Serum tumour necrosis factor-alpha as a marker of disease activity in children with nephrotic syndrome.

Idiopathic nephrotic syndrome (NS) is a common glomerular disease in children throughout the world; however, the exact pathogenesis of the disease remains unknown. Several studies have shown that tumour necrosis factor-alpha (TNF-α), a proinflammatory cytokine, plays a significant role in the pathogenesis of NS. The literature lacks sufficient data to establish the relationship between TNF-α and NS. This prospective study was conducted on children aged 1-14 years diagnosed with idiopathic NS. All enrolled individuals were followed up from disease onset or relapse of NS until remission or at least 42 days with steroid therapy if remission was not achieved. Serum TNF-α levels were measured at presentation and remission or after 42 days of steroid therapy if remission was not achieved. The role of TNF-α levels in response to steroid therapy in NS was also assessed. One hundred and twelve children (68% boys) with idiopathic NS were enrolled. The median age (interquartile range) at enrolment was 58.5 (37-84.7) months, while the median age at symptom onset was 47.5 (24-60.7) months. The median TNF-α level at presentation was 7.5 (3.5-12.1) pg/ml, and that at remission was 5.25 (1.62-8.8) pg/ml. The median TNF-α levels among first-episode NS at presentation were 3.98 pg/ml and 1.88 pg/ml (P = .04) at remission, whereas in steroid-resistant NS, it was 6.59 pg/ml at presentation and 9.02 pg/ml at 42 days (P = .45). There was a significant negative correlation between the duration of steroid therapy and TNF-α levels, with a correlation factor of -0.021 and R2 of 0.154 (P≤.001). Serum TNF-α levels decrease with steroid therapy in children with steroid-sensitive NS, which correlates clinically with the achievement of remission.

Factors predicting the occurrence of disease-causing variants on next-generation sequencing in children with steroid-resistant nephrotic syndrome - implications for resource-constrained settings.

BACKGROUND: Enhanced availability of high-throughput sequencing (at progressively reducing costs) has revolutionized the identification of monogenic SRNS. However, in resource-poor settings, it may not be possible to perform next-generation sequencing (NGS) in all children wherein monogenic SRNS is suspected. Besides, the optimal strategy of genetic evaluation (in patients with SRNS) in routine clinical practice in resource-limited settings is unknown. METHODS: Patients with newly diagnosed SRNS were recruited from our center and followed up prospectively. We analyzed the factor(s) independently predicting the occurrence of disease-causing variants in these patients. RESULTS: In our study, 36 children/adolescents with SRNS were included (initial steroid resistance in 53%). On targeted NGS, pathogenic/likely pathogenic variants were identified in 31% (n = 11). These included homozygous or compound heterozygous variants in the following genes: ALOX12B, COL4A3, CRB2, NPHS1, NPHS2, PLCE1, and heterozygous variant in WT1 gene. Overall, 14 variants were identified of which 5 (36%) were novel. Age of < 1 or < 2 years and presence of family history of nephrotic syndrome independently predicted the occurrence of monogenic SRNS on multivariate analysis. CONCLUSIONS: While NGS-based genetic testing in SRNS is increasingly being incorporated in routine clinical practice the world over, the scenario is far from optimal in resource-limited settings. Our study highlights that resources for genetic testing in SRNS should be prioritized for patients with early age at disease onset and presence of family history. Larger studies composed of diverse multi-ethnic cohorts of patients with SRNS are required to further delineate the optimal strategy of genetic evaluation in resource-poor settings. A higher resolution version of the Graphical abstract is available as Supplementary information.

Incidence, predictors, and short-term outcomes of acute kidney injury in children with diabetic ketoacidosis: a systematic review.

BACKGROUND: One-third of children with type 1 diabetes mellitus manifest with diabetic ketoacidosis (DKA). Most children presenting with DKA are in a volume-depleted state, leading to acute kidney injury (AKI). Besides volume depletion, hyperglycemia can induce tubular injury and kidney inflammation. Therefore, a thorough knowledge of incidence of AKI, risk factors, and outcomes in pediatric DKA is desirable to improve its management and outcomes. OBJECTIVE: To synthesize currently available evidence on the incidence, risk factors, and outcomes of AKI in children with DKA. DATA SOURCES: We searched three electronic databases (EMBASE, PubMed, and Web of Science) from inception to September 2022 for original studies reporting AKI in children with DKA. Search strategies for the individual databases were drafted using free text words and MeSH incorporating "acute kidney injury" and "diabetic ketoacidosis." STUDY ELIGIBILITY CRITERIA: Cohort and cross-sectional studies reporting AKI in children with type 1 DM and DKA were included. PARTICIPANTS AND INTERVENTIONS: Children (aged less than 18 years) with type 1 DM and DKA. STUDY APPRAISAL AND SYNTHESIS METHODS: The critical appraisal tool of NHLBI for cohort studies was used to assess the quality of the studies. We estimated the pooled incidence of AKI with 95% CI in children with DKA using a random effects model. The primary outcome was the pooled incidence of AKI during the DKA episodes. RESULTS: Twenty-one studies assessing 4087 children (4500 DKA episodes) reported AKI during DKA episodes. The pooled incidence of any stage of AKI during the DKA episode was 47% (95% CI: 40 to 55). Severe AKI was observed in 28% (21 to 35) of DKA episodes; however, only 4% (1 to 11%) of children with AKI received dialysis. Low serum bicarbonate, low corrected sodium, higher blood sugar, and high blood urea nitrogen at presentation have been reported to be associated with the development of AKI. CONCLUSION: AKI developed in almost half of the DKA episodes, and every fourth DKA episode was associated with severe AKI. The recovery rate from DKA-associated AKI appears to be high; however, further studies are needed to assess the exact impact of AKI on long-term outcomes. REGISTRATION: PROSPERO (CRD42022303200). A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-term complications in patients with childhood-onset nephrotic syndrome.

BACKGROUND: Reports on long-term complications of childhood-onset nephrotic syndrome (NS), such as obesity, osteoporosis, growth failure, and hypertension, are mostly from developed countries not representing South Asian ethnicities. Furthermore, data on cardiovascular health among patients with childhood-onset NS are limited. METHODS: This was an observational study involving patients attending a tertiary care center. Patients aged 15 years and older were examined for long-term complications and remission of NS at their visit in December 2021. Childhood-onset NS meant onset of NS before 10 years of age. Long-term complications included obesity, growth failure, low bone mineral density (BMD) Z score, hypertension, and increased carotid intima-media thickness (cIMT). Long-term remission was defined as no relapse for the last [Formula: see text] 3 consecutive years without immunosuppressive medication to maintain remission. RESULTS: Of 101 patients studied (~ 80% with frequent relapsing (FR)/steroid-dependent (SD) NS), the mean age was 17.6 (± 2.4) years at the time of study. Long-term complications were noted in 89.1% of patients which included one or more of the following: obesity (22.7%), growth failure (31.7%), low BMD Z score (53.5%), hypertension (31.7%), and high cIMT (50.5%). Thirty-nine patients (38.6%) were in long-term remission at the time of the study. Growth failure and low BMD Z scores were less frequent in patients with long-term remission compared to those without long-term remission. CONCLUSIONS: In patients with childhood-onset NS (predominantly FR/SDNS) who were studied at [Formula: see text] 15 years of age, ~ 90% had long-term complications which included high cIMT in 50%. Only ~ 40% were in long-term remission. A higher resolution version of the Graphical abstract is available as Supplementary information.

Prevalence and risk factors for functional iron deficiency in children with chronic kidney disease.

INTRODUCTION: Anemia in chronic kidney disease (CKD) is multifactorial. The presence of functional iron deficiency (FID), whereby, there is a block in the transport of iron from macrophage to erythroid marrow is one possible etiology. In this study, we aim to assess the prevalence and risk factors of FID in pediatric CKD. METHODS: A cross-sectional study was performed from March to December 2018, after obtaining Institute Ethical Clearance. Children aged ≤ 12 years with CKD, with or without iron supplementation who consented were enrolled. Patients on erythropoietin or on maintenance dialysis were excluded. Details of patients and diseases characteristics were recorded. Various laboratory parameters including complete blood count, red blood cell indices, hypochromic RBC, reticulocyte hemoglobin content, and serum ferritin were measured. Appropriate statistical tests were applied. RESULTS: Out of 174 children, 127 (73%) had structural kidney disease as an etiology of CKD, and 110 (63%) had anemia. Prevalence of anemia was 44%, 43%, 74%, 64% and 92% in CKD stage 1, 2, 3, 4 and 5, respectively. Absolute iron deficiency was found in 66 (38%) even when some children were already on iron supplementation. FID was seen in 44 (25%) and on multivariate analysis, lower estimated glomerular filtration rate and mineral bone disease are associated risk factors. CONCLUSION: FID is present in one-fourth of our CKD cohort. It should be considered when the response to adequate measures of improving hemoglobin level fails. More studies are required to know its impact on short-term and long-term patient-related outcomes such as quality of life and mortality.

Diagnostic accuracy of renal angina index alone or in combination with biomarkers for predicting acute kidney injury in children.

Early recognition of patients at risk for severe acute kidney injury (AKI) by renal angina index (RAI) may help in the early institution of preventive measures. Objective was to evaluate performance of RAI alone or in combination with biomarkers in predicting severe AKI (KDIGO stage 2 and 3 or equivalent) and receipt of kidney replacement therapy (KRT) in critically ill children. We searched PubMed, EMBASE, Web of Sciences, and CENTRAL for studies published till May 2021. Search terms included acute kidney injury, pediatrics, adolescent, renal angina index, and biomarker. Proceedings of relevant conferences and references of included studies were also scrutinized. Two reviewers independently assessed the study eligibility. Cohort and cross-sectional studies evaluating the diagnostic performance of RAI in predicting AKI or receipt of KRT in children were included. Eligible participants were the children less than 18 years with RAI assessment on day 0 ofadmission. We followed PRISMA-DTA guidelines and used the QUADAS-2 tool for quality assessment. A bivariate model for meta-analysis was used to calculate the summary estimates of diagnostic parameters. Major outcomes were the diagnostic accuracy of RAI (≥ 8) alone or with biomarkers in predicting severe AKI and KRT receipt. Diagnostic accuracy was reported using summary sensitivity, specificity, and area under the curve (AUC). Overall, 22 studies (24 reports, 14,001 participants) were included. RAI ≥ 8 on day 0 has summary sensitivity, specificity, and AUC of 0.86 (95% CI, 0.77-0.92), 0.77 (0.68-0.83), and 0.88 (0.85-0.91) respectively for prediction of severe AKI on day 3. In comparison, a combination of RAI and urinary neutrophil gelatinase-associated lipocalin (NGAL) showed summary sensitivity, specificity, and AUC of 0.76 (0.62-0.85), 0.89 (0.74-0.96), and 0.87 (0.84-0.90) respectively for predicting severe AKI. The sensitivity, specificity, and AUC of RAI for predicting receipt of KRT were 0.82 (0.71-0.90), 0.74 (0.66-0.81), and 0.85 (0.81-0.88) respectively. In meta-regression, only the study setting (sepsis vs. heterogenous) was associated with heterogeneity. We observed substantial heterogeneity among eligible studies. Five studies had concerns in patient selection, and seven studies also had applicability concerns in patient selection for this review. Moderate certainty evidence showed that RAI ≥ 8 has good predicting ability in recognizing children at risk of severe AKI and receipt of KRT. The combination of urinary NGAL and RAI further improves the predicting ability (low-certainty evidence). Further studies are required on the context-driven assessment of novel biomarkers in the early prediction of AKI in RAI-positive children. Systematic review registration number: CRD4202122268. A higher resolution version of the Graphical abstract is available as Supplementary information.

Efficacy of lacosamide and phenytoin in status epilepticus: A systematic review.

OBJECTIVES: To compare the evidence on efficacy, safety, tolerability, and impact on short term/long functional outcome of lacosamide (LCM) and phenytoin (PHT) in patients with status epilepticus. MATERIALS & METHODS: We conducted a systematic literature search of relevant electronic databases using a suitable search strategy to identify studies directly comparing PHT and LCM, irrespective of dose and duration in patients with convulsive and/or nonconvulsive status epilepticus (SE). We used a standardized assessment form to extract information on the study design, data sources, methodologic framework, efficacy, and adverse events attributed to PHT and LCM from included studies and compared the efficacy and safety outcomes, using a fixed/random effect model. RESULTS: Five studies were found to be eligible for inclusion out of 192 search items, enrolling a total of 115 and 166 participants (predominantly with SE) in LCM and PHT arm, respectively. Baseline characteristics were comparable between both arms. The proportion with seizure control was comparable between both arms (57.3% in LCM vs. 45.7% in PHT arm, p = 0.28) and even in the subgroup analysis separately for convulsive and non-convulsive SE. Proportion with treatment-emergent adverse events (TEAE) were comparable in both (17.6% vs. 12.2%, p = 0.20), but serious adverse events (SAE) were higher in PHT arm (5.1% vs. 0.8%, p = 0.049). The proportion with all-cause mortality and survival with moderate-severe disability were comparable between both arms (p = 0.23 and 0.37, respectively). CONCLUSION: LCM has comparable efficacy with fewer SAEs as compared to PHT for achieving seizure control in patients with SE.

Clinical Characteristics and Genotype-Phenotype Correlation in Children with KMT2E Gene-Related Neurodevelopmental Disorders: Report of Two New Cases and Review of Published Literature.

BACKGROUND: In recent years, many new candidate genes are being identified as putative pathogenic factors in children with developmental delay and autism. Recently, heterozygous mutations in the KMT2E gene have been identified as a cause of a unique neurodevelopmental disorder with variable combination of global developmental delay or isolated speech delay, intellectual disability, autistic features, and seizures. METHODS: Here, we present two new cases of KMT2E mutation-associated neurodevelopmental disorder in a 4-year-old girl and 5-year-old boy. We also performed a pooled review of the previously published cases of KMT2E-related neurodevelopmental disorder. Articles were identified through search engines using appropriate search terms. RESULTS: Along with the presented 2 cases, 40 cases were analyzed. Out of them, 30, 6, and 4 children had protein-truncating mutations, missense mutations, and copy number variants, respectively. The common features were global developmental delay (97%) followed by macrocephaly (35%), seizures (30%), and autism (25%). Children with missense variants had severe phenotype, with microcephaly, profound developmental delay, and increased frequency of seizures. Neuroimaging revealed nonspecific changes, including cerebral white matter signal abnormalities. CONCLUSION: KMT2E-related neurodevelopmental disorder remains one of the clinical differentials in children with global developmental delay and/or autistic features/seizure. With the reporting of more cases in the future, the already heterogeneous clinical spectrum of this disease is likely to be widened.

Screening of renal anomalies in first-degree relatives of children diagnosed with non-syndromic congenital anomalies of kidney and urinary tract.

BACKGROUND: Non-syndromic congenital anomalies of kidney and urinary tract (CAKUT) are usually sporadic in nature but familial clustering of cases have been observed suggesting a genetic predisposition to this condition. We aimed to determine the frequency and pattern of renal anomalies in first-degree relatives of children with non-syndromic CAKUT. METHODS: We screened all the first-degree relatives of children with CAKUT. A total of 149 first-degree relatives, belonging to 62 families were screened with ultrasonography. RESULTS: A renal anomaly was detected in 9 out of the 62 families. Two of these nine families had identical anomalies (child and a parent) indicating single-gene disorders with possible autosomal dominant inheritance, while the rest of families had a non-identical anomaly. The anomalies detected in the first-degree relatives were renal hypodysplasia (n = 2), multicystic dysplastic kidney (n = 3), pelviureteric junction obstruction (n = 2) and mild hydronephrosis (n = 2). The incidence of a sonographically detected anatomic renal anomaly in first-degree relatives of children with CAKUT was found to be 6.0%. Familial cystic kidney disease was found in two out of the 4 families with cystic kidney disease. CONCLUSION: Significant renal anomalies were identified in first-degree relatives of children with non-syndromic CAKUT and hence, attempts must be made to screen the family members of children with non-syndromic CAKUT.

Efficacy and safety of corpus callosotomy and ketogenic diet in children with Lennox Gastaut syndrome: a systematic review and meta-analysis.

BACKGROUND: Both corpus callosotomy (CC) and the ketogenic diet (KD) are commonly used in patients with Lennox Gastaut syndrome (LGS), as a significant proportion of these patients develop pharmacoresistant epilepsy. But no systematic review has yet compared the efficacy and safety of these two measures. METHODS: We conducted a systematic search on various databases to collating all available literature until 30th November 2020 with a primary objective to compare the efficacy of KD and CC in terms of the proportion of patients with complete seizure freedom, at least 75% and 50% reduction in seizure frequency at various time points after the institution of these modalities. We also attempted to compare the proportion and nature of adverse effects, impact on EEG, cognition, and behavior with these modalities. We only included original articles enrolling at least 10 patients with CC or KD for quantitative synthesis to determine a pooled estimate. We used a fixed or random effects model, depending on the degree of heterogeneity. RESULTS: We selected 23 and 7 articles describing the efficacy of CC and KD in 436 and 185 LGS patients out of 217 search items, but none of the studies compared directly these two entities. The indirect comparison between the pooled estimate of all patients with individual modalities revealed more patients with CC had seizure freedom, at least 75% and 50% reduction in seizure frequency (p=0.0001, 0.01, and 0.04 respectively). The proportion of patients with adverse effects was also higher for CC patients (p=0.01), although the proportion with serious adverse effects was not significantly different between the two modalities. Patients selected for CC were older, had higher seizure burden, more lag time after the onset of seizures, and received more number of antiseizure medications previously. Due to the availability of limited data, a firm conclusion could not be determined regarding the effect on EEG, cognition, and behavior with CC and KD. CONCLUSION: CC is more efficacious than KD in reducing seizure frequency in patients with LGS, although it has relatively more adverse effects during the immediate perioperative period.

Cardiac Abnormalities in Children with Pre-Dialysis Chronic Kidney Disease in a Resource-Limited Setting: A Cross-Sectional Observational Study.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in children with chronic kidney disease (CKD). We aim to estimate the prevalence of cardiac abnormalities in children up to age 16 years with CKD and their association with various risk factors. METHODS: This cross-sectional observational study was conducted on 107 CKD children. We assessed the systolic and diastolic function using 2D echocardiographic evaluation and M-mode measurements of the left ventricle (LV) indexed for BSA and z-scores were calculated. Results were compared with age, sex, stage of CKD, anaemia, estimated glomerular filtration rate (eGFR) and various laboratory parameters. RESULTS: LV diastolic dysfunction was seen in 88%, followed by increased LV dimensions in 33.6%, LV systolic dysfunction in 16%, right ventricle systolic dysfunction in 11.2% while increased pulmonary artery (PA) systolic pressure was seen in 9.3% of cases. LV dimensions correlated directly with parathormone levels and inversely with eGFR, serum calcium and haemoglobin levels. Left ventricular hypertrophy correlated directly with parathormone while inversely with eGFR, serum calcium and haemoglobin. Ejection fraction directly correlated to eGFR and serum calcium while inversely related to parathormone. Left PA pressure directly correlated with age and inversely with eGFR. Right ventricular systolic function assessed by tricuspid annular plane systolic excursion correlated inversely with haemoglobin. CONCLUSION: LV diastolic dysfunction and increased LV dimensions were the most common cardiac abnormality in children with CKD. LV dimensions correlated directly with parathormone levels and inversely with eGFR, serum calcium and haemoglobin. Diastolic dysfunction positively correlated with serum creatinine and parathormone levels.

Neurological Complications of SARS-CoV-2 Infection in Children: A Systematic Review and Meta-Analysis.

BACKGROUND: Knowledge about neurological complications of COVID-19 in children is limited due to the paucity of data in the existing literature. Some systematic reviews are available describing overall clinical features of COVID-19 in children and neurological complications of COVID-19 in adults. But to the best of our knowledge, no systematic review has been performed to determine neurological manifestations of COVID-19. METHODS: Six different electronic databases (MEDLINE, EMBASE, Web of Science, CENTRAL, medRxiv and bioRxiv) were searched for articles related to COVID-19 and neurological complications in children. Studies/case series reporting neurological manifestations of COVID-19 in patients aged ≤18 years, as well as case reports, as neurological complications appear to be rare. The pooled estimate of various non-specific and specific neurological manifestations was performed using a random effect meta-analysis. RESULTS: Twenty-one studies/case series and five case reports (3707 patients) fulfilled the eligibility criteria and were included in this systematic review, from a total of 460 records. Headache, myalgia and fatigue were predominant non-specific neurological manifestations, presenting altogether in 16.7% cases. Total of 42 children (1%) were found to have been reported with definite neurological complications, more in those suffering from a severe illness (encephalopathy-25, seizure-12, meningeal signs-17). Rare neurological complications were intracranial hemorrhage, cranial nerve palsy, Guillain-Barré syndrome and vision problems. All children with acute symptomatic seizures survived suggesting a favorable short-term prognosis. CONCLUSION: Neurological complications are rare in children suffering from COVID-19. Still, these children are at risk of developing seizures and encephalopathy, more in those suffering from severe illness.

Toddler With Intermittent Abnormal Behavior: Is It Isoniazid-Induced Psychosis?

ABSTRACT: Psychosis is a state of altered behavior and mentation, and it is rarely reported in preschool children. Isoniazid is a commonly used drug in the treatment and prophylaxis of tuberculosis. It may cause psychosis in overdose but rarely with usual recommended doses. We report a case of drug-induced psychosis secondary to isoniazid intake in a 3-year-old child. She developed intermittent abnormal behavior for 2 weeks after intake of isoniazid. Drug-induced psychosis was a possibility, and the responsible drug was stopped. She improved following the withdrawal of isoniazid.

Bladder Mass Masquerading as Eosinophilic Cystitis in a Child: When to Think Beyond Malignancy?

Eosinophilic cystitis is a rare inflammatory disease in the pediatric population with varied presentations. Diagnosis requires a high index of suspicion and cystoscopy with biopsy of the bladder mass. There are no standard treatment guidelines, however, these patients usually respond with medical management, but recurrence is a possibility. We present a case of eosinophilic cystitis in a 6-year-old boy who presented with lower urinary tract symptoms, gross hematuria, and bladder mass.

Lipomatosis of spinal epidural space, peritoneum, and renal sinus: a rare complication of long-term steroid therapy in a child with nephrotic syndrome.

Excessive visceral adipose tissue proliferation, resulting in diffuse lipomatosis, is a rare complication of long-term steroid therapy. A 10-year-old boy presented with severe radicular back pain with limitation of lower limb movements. He was diagnosed with steroid-resistant nephrotic syndrome and was on unregulated steroid therapy. Magnetic resonance imaging of the spine showed increased adipose tissue in the epidural space of the lumbo-sacral spine causing clumping of cauda equina nerve roots along with marked proliferation of fat in the renal sinus as well as peritoneum. He was started on pregabalin with tapering of steroids, following which there was a gradual decrease in pain and improvement of activity. Our patient had diffuse lipomatosis involving spinal epidural space, bilateral renal sinus, and peritoneum, secondary to steroid overuse. With the availability of advanced imaging techniques, the condition can be prevented by judicious and proper use of steroids with close follow-up for any untoward complications.

Acute Focal Dystonia After a Single Dose of Oral Cetirizine in a 9-Year-Old Boy.

Common cold is an acute illness affecting pediatric population in particular. The use of antihistamines is a common practice, with cetirizine being a frequently used drug with a good safety profile. However, adverse events due to the use of antihistamines have been rarely reported, such as drug-induced dystonia with the use of cetirizine. In our present case, dystonia due to the intake of cetirizine was observed, which the patient responded well to the use of benzodiazapines, namely, clonazepam. We report this case to highlight the occurrence of this adverse event with the use of cetirizine.