of C3 glomerulopathy. Archival cases from 2011 to 2017 were reviewed and immunohistochemistry for C4d was performed, scored (scale of 0 to 3+), and correlated with the immunofluorescence and ultrastructural findings. Paraffin immunofluorescence was performed in cases of "discordant C4d" to unmask Igs.

Results: Twenty-seven cases of dense deposit disease (DDD) and 14 cases of C3 glomerulonephritis (C3GN) were retrieved. C4d demonstrated a range of staining intensities with negative/traces in only 22% of DDD and 64% of C3GN. Lower-intensity C4d staining (1 to 2+) was mostly concordant with similar amounts of Igs/C1q. Discordant 3+ staining was noted in approximately 50% of cases of DDD and 20% of cases of C3GN. Among them, paraffin immunofluorescence unmasked polyclonal Igs in 2 of 5 cases of DDD and 1 of 3 cases of C3GN.

Conclusion: This observational study suggests that the presence of glomerular C4d should not exclude a C3 glomerulopathy. In lower intensities, it appears to represent overlying classical/lectin pathway activation with concordant Ig/C1q deposits. A subset of cases, however, displays intense and discordant C4d staining, which raises the possibility of an associated lectin pathway abnormality, a potential future area of study.
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http://dx.doi.org/10.1016/j.ekir.2019.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506704PMC
May 2019
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