Clinical characteristics, genetic profile and short-term outcomes of children with primary hyperoxaluria type 2: a nationwide experience.

BACKGROUND: Three types of primary hyperoxaluria (PH) are recognized. However, data on PH type 2 (PH2), caused by defects in the GRHPR gene, are limited. METHODS: We reviewed the medical records of patients < 18 years of age with genetically-proven PH2 from seven centres across India to identify the age of onset, patterns of clinical presentation, short-term outcomes and genetic profile, and to determine if genotype-phenotype correlation exists. RESULTS: We report 20 patients (all with nephrolithiasis or nephrocalcinosis) diagnosed to have PH2 at a median (IQR) age of 21.5 (7, 60) months. Consanguinity and family history of kidney stones were elicited in nine (45%) and eight (40%) patients, respectively. The median (IQR) serum creatinine at PH2 diagnosis was 0.45 (0.29, 0.56) mg/dL with the corresponding estimated glomerular filtration rate being 83 (60, 96) mL/1.73 m2/min. A mutational hotspot (c.494 G > A), rare in Caucasians, was identified in 12 (60%) patients. An intronic splice site variant (c.735-1G > A) was noted in five (25%) patients. Four (20%) patients required surgical intervention for stone removal. Major adverse kidney events (mortality or chronic kidney disease (CKD) stages 3-5) were noted in six (30%) patients at a median (IQR) follow-up of 12 (6, 27) months. Risk factors for CKD progression and genotype-phenotype correlation could not be established. CONCLUSIONS: PH2 should no longer be considered an innocuous disease, but rather a potentially aggressive disease with early age of presentation, and possible rapid progression to CKD stages 3-5 in childhood in some patients. A mutational hotspot (c.494 G > A variant) was identified in 60% of cases, but needs further exploration to decipher the genotype-phenotype correlation.

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.

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.

Primary membranous nephropathy in children and adolescents: a single-centre report from South Asia.

BACKGROUND: Unlike adults, primary membranous nephropathy (PMN) comprises only 1-2% of childhood nephrotic syndrome. The clinical behaviour of PMN in children is not explicit and we report upon clinical presentation and outcome. METHODS: This prospective study includes children and adolescents (< 20 years) with biopsy-proven PMN without secondary causes. Anti-PLA2R assessment: before and after completing therapy. OUTCOME: percentage of patients achieving remission. RESULTS: Study cohort included 48 (M:F ratio 1.1:1) patients and median age 17 (IQR 15-18) years, with 35 (72.9%) PLA2R related. Median interval from symptom onset to presentation was 5 months, where median proteinuria, serum albumin and creatinine were 4.9 g/day, 2.1 g/dL and 0.63 mg/dL, respectively. Forty-seven patients received immunosuppressive therapy, with various agents used as first-line therapy: cyclical CYC/GC (53.1%), CNI/GC (21.3%), rituximab (14.9%), prednisolone alone (4.3%), azathioprine (4.3%) and mycophenolate mofetil (2.1%). Median follow-up was 29 (14, 59) months. At 6 months, 11 (24.4%) and 17 (37.7%) had complete remission (CR) or partial remission (PR), while at last follow-up (median 29 months), 20 (45.4%) and 14 (31.8%) had CR and PR respectively. No significant differences in outcome were observed with different agents. A total of 60% patients treated with rituximab as first line/for relapsing disease, and all cases with resistant disease receiving rituximab had CR or PR at last follow-up. PLA2R antibody presence was associated with clinical outcome. CONCLUSIONS: Three-quarters of PMN in children and adolescents is PLA2R related and two-thirds respond to immunosuppressive therapy. Rituximab is a promising agent to manage PMN in children. Anti-PLA2R is associated with clinical outcomes.

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.

ALK-1-negative anaplastic large-cell lymphoma presenting as a dura-based mass in an infant.

INTRODUCTION: Anaplastic large-cell lymphoma (ALCL) rarely occurs in the central nervous system in the pediatric population. CASE PRESENTATION: We describe a diagnostically challenging case of an 11-month-old infant presenting with cranial nerve palsies and peripheral eosinophilia. Imaging demonstrated meningeal thickening with enhancement and dura-based deposits, the biopsy of which revealed features of ALK-1 negative ALCL on histologic and immunophenotypic analysis. A thorough investigation excluded the possibility of any extra-cranial origin. Hence, a diagnosis of "primary" ALCL was rendered. CONCLUSION: ALCL arising in the dura in an infant has not been described earlier, to the best of our knowledge.

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.

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.

Copeptin as a potential biomarker of chronic kidney disease to predict the disease progression in children with chronic kidney disease.

Background: Biomarkers to predict the onset and progression of chronic kidney disease (CKD) in children are lacking, and no such definite biomarkers have been implicated in the diagnosis of CKD. We conducted this study to evaluate copeptin as a CKD marker and predict the disease progression by estimating the copeptin levels at baseline and 12 months follow-up in children with CKD stage 2 and above. Materials and Methods: This prospective single-centre cohort study was conducted in children under 14 years with CKD stages 2-4. Blood and urine samples were collected at enrolment and 1-year follow-up for routine investigations and serum copeptin, cystatin C and urinary neutrophil gelatinase-associated lipocalcin (uNGAL) estimation. Results: A total of 110 children (60 cases and 50 controls) were enrolled in the study. The mean estimated glomerular filtration rate (eGFR) of cases was 58.3 ± 18.7 ml/min/1.73 m2. Among the cases, there was a significant rise in the serum copeptin levels from baseline 483.08 ± 319.2 pg/ml to follow-up at 1 year, that is, 1046.82 ± 823.53 pg/ml (P < 0.0001). A significant difference was noted in the baseline values of serum cystatin C, that is, 1512.98 ± 643.77 ng/ml and 719.68 ± 106.96 ng/ml (P < 0.0001), and uNGAL, that is, 13.53 ± 11.72 and 1.76 ± 2.37 ng/ml (P < 0.0001) between the cases and controls. There was no significant correlation (correlation coefficient = 0.10) between change in eGFR and copeptin levels during 12 months of follow-up. Conclusion: No significant correlation was found between the change in eGFR and copeptin levels during 12 months of follow-up. This can be due to the slow deterioration of renal functions, as most of the cases had underlying congenital anomalies of the kidney and urinary tract (CAKUT), which is known to have a slow progression of CKD and a small sample size.

Diptheroids can cause nosocomial UTI and be multidrug resistant: A case report of Corynebacterium striatum, first from India.

Gram positive bacilli in the urine are usually dismissed as contaminants in urine specimens as these are commensal flora of skin and mucous membranes. Corynebacterium species were misidentified in the past due to complex biochemicals but the advent of modern diagnostics has made their identification quicker and accurate. Corynebacterium species have recently emerged as pathogens of nosocomial outbreak potential. C. striatum has been identified as opportunistic nosocomial pathogen causing various infections. We report first case of C. striatum as nosocomial urinary tract infection (UTI) pathogen in a child with bilateral renal disease. C. striatum causing UTI is very rarely reported.

Shear wave elastography of kidneys in children: utility in distinguishing steroid-resistant and steroid-sensitive nephrotic syndrome.

PURPOSE: To assess the renal elasticity values using (SWE) and correlate the values with steroid sensitivity to distinguish between steroid-resistant nephrotic syndrome (SRNS) and steroid-sensitive nephrotic syndrome (SSNS) in children. METHODS: In this IRB-approved cross-sectional study, 83 children (4-14 years) diagnosed with nephrotic syndrome were included from July 2021 to December 2022. SWE measurements were done for each kidney's upper pole, interpolar region, and lower pole. Mean as well as median SWE were calculated. Correlation of the renal stiffness values was done with different laboratory findings (blood urea, serum creatinine, 24 h urine protein, serum albumin, and serum cholesterol), the grayscale findings (cortical echogenicity, and corticomedullary differentiation), and the final diagnosis of SRNS and SSNS. The statistical tests were done at a significance level of α = 0.05. RESULTS: The median (IQR) overall SWE of kidneys was higher in SRNS group 12.64 (8.4-19.68) kPa than SSNS group 9.87 (8.20-12.56) kPa. The difference was significant (p = 0.004). At a cut-off of ≥ 10.694 kPa (AUROC- 0.641), the overall SWE predicted SRNS group with a sensitivity of 70% and a specificity of 63%. A significant correlation (p < 0.05) was found between the SWE and 24-h urine protein, cortical echogenicity, and corticomedullary differentiation in SSNS, while only between SWE and corticomedullary differentiation in SRNS. CONCLUSION: The mean SWE was higher in children with SRNS. While SWE has potential to differentiate SSNS from SRNS, a different study design where SWE is performed at presentation is needed for confirmation.

Autosomal Recessive Congenital Ichthyosis and Steroid-Resistant Nephrotic Syndrome due to Homozygous Mutation in the ALOX12B gene: A Novel Association with Review of Literature.

Nephrotic syndrome (NS) associated with autosomal recessive congenital ichthyosis (ARCI) is a rare association. In this article, we described a 4-year-old boy with steroid-resistant NS (SRNS) who had a history of ichthyotic skin lesions since birth. Renal biopsy revealed focal segmental glomerulosclerosis (tip variant). The skin biopsy was consistent with the findings of ichthyosis. Next-generation sequencing revealed a homozygous pathogenic variant (c.1625_1626del) in the exon 12 of the ALOX12B gene, confirming the diagnosis of ARCI2. The ALOX12B gene belongs to the lipoxygenase family and has a pivotal role in the formation of lipid layers in the epidermis. Leukotrienes have a counter-regulatory effect within the inflamed glomeruli, which influences the vascular tone and glomerular basement membrane permeability, that can be implicated in the pathogenesis of the NS. This child is currently in remission, on tacrolimus and low-dose prednisolone, with emollients and is on regular follow-up. SRNS associated with congenital ichthyosis secondary to a mutation in the ALOX12B gene has never been reported so far. The knowledge regarding this novel association will help the treating physicians in diagnosing this condition early, which will enable proper genetic counseling and prognostication of the disease to the family.

Distress, anxiety, and its correlates among caregivers of children with kidney diseases during COVID-19 pandemic lockdown.

BACKGROUND: The COVID-19 pandemic has generated a significant amount of psychological burden in the form of stress, anxiety, uncertainty, depression, anger, and helplessness. The caregivers of children with chronic diseases in particular are at a higher risk of mental stress and burden. MATERIAL AND METHODS: We conducted an online survey among caregivers of children with kidney diseases to assess the psychosocial impact of COVID-19. The psychosocial impact of COVID-19 pandemic on their mental health was assessed through standardized psychological scales (Peritraumatic Distress Inventory, Insomnia Severity Scale [ISI], Depression Anxiety and Stress Scale [DASS], and Positive and Negative Aspect Scale) and a semi-structured interview was conducted telephonically. RESULTS: A total of 200 caregivers participated in the study. The mean age of the participants was 36±5.56 years, and 76% were males. Participants experienced maximum distress in terms of life threat (6.27±4.64), followed by helplessness and anger (2.66 ± 1.65). Among participants, 38% of them exhibited significant distress. The majority scored below the cut-off on positive affect (98%), and thus could not experience positive emotions and interaction, and 37.5% of participants were feeling significant negative affect. On the ISI, 38.5% of participants experienced significant sleep problems. On the DASS, 65% of participants exhibited significant stress, 76% anxiety, and 78.5% depression. CONCLUSION: A high prevalence of stress, anxiety, and depression along with insomnia was detected among the caregivers of children with kidney diseases during the COVID-19 pandemic.