New insights from the genetic work-up in early onset nephrotic syndrome: report from a registry in western India.

BACKGROUND: Eighty-five percent of infants with congenital nephrotic syndrome (CNS) and 66% with infantile NS (INS) are likely to have a monogenic etiology. There exists a significant genetic variability between different regions and ethnic groups. This study aimed to determine the genetic defects in children with CNS and INS by establishing a registry in western India. METHODS: In this cross-sectional study, pediatric nephrologists from 13 private and government institutions shared relevant clinical data and details of the genetic evaluation of children presenting with NS within the first year of life. RESULTS: The median age at presentation was 9 months (range 1-23, IQR 3-13 months), history of consanguinity between parents existed in 14 patients (34%), family history of similar illness in 6 (15%), and extra-renal manifestations in 17 (41%). Twenty-five (61%) were confirmed to have a monogenic etiology. NPHS1 gene was the most implicated (9/25) followed by PLCE1 (5/25). There were 12 variants of uncertain significance (VUS) involving 10 genes (10/25, 40%), and no definite genetic abnormality was found in 4 (25%). A re-analysis of these VUS attempted 2-3 years later facilitated reclassification of 7/12 (58%); increasing the diagnostic yield from 61 to 68.2%. CONCLUSIONS: Consistent with worldwide data, variants in NPHS1 gene were the most common cause of NS in infancy; however, PLCE1 was implicated more frequently in our cohort. NUP93 and COL4A3 were reported in early onset NS for the first time. Reclassification of VUS should be attempted, if feasible, since it may lead to a useful revision of diagnosis.

Screening for protein energy wasting in children with chronic kidney disease using dual energy x-ray absorptiometry as an additional tool.

BACKGROUND: The current diagnosis of protein energy wasting (PEW) is based on scoring systems that lack precision in measuring muscle deficits. We undertook this cross-sectional study to determine the prevalence of PEW in children with chronic kidney disease (CKD) using a scoring system that included dual energy x-ray absorptiometry (DEXA) for measuring lean body mass (LBM) and to determine the prevalence of selected markers in PEW. METHODS: Thirty CKD and 20 healthy children (1-18 years) were evaluated for (1) reduced dietary protein intake (DPI); (2) BMI < fifth centile for height age (BMI/HA); (3) serum albumin < 3.8 g/dl, cholesterol < 100 mg/dl, or CRP > 3 mg/L; (4) LBM < fifth centile for height age [LBMr] on DEXA. PEW was scored as minimal-one parameter positive in 2/4 categories; standard-one parameter positive in 3/4 categories; or modified-standard plus height < 2 SD. RESULTS: Twenty children with CKD (66.7%) had PEW, (5/9) 55% in CKD 3, and (15/21) 71% in advanced CKD; minimal 12, standard 1, and modified 7. LBMr was seen in 20 (100%), reduced DPI in 16 (80%), and BMI/HA in 6 (30%) children with PEW. LBMr had 100% sensitivity and BMI/HA 100% specificity. LBMr was seen in 8 who had no other criteria for PEW. None of the parameters were positive in controls (p < 0.01). CONCLUSIONS: PEW prevalence in CKD was high. Both prevalence and severity were higher in advanced CKD. LBMr was a highly sensitive marker to detect PEW. LBMr seen in some children with CKD who were negative for other markers could represent subclinical PEW.

Survival of Tunneled Double Lumen-Cuffed Catheters in Children on Maintenance Hemodialysis - A Retrospective Cohort Study.

Introduction: Survival of tunneled cuffed catheters (TCC), used widely in children, is complicated by infections and catheter dysfunction. In resource limited settings, where risk of complications could be higher and waiting period for transplantation longer, catheter survival determines patient survival. This study was conducted to determine infection free catheter survival rates, incidence of catheter failure and associated risk factors. Methods: Children <18 years of age receiving maintenance hemodialysis through TCC at nephrology division of a pediatric hospital, over a period of 6 years. Data was collected with consecutive selection by a complete enumeration technique from pre-collected data sheets in the records. Exposure detected were catheter infections, thrombosis, and mechanical complications. Results: Forty-five TCCs in 36 children studied for 12,590 catheter days showed catheter failure in 36%, due to catheter related infections in 75% and mechanical complications in 25%. The incidence of complications per 1000 catheter days was 1.19 infection, 1.03 thrombus, and 0.39 mechanical. Catheter-related blood stream infection (CRBSI) (15/36) was associated with thrombus in nine and led to mortality in three. The mean infection free catheter survival was 449 ± 42 days for cohort with 388 ± 38 days in Group A (premature catheter removal) and 593 ± 43 days in Group B (elective removal) (P = 0.03). Catheterization duration of 267 days predicted CRBSI (sensitivity 93%, specificity 66.7%) with area under the curve of 0.808. Conclusions: Median infection free catheter survival was 449 days with catheter failure in 36%. CRBSI was the main cause of failure. Duration of catheterization greater than 267 days was a predictor of CRBSI.

Time for Precision Medicine in the Diagnosis of Acute Kidney Injury.

How to cite this article: Ali U. Time for Precision Medicine in the Diagnosis of Acute Kidney Injury. Indian J Crit Care Med 2022;26(5):547-548.

Prevalence and subtypes of hypertension in normal-weight and obese Indian adolescents: a cross-sectional study.

This cross-sectional study examined the prevalence, stages, subtypes of hypertension, and the associated risk factors in adolescent school children in Western India. We screened 2,644 adolescents, from 10 different private and government schools in urban and rural areas for hypertension, as defined by the 2017 Clinical Practice Guidelines. The association of stages and subtypes with age, gender, body mass index, type of school, and place of residence was analysed. 197 children (7.5%) had hypertension; 170 (6.4%) had stage I, 27 (1%) had stage II and 76 (2.9%) had elevated blood pressure (EBP). The risk of EBP was higher in children > 15 years of age (p = 0.006). Compared with normal-weight children, obese, and overweight children had a higher risk of hypertension [odds ratio (OR) 9 (5.84, 13.88) and 3.77 (2.59, 5.48) respectively], whereas underweight children had a lower risk [OR 0.39 (0.16, 0.98)]. Normal-weight hypertension was seen in 5.2% and was higher in children from government schools (9.4%). Systolic-diastolic hypertension (SDH) was the most common subtype, seen in 136 (5.1%). SDH was more common in girls, in rural children, and in those with stage II hypertension. Isolated diastolic hypertension, seen in 51 (1.9%), was more common in boys, in urban children, and in those with EBP.

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.

Clinico-pathological Profile and Outcome of C-3 Glomerulopathy in Indian Children.

INTRODUCTION: There is paucity of data of C3 glomerulopathy in Indian children. METHODS: First Indian pediatric case series where consecutive renal biopsies done over a period of ten years were reviewed to identify those patients who had isolated or predominant C3 deposits on immunofluorescent microscopy, fulfilling the criteria for C-3 glomerulopathy. The clinical, biochemical, serological, histopathological profile, eGFR and the need for renal replacement therapy was analyzed. RESULTS: Eighteen patients, comprising 5.3% (18/298) of all renal biopsies, had C3 glomerulopathy, four with Dense Deposit Disease (DDD) and fourteen with C3 Glomerulonephritis (C3GN) with a median follow-up of 38.2 months. Median age of presentation was 7.45±3.03 years (2.5yrs- 13.5yrs) with nine boys and nine girls. Presentation was nephrotic syndrome in seven (39%), acute nephritic syndrome in three (16.7%), hematuria in five (27.7%) and acute kidney injury in three (16.7%). Median eGFR was 69 ml/min/1.73m2 (8.2-107 ml/min/1.73m2). Hematuria was seen in 16 (88%), proteinuria in 18 (100%) and low C3 in 16 (88%) at the time of presentation. Mesangioproliferative glomerulonephritis was the predominant pattern in DDD while C3GN showed a mix of mesangioproliferative, membranoproliferative, endocapillary and crescentic GN (p = 0.43).Complete or partial remission was seen in seven patients who received long term alternate day steroids alone or with added mycophenolate mofetil. The cumulative patient survival was 70.8%. Kaplan Meir analyses for renal survival without progression to ESRD was 60.2% at one year and 48.1% at five and ten years. CONCLUSION: Interstitial fibrosis and tubular atrophy on renal biopsy was an independent predictor of adverse renal outcome in the cohort (p = 0.013, HR8.1;95% CI -1.6-42).

Efficacy and safety of prolonged daily hemodialysis in critically ill children weighing less than 10 kg.

INTRODUCTION: Extracorporeal renal replacement therapy may be needed in those infants in whom peritoneal dialysis is not feasible or is ineffective. Prolonged daily hemodialysis (PDHD) remains the only available extracorporeal dialytic modality in children weighing less than 10 kg, in setups where continuous renal replacement therapy is unavailable and sustained low-efficiency dialysis is not feasible due to lack of dedicated HD machines capable of delivering very low dialysate flows. The use of PDHD in critically ill children weighing less than 10 kg has not received much attention. METHODS: Retrospective analysis of the efficacy and safety of PDHD in critically ill children weighing less than 10 kg. FINDINGS: Four critically ill children received a total of 49 sessions of PDHD for acute kidney injury (AKI) associated with sepsis and multiorgan dysfunction syndrome (MODS). PDHD was delivered for a duration of 6 to 8 hours daily with low ultrafiltration rates, low blood flow rates but with dialysate rates that were four times the blood flow rates, due to limitations of minimal dialysate flow rate on standard machines. The mean duration of the sessions was 6.59 ± 1.61 hours. Mean hourly ultrafiltrate (UF) rate during the sessions was 9.28 ± 2.57/kg/hour with mean patient fluid removal rate of 5.4 ± 2.56 mL/kg/hour. Predialysis serum creatinine decreased to 30% of the starting value by the fourth hemodialysis (HD) session. Thirty-three (67.4%) sessions were heparin free. Intradialytic hypotension occurred in 10 (20.4%) sessions. Premature termination of the session occurred in six (12.4%), due to hypotension in two and filter clotting in four. Hypokalemia was seen in 12 (24.4%) and hypophosphatemia in 6 (12.24%). All four patients survived. On follow-up, three are dialysis free and one is on maintenance hemodialysis. CONCLUSION: PDHD is effective and safe in critically ill small children.

The Burden of Acute Kidney Injury in Indian Pediatric Intensive Care Units.

How to cite this article: Ali U. The Burden of Acute Kidney Injury in Indian Pediatric Intensive Care Units. Indian J Crit Care Med 2019;23(8):349.

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.

Diabetic Ketoacidosis with Extreme Hypernatremia in a 4-Year-Old Girl.

A 4-year-old girl admitted with altered mental status, new-onset diabetes mellitus, and diabetic ketoacidosis (DKA) had a rapid rise in serum sodium from 158 mEq/L (corrected sodium 165 mEq/L) at the admission to 204 mEq/L within 18 hours of admission despite standard fluid and insulin therapy recommended for the treatment of DKA. During her illness, she developed arterial and deep vein thrombosis (DVT), bloodstream infection with Candida species, and extensive skin blistering and denudation. The child needed mechanical ventilation, insulin infusion, careful fluid titration to bring down the sodium gradually, and low-molecular weight heparin for her DVT. She had a prolonged Intensive Care Unit and hospital stay but recovered completely without any neurological sequelae.

Acute Renal Failure in the Neonate.

Acute renal failure (ARF) is a common disorder in high-risk neonates. ARF may be oliguric or nonoliguric, the latter having a better prognosis. Risk factors for ARF include prematurity, respiratory and vascular disorders, heart failure, congenital uropathies, and the use of nephrotoxic drugs. Chemical analysis of urine and ultrasounds help differentiate the nature and the type of ARF: prerenal, intrinsic, or postrenal. Conservative management of prerenal forms of ARF consists in carefully restoring cardiac output and controlling fluid and electrolyte balances. Early relief of obstruction is mandatory in severe postrenal forms of ARF. Renal replacement therapy is often necessary when ARF is secondary to intrinsic renal damage: peritoneal dialysis is the treatment of choice. Hemodialysis and continuous venovenous hemofiltration may be used in specific cases. Overall prognosis of ARF depends on the nature and severity of the renal injury that has led to renal failure.

Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children.

Antibodies to complement factor H are an uncommon cause of hemolytic uremic syndrome (HUS). Information on clinical features and outcomes in children is limited. In order to explore this we studied a multicenter cohort of 138 Indian children with anti-complement factor H antibody associated HUS, constituting 56% of patients with HUS. Antibody titers were high (mean 7054 AU/ml) and correlated inversely with levels of complement C3, but not complement factor H. Homozygous deletion of the CFHR1 gene was found in 60 of 68 patients. Therapies included dialysis in 119 children, 105 receiving plasma exchanges and 26 intravenous immunoglobulin. Induction immunosuppression consisted of 87 children receiving prednisolone with or without intravenous cyclophosphamide or rituximab. Antibody titers fell significantly following plasma exchanges and increased during relapses. Adverse outcome (stage 4-5 CKD or death) was seen in 36 at 3 months and 41 by last follow up, with relapse in 14 of 122 available children. Significant independent risk factors for adverse outcome were an antibody titer over 8000 AU/ml, low C3 and delay in plasma exchange. Combined plasma exchanges and induction immunosuppression resulted in significantly improved renal survival: one adverse outcome prevented for every 2.6 patients treated. Maintenance immunosuppressive therapy, of prednisolone with either mycophenolate mofetil or azathioprine, significantly reduced the risk of relapses. Thus, prompt use of immunosuppressive agents and plasma exchanges are useful for improving outcomes in pediatric patients with anti-complement factor H-associated HUS.

Acute respiratory distress during paradoxical reaction to antituberculous therapy in an 8-month-old child.

Paradoxical reaction during antituberculosis treatment (ATT) is commonly seen as tuberculous lymphadenitis of peripheral lymph node, cerebral tuberculomas, pulmonary infiltrates, and pleural disease. This phenomenon is more commonly associated with extrapulmonary tuberculosis and disseminated tuberculosis. Respiratory distress, as presentation of paradoxical reaction, is rare. We report an 8-month-old child with primary progressive tuberculosis without mediastinal adenopathy, who developed paradoxical reaction with extensive mediastinal adenopathy within 15 days of ATT and presented with severe respiratory distress. The child responded to short course of high-dose steroids.

Smith-Lemli-Opitz-syndrome.

Smith-Lemli-Opitz syndrome is an autosomal recessively inherited disorder. A severe defect in cholesterol biosynthesis has been identified leading to abnormally low plasma cholesterol levels and elevated levels of the cholesterol precursor 7-dehydrocholesterol, the result of deficiency of 7-dehydrocholesterol reductase. We describe one such child with Smith-Lemli-Opitz syndrome. This child had clinical features similar to Smith-Lemli-Opitz syndrome like facial dysmorphism and cardiac and renal anomalies with failure to thrive.

Joubert syndrome with nephronophthisis in neurofibromatosis type 1.

Joubert syndrome (JS) is a rare developmental disorder of the central nervous system, characterised by brainstem and cerebellar malformations, hypotonia, episodic hyperapnea and apnea and mental retardation. It may be associated other systemic abnormalities like ocular (e.g., retinal dysplasia, etc.), oculomotor, musculoskeletal and renal (e.g., cystic dysplasia, nephronophthisis), with renal failure. We describe a case of JS with nephronophthisis in neurofibromatosis Type 1 leading to end-stage renal disease, a association that has never been described earlier in the medical literature to the best of our knowledge.

Moyamoya disease with renal artery and external iliac artery stenosis.

Moyamoya disease is a rare, progressive occlusive disease of the cerebral vasculature, mainly involving internal carotid and proximal cerebral arteries with development of fine collateral vascular network in brain. Coexistence of renal vascular lesion with cerebral vascular lesion has rarely described and association with external iliac and femoral vascular stenosis is not known to the best of our knowledge. This is the first case of renovascular hypertension with Moyamoya disease being reported in India with involvement of other extra cranial vessels.

Pediatric Sepsis Guidelines: Summary for resource-limited countries.

JUSTIFICATION: Pediatric sepsis is a commonly encountered global issue. Existing guidelines for sepsis seem to be applicable to the developed countries, and only few articles are published regarding application of these guidelines in the developing countries, especially in resource-limited countries such as India and Africa. PROCESS: An expert representative panel drawn from all over India, under aegis of Intensive Care Chapter of Indian Academy of Pediatrics (IAP) met to discuss and draw guidelines for clinical practice and feasibility of delivery of care in the early hours in pediatric patient with sepsis, keeping in view unique patient population and limited availability of equipment and resources. Discussion included issues such as sepsis definitions, rapid cardiopulmonary assessment, feasibility of early aggressive fluid therapy, inotropic support, corticosteriod therapy, early endotracheal intubation and use of positive end expiratory pressure/mechanical ventilation, initial empirical antibiotic therapy, glycemic control, and role of immunoglobulin, blood, and blood products. OBJECTIVE: To achieve a reasonable evidence-based consensus on the basis of published literature and expert opinion to formulating clinical practice guidelines applicable to resource-limited countries such as India. RECOMMENDATIONS: Pediatric sepsis guidelines are presented in text and flow chart format keeping resource limitations in mind for countries such as India and Africa. Levels of evidence are indicated wherever applicable. It is anticipated that once the guidelines are used and outcomes data evaluated, further modifications will be necessary. It is planned to periodically review and revise these guidelines every 3-5 years as new body of evidence accumulates.