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.

Advancing Treatment Frontiers: Radiofrequency Ablation for Small Renal Mass-Intermediate-Term Results.

Our study aims to discern the immediate and intermediate-term oncological outcomes of the patients with small renal mass and who were surgically unfit or were having a bilateral tumor and underwent radiofrequency ablation (RFA) of the mass. We retrospectively and prospectively analyzed the status of the patients who were diagnosed to have small renal masses and were biopsy-proven renal cell carcinoma (RCC) cases, who underwent RFA at our institute from the year 2013 to 2022. Patients were followed-up for 3 years. Data regarding complications were analyzed for all patients who underwent renal RFA along with the 3-year recurrence-free survival (RFS) rate. A total of 28 patients were eligible for the study based on our inclusion and exclusion criteria. Their renal function was recorded. They underwent RFA and were followed-up for a period of 3 years for RFS. Four patients out of the total had immediate complications, out of which two developed a hematoma. Three-year-follow-ups showed six recurrences, overall having 78.6% RFS. Post-procedural renal function was stable as documented by Estimated glomerular filtration rate. Oncological results of RFA in patients with small renal masses who are surgically unfit are associated with a low risk of immediate and intermediate-term deterioration of renal function.

Biomarkers for prediction of acute kidney injury in pediatric patients: a systematic review and meta-analysis of diagnostic test accuracy studies.

BACKGROUND: Severity of acute kidney injury (AKI) confers higher odds of mortality. Timely recognition and early initiation of preventive measures may help mitigate the injury further. Novel biomarkers may aid in the early detection of AKI. The utility of these biomarkers across various clinical settings in children has not been evaluated systematically. OBJECTIVE: To synthesize the currently available evidence on different novel biomarkers for the early diagnosis of AKI in pediatric patients. DATA SOURCES: We searched four electronic databases (PubMed, Web of Science, Embase, and Cochrane Library) for studies published between 2004 and May 2022. STUDY ELIGIBILITY CRITERIA: Cohort and cross-sectional studies evaluating the diagnostic performance of biomarkers in predicting AKI in children were included. PARTICIPANTS AND INTERVENTIONS: Participants in the study included children (aged less than 18 years) at risk of AKI. STUDY APPRAISAL AND SYNTHESIS METHODS: We used the QUADAS-2 tool for the quality assessment of the included studies. The area under the receiver operating characteristics (AUROC) was meta-analyzed using the random-effect inverse-variance method. Pooled sensitivity and specificity were generated using the hierarchical summary receiver operating characteristic (HSROC) model. RESULTS: We included 92 studies evaluating 13,097 participants. Urinary NGAL and serum cystatin C were the two most studied biomarkers, with summary AUROC of 0.82 (0.77-0.86) and 0.80 (0.76-0.85), respectively. Among others, urine TIMP-2*IGFBP7, L-FABP, and IL-18 showed fair to good predicting ability for AKI. We observed good diagnostic performance for predicting severe AKI by urine L-FABP, NGAL, and serum cystatin C. LIMITATIONS: Limitations were significant heterogeneity and lack of well-defined cutoff value for various biomarkers. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Urine NGAL, L-FABP, TIMP-2*IGFBP7, and cystatin C showed satisfactory diagnostic accuracy in the early prediction of AKI. To further improve the performance of biomarkers, they need to be integrated with other risk stratification models. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42021222698). A higher resolution version of the Graphical abstract is available as "Supplementary information".

Clinical features and outcomes of patients with diacylglycerol kinase epsilon nephropathy: a nationwide experience.

BACKGROUND: Thrombotic microangiopathy (TMA) is usually caused due to dysregulation of the alternative complement pathway. Rarely, thrombotic microangiopathy is caused by non-complement mediated mutations in diacylglycerol kinase epsilon (DGKE); information about therapy and outcome of these patients is limited. METHODS: Medical records of patients, younger than 18 years, diagnosed with TMA and variants in DGKE were reviewed to include 12 patients from seven centers. Genetic studies included targeted exome sequencing and multiplex-ligation dependent probe amplification of CFH-CFHR5. RESULTS: Patients presented at a median age of 11 (7.5, 12.3) months; all were younger than 2 years. All patients had an infectious prodrome; enteroinvasive, enteropathogenic, and enterotoxigenic Escherichia coli were detected in two patients with diarrhea. Chief features included those of microangiopathic hemolysis (n = 11), microscopic hematuria (n = 10), nephrotic range proteinuria (n = 10), hypoalbuminemia (n = 6), elevated total cholesterol (n = 6), and hypocomplementemia (n = 4). Histopathology showed thrombotic microangiopathy (n = 4), overlapping with membranoproliferative pattern of injury (n = 1). At median 3.3 years of follow-up, significant hypertension and/or proteinuria (40%), relapses (66.7%), and death or progression to CKD (60%) were common. Genetic sequencing showed 13 homozygous and compound heterozygous variants (7 pathogenic, 3 likely pathogenic) located throughout DGKE; 11 variants were novel. CONCLUSIONS: This case series highlights the need to suspect DGKE nephropathy in young patients with TMA, especially those with severe proteinuria. Medium-term outcomes are unsatisfactory with risk of relapses, progressive kidney failure, and death. A higher resolution version of the Graphical abstract is available as Supplementary information.

Usefulness of urinary calprotectin as a novel marker differentiating functional from structural acute kidney injury in the critical care setting.

BACKGROUND: Biomarkers are fundamental tools for differentiating between types of acute kidney injury (AKI) and may thus be crucial in management and prognosis. We report on a recently described biomarker, calprotectin, that appears to be a promising candidate in differentiating hypovolemic/functional AKI from intrinsic/structural AKI, whose acknowledgement may play a role in improving outcomes. We aimed to study the efficacy of urinary calprotectin in differentiating these two forms of AKI. The effect of fluid administration on the subsequent clinical course of AKI, its severity and the outcomes were also studied. METHODOLOGY: Children who presented with conditions predisposing to AKI or with diagnosis of AKI were included. Urine samples for calprotectin analysis were collected and stored at - 20 ºC for analysis at the end of the study. Fluids were administered as per clinical conditions, followed by intravenous furosemide 1 mg/kg, and patients were observed closely for at least 72 h. Children with serum creatinine normalization and clinical improvement were classified as with functional AKI, while those with no response were classified as with structural AKI. Urine calprotectin levels between these two groups were compared. Statistical analysis was performed with SPSS 21.0 software. RESULTS: Of the 56 children enrolled, 26 were classified as with functional AKI and 30 as with structural AKI. Stage 3 AKI was observed in 48.2% of patients and stage 2 AKI in 33.8%. Mean urine output, creatinine and stage of AKI improved with fluid and furosemide or furosemide alone (OR 6.08, 95% CI 1.65-27.23) (p < 0.01). A positive response to fluid challenge was in favor of functional AKI (OR 6.08, 95% CI 1.65-27.23) (p = 0.008). Presence of edema, sepsis and need for dialysis were hallmarks of structural AKI (p < 0.05). Urine calprotectin/creatinine values were 6 times higher in structural AKI compared to functional AKI. Urine calprotectin/creatinine ratio showed the best sensitivity (63.3%) and specificity (80.7%) at a cut-off value of 1 mcg/mL in differentiating the two types of AKI. CONCLUSION: Urinary calprotectin is a promising biomarker that may help differentiating structural from functional AKI in children.

Incidence of Acute Kidney Injury in Hospitalized Children: A Meta-analysis.

BACKGROUND AND OBJECTIVES: There is limited literature on the incidence of acute kidney injury (AKI) and associated mortality in hospitalized children. To systematically assess the worldwide incidence of AKI in hospitalized children to inform policymakers regarding appropriate health resource allocation. METHODS: Three different databases were searched (PubMed, Embase, Web of Sciences) from March 2012 to January 2022 without language or geographical restrictions. We included cohort and cross-sectional studies that reported AKI incidence in hospitalized children. Eligible studies had at least 100 participants and used the standard Kidney Disease Improving Global Outcomes criteria to define AKI. Two authors extracted data on the study and patients' characteristics and outcomes (incidence and AKI-associated mortality) and performed the risk of bias assessment. We used a random-effects meta-analysis to generate pooled estimates. RESULTS: We included 94 studies (202 694 participants) from 26 countries. The incidence of any AKI was 26% (95% confidence interval: 22-29), and that of moderate-severe AKI was 14% (11-16). The incidence of AKI was similar in high-income 27% (23-32), low-middle-income 25% (13-38), and low-income 24% (12-39) countries. Overall, AKI-associated mortality was observed in 11% (9-13) of the pediatric population. AKI-associated mortality rate was highest at 18% (11-25) and 22% (9-38) in low-income and low-middle-income countries, respectively. CONCLUSIONS: AKI was observed in one-quarter of the hospitalized children and is associated with increased mortality risk. Low-income and low-middle-income countries had observed higher mortality rates compared with high-income countries despite a similar AKI burden.

Epidemiology and outcomes of pneumococcal sepsis in children with nephrotic syndrome in a developing country.

BACKGROUND: Pneumococcal infections are common in children with nephrotic syndrome. Knowledge of the commonly available serotypes and antibiotic susceptibility will help in prevention and appropriate management of pneumococcal sepsis, especially in resource-limited countries. METHODS: Demographic, clinical, and laboratory data on children with nephrotic syndrome and pneumococcal infections were extracted from the electronic medical records. RESULTS: Sixty-three isolates of pneumococci obtained from 60 children with nephrotic syndrome, over a period of 14 years, were included in the study. This represented 18% of all pneumococcal infections occurring in children during the same period. Commonly available vaccines covered up to 58% of all the serotypes causing infection. Severe disease, with shock, intensive care admission and/or meningitis, was observed in 38% children and mortality was observed in 10%. Resistance to commonly used antibiotics was not observed, except for erythromycin. CONCLUSIONS: Pneumococcal sepsis was observed to be common in children with nephrotic syndrome and results in significant morbidity and mortality. Commonly used antibiotics were observed to be effective in management of the infections.

Sequential rituximab therapy sustains remission of nephrotic syndrome but carries high risk of adverse effects.

BACKGROUND: Sequential rituximab (RTX) administration has emerged as an important strategy to sustain remission of disease in patients with difficult-to-treat nephrotic syndrome. METHODS: We report the efficacy and safety of sequential therapy with two or more courses of intravenous RTX in 250 patients with difficult-to-treat steroid dependence (n = 127) and calcineurin inhibitor (CNI)-dependent or CNI-refractory steroid resistance (n = 123) managed at one center during 2015-2021. Subsets of patients were cross-sectionally tested for hypogammaglobulinemia, seroprotection against and hyporesponsiveness to vaccines for hepatitis B and tetanus, BK/JC viruria and human antichimeric antibodies (HACAs). RESULTS: Sequential RTX therapy, initiated at a median of 10 years [interquartile range (IQR) 7.3-14.4], was administered for 1.8 courses/person-year [95% confidence interval (CI) 1.7-2.0] over 2.0 years (95% CI 1.2-3.0). Therapy was associated with postponement of relapses by a median of 3 years in patients with steroid-sensitive disease and 2 years in those with steroid resistance. Relapses were reduced by a mean of 2.0 relapses/person-year (95% CI 1.8-2.2), enabling a reduction in prednisolone dose to 0.04 mg/kg/day (95% CI 0.01-0.11) and withdrawal of additional immunosuppression in 154 (62%) patients. RTX-associated adverse events, occurring at 0.20 events/person-year (95% CI 0.17-0.23), were chiefly comprised of infusion reactions (n = 108) and infections (n = 46); serious adverse events were observed in 10.8% patients, at 0.03 events/person-year (95% CI 0.02-0.05). Hypogammaglobulinemia was observed in 35% of 177 patients and was moderate to severe in 8.5% of cases. Rates of seroprotection at baseline and response following vaccination were lower for hepatitis B [1.9% and 29.4% (n = 52)] than tetanus [65.5% and 34.5% (n = 58)]. BK/JC viruria, without viremia, was observed in 7.3% of 109 cases. A total of 19 of 107 patients (17.8%) had HACAs, which were associated with B cell nondepletion and serum sickness. Age at therapy of <9-10 years was associated with a risk of early relapse, treatment failure and hypogammaglobulinemia following RTX therapy. CONCLUSIONS: Sequential therapy with RTX effectively reduces relapses in patients with difficult-to-treat steroid- and/or CNI-dependent or CNI-refractory nephrotic syndrome. Therapy is associated with high rates of hypogammaglobulinemia and infusion reactions.

The Clinical Profile and Long-Term Outcome of Children with Membranous Nephropathy, and the Evaluation of Anti-Phospholipase A2 Receptor Antibody Immunohistochemistry in Kidney Biopsy.

Introduction: Idiopathic membranous nephropathy (iMN) is a rare cause of nephrotic syndrome in children (1%-7%). Anti-phospholipase A2 receptor (PLA2R) antibody positivity in kidney biopsy is observed in 52%-78% of adults and 45% of children with iMN. The objectives of the study are to analyze the clinical profile and outcome of membranous nephropathy in children, to assess the prevalence of anti-PLA2R immunohistochemistry (IHC) in kidney biopsy, and to correlate their presence with disease characteristics. Methods: We are reporting a single-center retrospective study conducted in pediatric nephrology division. Clinical data and outcome parameters of children with membranous nephropathy were analyzed. PLA2R IHC was performed in kidney biopsy specimens retrospectively. Results: We analyzed 43 children with membranous nephropathy (MN) from a single center. 18 (42%) had idiopathic MN (iMN). PLA2R IHC was performed in kidney biopsy specimens in 14/18 (78%) patients with iMN and 7/9 (78%) non-lupus secondary membranous nephropathy (SMN) patients. The most common cause of SMN was lupus nephritis in 16 patients (64%). The mean estimated glomerular filtration rate (eGFR) at onset was 156 ± 81 ml/min/1.73m2. The sensitivity and specificity of PLA2R IHC in diagnosing pediatric MN was 50% and 57%, respectively; positive and negative predictive values were 70% and 36%, respectively. At the final follow-up, chronic kidney disease stage 5 (CKD 5) developed in 2/14 (14.3%) iMN patients. Conclusions: IHC PLA2R staining of glomerular tissue is a useful diagnostic marker of IMN. Though PLA2R prevalence is lower in children, its role in guiding treatment needs further exploration.

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

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.

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

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.

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.