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Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, hypoalbuminemia, and/or concomitant edema. Approximately 85-90% of patients attain complete remission of proteinuria within 4-6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70-80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given., (© 2022. The Author(s).)

There is a paucity of data identifying genetic mutations that account for the high rate of steroid-resistant nephrotic syndrome (SRNS) in a South African paediatric population. The aim was to identify causal mutations in genes implicated in SRNS within a South African paediatric population. We enrolled 118 children with primary nephrotic syndrome (NS), 70 SRNS and 48 steroid-sensitive NS. All children with SRNS underwent kidney biopsy. We first genotyped the NPHS2 gene for the p.V260E variant in all NS cases (n = 118) and controls (n = 219). To further identify additional variants, we performed whole-exome sequencing and interrogated ten genes (NPHS1, NPHS2, WT1, LAMB2, ACTN4, TRPC6, INF2, CD2AP, PLCE1, MYO1E) implicated in SRNS with histopathological features of focal segmental glomerulosclerosis (FSGS) in 56 SRNS cases and 29 controls; we also performed exome sequencing on two patients carrying the NPHS2 p.V260E mutation as positive controls. The overall detection rate of causal and putative pathogenic mutations in children with SRNS was 27/70 (39%): 15 (21%) carried the NPHS2 p.V260E causal mutation in the homozygous state, and 12 (17%) SRNS cases carried a putative pathogenic mutation in the heterozygous state in genes (INF2 (n = 8), CD2AP (n = 3) and TRPC6 (n = 1)) known to have autosomal dominant inheritance mode. NPHS2 p.V260E homozygosity was specifically associated with biopsy-proven FSGS, accounting for 24% of children of Black ethnicity (15 of 63) with steroid-resistant FSGS. No causal or putative pathogenic mutations were identified in NPHS1, WT1, LAMB2, PLCE1, MYO1E and ACTN4. We report four novel variants in INF2, PLCE1, ACTN4 and TRPC6.   Conclusion: We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant-FSGS children. However, the NPHS2 p.V260E mutation is a prevalent cause of steroid-resistant FSGS among Black South African children occurring in 24% of children with SRNS. Screening all Black African children presenting with NS for NPHS2 p.V260E will provide a precision diagnosis of steroid-resistant FSGS and inform clinical management. What is Known: • Limited data is available on the genetic disparity of SNRS in a South African paediatric setting. • The high rate of steroid resistance in Black South African children with FSGS compared to other racial groups is partially explained by the founder variant NPHS2 p.V260E. What is New: • We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant FSGS children. • NPHS2 p.V260E mutation remains a prevalent cause of steroid-resistant FSGS among Black South African children, demonstrating precision diagnostic utility., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Despite adverse events associated with the long-term use of immunosuppressants, their long-term discontinuation remains challenging in children with idiopathic nephrotic syndrome. Relapse and resumption of immunosuppressants after discontinuation and associated risk factors were analyzed., Methods: This single-center retrospective cohort study included children with frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) or steroid-resistant nephrotic syndrome (SRNS) who initiated immunosuppressant treatment between 2010 and 2020. Patients treated with immunosuppressants for less than two years, those with genetic SRNS, and those with continuation of immunosuppressants were excluded., Results: Sixty-eight patients with FRNS/SDNS or SRNS discontinued immunosuppressants. Discontinuation of immunosuppressants was more frequently tried in patients with less relapse on initial immunosuppressants and less rituximab administration. Of 68 patients who discontinued immunosuppressants, 45 (66%) relapsed and 31 (46%) resumed immunosuppressants with a median follow-up of 39.8 months (IQR 24.6-71.2 months) after discontinuation. The relapse-free survival rates were 40.0%, 35.3%, and 35.3% in 1, 2, and 3 years from discontinuation of immunosuppressants, respectively. Relapse on initial immunosuppressants (HR 2.038, 95%CI 1.006-4.128, P = 0.048) and the relapse-free interval before discontinuation of immunosuppressants (HR 0.971, 95%CI 0.944-0.998, P = 0.037) were significant risk factors associated with relapse after the discontinuation of immunosuppressants, adjusting for sex, age at immunosuppressant treatment initiation, SRNS, and rituximab use., Conclusions: Long-term discontinuation of immunosuppressants can be feasible in patients without a relapse on initial immunosuppressants, those with longer relapse-free interval before discontinuation of immunosuppressants, and those without a relapse for one year after discontinuation of immunosuppressants., Trial Registration: Not applicable., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: The outcome and response of idiopathic nephrotic syndrome (NS) to steroids have been linked to race., Objectives: To determine the age of presentation, sex, race, histopathology, kidney function and disease status at the last hospital visit and correlate these with steroid response in Indian and black African children with idiopathic NS., Methods: This is a retrospective review of 231 children aged 1 - 14 years, who were seen at Inkosi Albert Luthuli Central Hospital, Durban, South Africa (SA) from 2003 to 2018., Results: The mean (standard deviation (SD)) age of presentation was 6.2 (3.4) years, with the majority of children (n=107; 46.3%) presenting at an early age (1 - 3 years) with a mean (SD) follow-up of 3.0 (2.4) years. One-hundred and twenty-one (52.4%) were males and 110 (47.6%) were females, with a male/female ratio of 1.1:1. There were 166 (71.9%) black African and 65 (28.1%) Indian children. The latter presented at a younger age than black African children (p<0.001). Seventy-six (32.9%) children were steroid sensitive (SS) and 155 (67.1%) were steroid resistant (SR). Black African children were more likely to be SR (odds ratio (OR) 2.0; p=0.02; 95% confidence interval (CI) 1.1 - 3.7). A kidney biopsy was performed in 209 (90.5%) children. Minimal change disease (MCD) was observed in 32 (13.9%) children and 162 (70.1%) had focal segmental glomerulosclerosis (FSGS). Black African children were slightly more likely to have FSGS; this, however, did not reach statistical significance (122/166 (73.5%) v. 40/65 (61.5%); OR 1.73; p=0.08; 95% CI 0.94 - 3.18). On comparing disease status at last hospital visit by race, 49/65 (75.4%) Indian and 94/166 (56.6%) black African children were in remission. At last hospital visit, black African children were less likely to be in remission than Indian children (OR 0.47; p=0.02; 95% CI 0.2 - 0.9), while 15/65 (23.1%) Indian and 47/166 (28.3%) black African children had relapsed, with no significant difference between the two groups. One (1.5%) Indian child and 25 (15.1%) black African children had end-stage kidney disease (ESKD) (OR 9.27; p=0.03; 95% CI 1.2 - 70.4) ‒ the majority had FSGS. Sixteen (61.5%) received renal replacement therapy., Conclusions: Our study shows a rising incidence of FSGS, with the majority of patients having SRNS, particularly black African children. This highlights the need for alternative efficacious therapy in the management of this disease. Also, a higher percentage of black African children with both MCD and FSGS were SS on histopathological examination, which was in keeping with reports from other regions in SA. There are still major challenges for the inclusion of all children into a chronic dialysis and transplant programme.

Background: Levamisole is a commonly used steroid-sparing agent (SSA), but the reported incidence of antineutrophil cytoplasmic antibody (ANCA) positivity has been concerning., Methods: Observational cross-sectional study wherein children aged 2 to 18 years with frequently relapsing/steroid dependent nephrotic syndrome (FRNS/SDNS) on levamisole for ≥ 12 months were tested for ANCA., Results: A total of 210 children (33% female), median age of 7.3 (IQR: 5.6-9.6) years, and a median duration of levamisole exposure of 21 (IQR: 15-30) months were tested. ANCA was positive in 18% (n = 37): 89% (n = 33) perinuclear ANCA (pANCA), 3% (n = 1) cytoplasmic ANCA (cANCA), and 8% (n = 3) both. Of ANCA-positive children, none had reduced eGFR or abnormal urinalysis. The majority of these children were asymptomatic (81%, n = 30). Rash was more common among ANCA-positive children [6/37 (16%) vs. 3/173 (2%), p = 0.0001]. On multivariate analysis, higher age (OR = 1.02, [95th CI: 1.01 to 1.03], p = 0.007) and longer duration of levamisole exposure (OR = 1.05, [95th CI: 1.02 to 1.08], p = 0.0007) were associated with ANCA positivity. Levamisole was stopped in ANCA-positive children with the resolution of any clinical manifestations if present. Repeat ANCA testing was performed in 54% (20/37), and all were ANCA negative by 18 months., Conclusions: Children with FRNS/SDNS on longer duration of levamisole were associated with increasing prevalence of ANCA positivity, but most of these children were clinically asymptomatic. Prospective studies are required to determine the chronology of ANCA positivity and its clinical implication., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children. We performed this study to report histopathological findings, the correlation between clinical and histopathological features, and the response to steroids and other immunosuppressive drugs and outcomes in Syrian children with INS., Methods: A single-center retrospective observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients aged 1-14 years, admitted from January 2013 to December 2022, with INS and who underwent kidney biopsy., Results: The study included 109 patients, with a male/female ratio of 1.13:1, and a median age of 5 years with interquartile range (2.8-10). The main indication of kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) (57.8%). The main histopathological patterns were minimal change disease (MCD) (45%) and focal segmental glomerulosclerosis (FSGS) (37.6%). FSGS was the most common histopathological pattern in SRNS (44.3%). In SRNS, we used calcineurin inhibitors to induce remission. Tacrolimus was used in 49 patients with response rate (complete remission of proteinuria) of 69.4% and cyclosporine in 20 patients with response rate of 50%. In steroid-dependent nephrotic syndrome (SDNS), we used mycophenolate mofetil (MMF) and cyclophosphamide to prevent relapses; MMF was used in 9 patients with response rate (maintaining sustained remission) of 89% and cyclophosphamide in 3 patients with response rate of 66.7%. Rituximab was used in four patients with FSGS, two SRNS patients and two SDNS patients, with sustained remission rate of 100%. Fifteen patients (13.7%) progressed to chronic kidney disease stage 5. Of them, 7 patients had FSGS and 8 patients had focal and global glomerulosclerosis;14 of them were steroid-resistant and one patient was steroid-dependent with persistent relapses. The most common outcome was sustained remission (47%) in MCD and frequent relapses (31.7%) in FSGS., Conclusions: FSGS was the most common histopathological pattern in idiopathic SRNS and had the worst prognosis. Calcineurin inhibitors could be an effective therapy to induce complete remission in SRNS. Rituximab may be an effective treatment to achieve sustained remission in SDNS and frequently relapsing NS and may have a potential role in SRNS with further studies required., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: In pediatric steroid-resistant nephrotic syndrome (SRNS), calcineurin inhibitors (CNIs) are recommended as first-line therapy, with efficacy ranging between 60 and 80%, implying a substantial proportion will exhibit CNI resistance. Which alternate immunosuppressive therapy should be used in non-genetic pediatric SRNS exhibiting CNI resistance is especially relevant in low- to middle-income countries (LMIC), where the prohibitive costs of certain drugs such as monoclonal antibodies often determine therapy choice., Methods: The primary objective was to assess the efficacy of intravenous cyclophosphamide in a proportion of children aged 1-18 years with CNI-resistant SRNS with a complete response (CR) or partial response (PR) at 6 months from commencement of pulse therapy. The secondary objectives were to assess the proportion and profile of infections and adverse effects., Results: Of 90 children with idiopathic SRNS presenting between January 2013 and December 2022, 29 (32.2%) had CNI resistance and were enrolled. They were administered monthly intravenous cyclophosphamide pulses (6 pulses). Median (IQR) duration of follow-up was 48 (29.5, 63.5) months. At the end of 6 months of cyclophosphamide therapy, 13 (44.8%) attained CR and 4 (13.8%) attained PR, with an overall cyclophosphamide success rate of 58.6%. The efficacy of intravenous cyclophosphamide was higher in secondary (9/10; 90%) versus primary CNI resistance (8/19; 42.1%) (p = 0.029). Three children (3/29; 10.3%) developed systemic infections within 12 months of initiation of cyclophosphamide therapy, similar to the rate of systemic infections among children receiving CNI for SRNS management (6/41; 14.6%) (p = 0.85)., Conclusions: It is prudent to try intravenous cyclophosphamide in CNI-resistant SRNS in LMIC, given the reasonable cost and good efficacy rates (58.6%)., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: We aimed to investigate the efficacy and safety of repeated use of rituximab (RTX) in pediatric patients with nephrotic syndrome (NS)., Methods: Retrospective review of 50 patients with steroid-dependent NS (SDNS) who had received more than three cycles of RTX was conducted; each consisted of one to four infusions until B lymphocytes were depleted., Results: The median age of starting the first RTX cycle was 12.4 years (interquartile ranges (IQR) 10.2-14.6). During a median follow-up period of 6.3 (IQR 3.6-8.6) years, patients received a median of 5.0 RTX cycles (IQR 4.0-7.3). The number of relapses decreased from a median of 2.0 relapses per year (IQR 1.0-3.0) to 0.2 relapses per year (IQR 0.0-0.5) after long-term RTX treatments (P < 0.001). Longer relapse-free periods were associated with more than four RTX cycles, longer B-cell depletion, older age at each RTX treatment, and lower cholesterol levels. B lymphocytes recovered to 1% at a median of 5.9 months (95% confidence interval 5.7-6.1) after RTX administration. Factors related to a longer period of B-cell depletion included more than five RTX cycles, a higher dose of RTX, older age at treatment, and concurrent use of antimetabolites. During repeated RTX treatments, 8.0%, 6.0%, and 2.0% of patients developed hypogammaglobulinemia, severe infection, and severe neutropenia, respectively., Conclusions: Long-term repeated use of RTX may be effective and safe in pediatric NS patients. Furthermore, the redosing of RTX could be chosen by considering predictive factors for relapse-free and B-cell depletion periods., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Although evidence has confirmed that cyclosporine (CS) is efficacious against childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome (SD/SRNS), some patients may continue to relapse during adulthood. However, predictive factors for adult active disease and kidney complications, such as chronic kidney disease (CKD) and hypertension, in this cohort remain unknown., Methods: We conducted a retrospective study on the long-term outcomes of 81 young adults with childhood-onset SD/SRNS treated with CS. The primary endpoint was the probability of active disease into adulthood. The secondary endpoint was the probability of developing kidney complications., Results: At the last follow-up (median age, 23.2 years; median disease duration, 15.8 years), 44 adult patients (54%) continued to have active disease, whereas 16 patients developed CKD or hypertension, respectively. The proportion of patients developing kidney complications was similar between the active disease and long-term remission groups. Young age at NS onset and history of relapse during the initial CS (median, 31 months) were independent predictive factors for active disease. Acute kidney injury at NS onset, focal segmental glomerulosclerosis, and irreversible CS nephrotoxicity were identified as risk factors for the development of CKD, whereas older age was identified as a risk factor for the development of CKD and hypertension., Conclusions: More than 50% of adult survivors treated with CS continued to have active disease, and each 20% developed CKD or hypertension. A long-term follow-up is necessary for patients with SD/SRNS to identify the development of kidney complications later in adulthood that can be attributed to prior disease and CS treatment in childhood, irrespective of disease activity. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

As the molecular mechanism of nephrotic syndrome remains largely undiscovered, patients continue to be exposed to the pros and cons of uniform glucocorticoid treatment. We explored whether the exposure of in vitro-cultivated podocytes to sera from children with steroid-sensitive or steroid-resistant nephrotic syndrome induces differences in gene expression profiles, which could help to elucidate the pathogenesis of the steroid response. Human immortalized podocytes were cultivated with patient sera for 3 days. After cell lysis, RNA extraction, 3'-mRNA libraries were prepared and sequenced. There were 34 significantly upregulated and 14 downregulated genes (fold difference <0.5 and >2.0, respectively, and false discovery rate-corrected p < 0.05) and 22 significantly upregulated and 6 downregulated pathways (false discovery rate-corrected p < 0.01) in the steroid-sensitive (n = 9) versus steroid-resistant group (n = 4). The observed pathways included upregulated redox reactions, DNA repair, mitosis, protein translation and downregulated cholesterol biosynthesis. Sera from children with nephrotic syndrome induce disease subtype-specific transcriptome changes in human podocytes in vitro. However, further exploration of a larger cohort is needed to verify whether clinically distinct types of nephrotic syndrome or disease activity may be differentiated by specific transcriptomic profiles and whether this information may help to elucidate the pathogenesis of the steroid response., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Immunosuppressants are commonly used as steroid-sparing agents in childhood idiopathic nephrotic syndrome (NS) to induce and sustain remissions. These drugs have narrow therapeutic indices with high inter- and intra-patient variability. Therapeutic drug monitoring (TDM) would therefore be essential to guide the prescription. Multiple factors in NS contribute to additional variability in drug concentrations, especially during relapses. In this article, we review the currently available evidence of TDM in NS and suggest a practical approach for clinicians' reference., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

The International Study of Kidney Disease in Children (ISKDC), begun in 1966, conducted the first international collaborative randomized blinded controlled trial in pediatric nephrology and one of the first in either pediatrics or nephrology. For this trial, the ISKDC developed the criteria, such as those for response and relapse, used today to describe the clinical course of the nephrotic syndrome, and the trial generated the nephropathologic terminology and criteria which largely remain the current standards. Over an approximately 20-year span, the ISKDC followed the natural history and evaluated the therapeutic effectiveness of therapies in over 500 children with the nephrotic syndrome from three continents. It published 14 peer-reviewed studies and several reports and commentaries, many of which helped create current standards of practice for therapy of childhood nephrotic syndrome and consequently remain highly cited today. The ISKDC continues to be an important model for subsequent collaborative studies and was the impetus for the development of regional and national pediatric nephrology societies leading to the recognition and growth of pediatric nephrology as a separate subspecialty. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Steroid-resistant (SR) forms of nephrotic syndrome (NS) have a poorer outcome in blacks compared to other racial groups. In this study, 223 children with SRNS, aged 1-16 years old, were analysed retrospectively for the period 1976-2004. Treatment schedules included oral cyclophosphamide (2-3 mg/kg) with prednisone 0.5-1 mg/kg (maximum 60 mg) only (n=90); prednisone on alternate days with methylprednisolone (30 mg/kg, maximum 1 g) and oral cyclophosphamide (n=117); oral prednisone on alternate days, three doses of intravenous methylprednisolone on alternate days and monthly doses of intravenous cyclophosphamide (500-750 mg m(-2) dose(-1)x7 doses monthly) (n=10); or cyclosporine 5 mg kg(-1) day(-1) adjusted to a trough level of 150-200 mg/ml (n=6). We compared the clinical and biochemical characteristics and outcome using different forms of therapies. A total of 183 (82.1%) underwent biopsy; 84 (45.9%) were Indian and 99 (54.1%) were black. Sixty-six (36.1%) had minimal change NS, 66 (36.1%) had focal segmental glomerulosclerosis (FSGS), 15 (8.2%) had a proliferative form of NS, and 36 (19.7%) had other forms of NS. Of the 84 Indian children biopsied, 58 (69.0%) were in complete remission, including 29 of 40 (72.5%) treated with oral cyclophosphamide and prednisone only. Of the 99 black children who were biopsied, 20 (20.2%) achieved complete remission; none of those treated with oral cyclophosphamide and prednisone only achieved complete remission. Of the 40 Indian children who were not biopsied who received only oral prednisone and cyclophosphamide, 32 (80%) achieved complete remission. This study shows Indian children with SRNS respond better to treatment than black children (69.0 vs. 20.2%). Since 80% of Indian children with SRNS responded to a trial of oral cyclophosphamide and prednisone, we propose the use of oral cyclophosphamide therapy in non-black children before embarking on renal biopsy.

We review our 20-year experience of 636 children with nephrotic syndrome (NS) in Durban, South Africa; 306 (48.2%) were blacks, 307 (48.2%) Indians and 23 (3.6%) were a mixed group (coloured); 91 (14.3%) could not be categorised and were excluded from the analysis. In Indian children, 134 of 286 (46.8%) had biopsy-proven minimal change NS (MCNS) and 94.8% of these were steroid sensitive (SS); 60 (21%) had SSNS but without renal biopsy; 59 (20.6%) had focal segmental glomerulosclerosis (FSGS), with only 4.4% of these being SS. In blacks, membranous nephropathy accounted for 40% of cases; 86.2% were associated with hepatitis B virus antigens. Typical SSNS continues to be uncommon among blacks. Only 14.4% had either biopsy-proven SS-MCNS or SSNS; 32 had MCNS lesions on biopsy, but 18 were steroid resistant (SR); 67 of 236 (28.4%) had FSGS, all of whom were SR. Among coloured patients, 5 of 23 (21.7%) had biopsy-proven SS-MCNS and or unbiopsied SSNS; 10 (43.5%) had FSGS and 6 of 23 (26.1%) had membranous nephropathy. Proliferative lesions were present in only 2 of 23 (8.6%) coloured patients and was uncommon in all population groups. Overall mortality was 3.1%. In brief, this is the largest reported series of NS among children in Africa and shows a typical pattern in Indians, an unusual pattern of histological types in blacks and an intermediate picture in coloureds.

Background: Oral cyclophosphamide (CYP) is an important therapeutic agent in treatment of steroid-sensitive nephrotic syndrome having a steroid-dependent (SD) or frequent relapsing (FR) course. This retrospective observational study aimed to determine response to oral CYP and factors associated with positive response in these patients., Methods: We studied 100 children (male; 75) with FR (19%) and SD (81%) NS treated with CYP in the Pediatric Nephrology clinic. Responders were defined as children in whom steroids were stopped for at least 6 months following CYP and factors affecting response were analysed. Relapse-free survival was estimated by Kaplan-Meier method., Results: Median age at onset of NS was 3 years (IQR 2-5.2). Median age at CYP was 5.7 years (IQR 3.7-7.9). Fifty percent of patients were in the responder group at 6 months of CYP. Relapse-free survival post CYP therapy was 31% at 1 year, 11% at 2 years. Factors predicting good response were age at onset of NS > 3 years with 61.2% response at 6 months (p = 0.028) and older age at CYP initiation (> 5 years) with 61% response (p = 0.008). Multivariate regression analysis showed age at start of CYP > 5 years was an independent factor for good response (p = 0.044, OR = 2.903, CI -1.03 to 8.18)., Conclusions: Judicious selection of patients, especially with age of onset of NS more than 3 years and initiation of CYP after age of 5 years, can predict better response in this group of patents., (© 2021. IPNA.)

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.

Background and Objectives: Ethnic differences in outcomes among children with nephrotic syndrome are unknown., Design, Setting, Participants, & Measurements: We conducted a longitudinal study at a single regional pediatric center comparing ethnic differences in incidence from 2001 to 2011 census data and longitudinal outcomes, including relapse rates, time to first relapse, frequently relapsing disease, and use of cyclophosphamide. Among 711 children, 24% were European, 33% were South Asian, 10% were East/Southeast Asian, and 33% were of other origins., Results: Over 10 years, the overall incidence increased from 1.99/100,000 to 4.71/100,000 among children ages 1-18 years old. In 2011, South Asians had a higher incidence rate ratio of 6.61 (95% confidence interval, 3.16 to 15.1) compared with Europeans. East/Southeast Asians had a similar incidence rate ratio (0.76; 95% confidence interval, 0.13 to 2.94) to Europeans. We determined outcomes in 455 children from the three largest ethnic groups with steroid-sensitive disease over a median of 4 years. South Asian and East/Southeast Asian children had significantly lower odds of frequently relapsing disease at 12 months (South Asian: adjusted odds ratio; 0.55; 95% confidence interval, 0.39 to 0.77; East/Southeast Asian: adjusted odds ratio; 0.42; 95% confidence interval, 0.34 to 0.51), fewer subsequent relapses (South Asian: adjusted odds ratio; 0.64; 95% confidence interval, 0.50 to 0.81; East/Southeast Asian: adjusted odds ratio; 0.47; 95% confidence interval, 0.24 to 0.91), lower risk of a first relapse (South Asian: adjusted hazard ratio, 0.74; 95% confidence interval, 0.67 to 0.83; East/Southeast Asian: adjusted hazard ratio, 0.65; 95% CI, 0.63 to 0.68), and lower use of cyclophosphamide (South Asian: adjusted hazard ratio, 0.82; 95% confidence interval, 0.53 to 1.28; East/Southeast Asian: adjusted hazard ratio, 0.54; 95% confidence interval, 0.41 to 0.71) compared with European children., Conclusions: Despite the higher incidence among South Asians, South and East/Southeast Asian children have significantly less complicated clinical outcomes compared with Europeans., (Copyright © 2016 by the American Society of Nephrology.)

Minimal Change Disease (MCD) is a predominant cause of idiopathic nephrotic syndrome in the pediatric population, yet presents significant clinical challenges due to its frequent relapses and steroid resistance. Despite its relatively benign histological appearance, MCD is characterized by severe proteinuria, hypoalbuminemia, and edema, which may affect patient outcomes. Current treatment strategies primarily rely on corticosteroids, which are effective in inducing remission but are associated with high relapse rates, steroid resistance, and numerous long-term side effects, underscoring the need for more targeted and effective therapeutic approaches. This narrative review synthesizes current knowledge on the pathophysiological mechanisms underlying MCD, focusing on the following three critical areas: podocyte dysfunction, immune dysregulation, and genetic susceptibility. Podocyte dysfunction, particularly involving alterations in nephrin, plays a central role in the breakdown of the glomerular filtration barrier, leading to the characteristic proteinuria observed in MCD. Immune dysregulation, including the presence of autoantibodies against nephrin and other podocyte components, exacerbates podocyte injury and contributes to disease progression, suggesting an autoimmune component to the disease. Genetic factors, particularly mutations in the NPHS1 and NPHS2 genes, have been identified as significant contributors to disease susceptibility, influencing the variability in treatment response and overall disease severity. Understanding these mechanisms is crucial for developing targeted therapies that address the underlying causes of MCD rather than merely managing its symptoms. This review highlights the need for further research into these pathophysiological processes to pave the way for more personalized and effective treatment strategies, ultimately improving patient outcomes and reducing reliance on corticosteroids. [ABSTRACT FROM AUTHOR]

Background: Infection is the most common complication of pediatric patients with nephrotic syndrome. The factors associated with infection in nephrotic syndrome are lacking. The objective of the study was to identify the prevalence and associated factors among children with nephrotic syndrome aged 2 to 18 years. Methods: We conducted a hospital-based retrospective cross-sectional study. The data collector installed an Epi5 collector electronic data-collecting tool from Google Play. Then, we exported the data to Stata version 15.1 for analysis. The mean, standard deviation, frequency, and percentage were used for descriptive statistics. The logistic regression model was used to identify the factors associated with infection. Results: In this study, the prevalence of infection among nephrotic syndrome children is 39.8% (95%CI: 30.7, 49.7). The types of infection identified were pneumonia, urinary tract infection, diarrheal disease, cutaneous fungal infection, intestinal parasitic infection, and sepsis. The presence of hematuria increased the odds of infection by 5-times. On the other hand, low level of serum albumin increased the odds of infection by 7%. Being a rural resident increased the odds of infection by 3.3-times as compared to urban. Conclusions: Serum albumin level, presence of hematuria, and rural residence were significantly associated with infection. We recommended a longitudinal incidence study on large sample size at multicenter to strengthen this finding. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome, especially the steroid-resistant form, is often complicated by hypertension in childhood. The syndrome is common in black children. However, the histopathological finding of membranous nephropathy in children with nephrotic syndrome is rare. Liddle's syndrome is a rare genetic abnormality that presents with salt-sensitive hypertension caused by constitutive activation of the amiloride-sensitive epithelial sodium channel. The epithelial sodium channel comprises homologous a, ß, and? subunits that share similar structures. Gene mutations associated with Liddle's syndrome occur in either the ß or? subunits and disturb or truncate a conserved proline-rich sequence (i.e., PY motif), leading to constitutive activation of the epithelial sodium channel. The association of nephrotic syndrome with Liddle's syndrome has only been described in an adult patient. We present here the first case of these two syndromes (nephrotic syndrome and Liddle's-like syndrome) co-existing in a child with membranous nephropathy in his histopathological finding on kidney biopsy. [ABSTRACT FROM AUTHOR]

Objective: To determine different risk factors associated with relapse in children with steroid-sensitive nephrotic syndrome. Study Design: Cross-sectional study. Setting: Department of Pediatric Nephrology, The National Institute of Child Health, Karachi. Period: April 2021 to October 2022. Material & Methods: With a sample size of 170 Children aged 1-12 years of either gender were included in the study by non-probability consecutive sampling. Patients who had congenital nephrotic syndrome previously received immunosuppressive treatment or had any other systemic disease leading to nephrotic syndrome were excluded from the study. Frequencies and percentages were calculated for the quantitative variables while chi-square test was applied for the qualitative variables-value of <0.05 was considered significant. Results: The mean age of the patients was 4.87±2.54 years. The majority of the frequent relapsers (76) were male. The mean serum cholesterol of the patients was 318.71±61.61mg/dl. Of the total sample, 37 (21.76%) were infrequent relapsers and 133 (78.23 %) were frequent relapsers. A significant association was found between upper respiratory tract infection and frequent relapse with a p-value of 0.038. Conclusion: Our study showed a significant association between upper respiratory tract infection and relapse in children with steroid-sensitive nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Membranous nephropathy is an autoimmune disease affecting the glomeruli and is one of the most common causes of nephrotic syndrome. In the absence of any therapy, 35% of patients develop end-stage renal disease. The discovery of autoantibodies such as phospholipase A2 receptor 1, antithrombospondin and neural epidermal growth factor-like 1 protein has greatly helped us to understand the pathogenesis and enable the diagnosis of this disease and to guide its treatment. Depending on the complications of nephrotic syndrome, patients with this disease receive supportive treatment with diuretics, ACE inhibitors or angiotensin-receptor blockers, lipid-lowering agents and anticoagulants. After assessing the risk of progression of end-stage renal disease, patients receive immunosuppressive therapy with various drugs such as cyclophosphamide, steroids, calcineurin inhibitors or rituximab. Since immunosuppressive drugs can cause life-threatening side effects and up to 30% of patients do not respond to therapy, new therapeutic approaches with drugs such as adrenocorticotropic hormone, belimumab, anti-plasma cell antibodies or complement-guided drugs are currently being tested. However, special attention needs to be paid to the choice of therapy in secondary forms or in specific clinical contexts such as membranous disease in children, pregnant women and patients undergoing kidney transplantation. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome (NS) is a common pediatric disease characterized by a dysfunction in the glomerular filtration barrier that leads to protein, fluid, and nutrient loss in urine. Corticosteroid therapy is the conventional treatment in children. Long-term complications of NS and prolonged exposure to steroids affect bones, growth, and the cardiovascular system. Diet can play an important role in preventing these complications, but there is a scarcity of scientific literature about nutritional recommendations for children with NS. They need individualized nutrition choices not only during the acute phase of the disease but also during remission to prevent the progression of kidney damage. The correct management of diet in these children requires a multidisciplinary approach that involves family pediatricians, pediatric nephrologists, dietitians, and parents. [ABSTRACT FROM AUTHOR]

Background: The pattern of paediatric kidney diseases across different regions is influenced by genetic, racial, and environmental differences. Objectives: The aim of this study was to review the current spectrum and outcome of childhood kidney diseases at Parirenyatwa Group of Hospitals and highlight the challenges of care. Design: Retrospective observational study. Methods: Data on all children below 16 years of age hospitalised for any kidney disease over an 8-month period (1 January-31 August 2022) were retrieved and retrospectively analysed. Kidney diseases were categorised as per standard definitions. Results: Kidney disease accounted for 2.2% (n = 50) of all 2264 admissions in the paediatric unit, with males constituting 60% (n = 30). Age ranged from 2 weeks to 13 years (mean 5.5 ± 3.5 years) with 58.0% being under 5 years. The commonest diagnoses in the unit were acute kidney injury (AKI) (n = 16, 32%) nephrotic syndrome (n = 16, 32%), hypertension (n = 12, 24%) and end stage kidney disease (ESKD) (n = 11, 22%) with some children presenting with more than 1 diagnosis. Only 3 out of 11 children with ESKD and 3 out of 8 children with AKI who required dialysis could be offered dialysis due to limited resources. Overall mortality rate was 32% (16/50): 5 children with AKI, 2 with nephrotic syndrome and normal kidney function, 8 with ESKD and 1 with Fanconi syndrome. Conclusion: Childhood kidney disease contributes significantly to hospitalisations at our institution with highest mortality among children with ESKD. The study highlighted the need for provision of essential drugs and kidney replacement therapy for children with kidney disease at our institution. [ABSTRACT FROM AUTHOR]

Background. Histopathological patterns of childhood primary nephrotic syndrome (PNS) and clinical response to steroids have been associated with certain race groups in parts of South Africa. However, there are no recent studies of childhood PNS in Cape Town. Objectives. To describe the demographics, histological subtypes and steroid response of patients with PNS who underwent kidney biopsies at Red Cross War Memorial Children's Hospital (RCWMCH) over a 10-year period. Methods. Details of patients with PNS who underwent kidney biopsies in the Paediatric Nephrology Department at RCWMCH between 2006 and 2015 were retrospectively recorded. Results. A total of 103 patients were included in the study. Most patients were either of mixed race (42%) or black (36%), with a mean age of 6.8 years and a male-to-female ratio of 1.19:1. The most identified histopathological subtype was mesangioproliferative glomerulonephritis (MesPGN; 60% (n/N=62/103)). Of the patients with focal segmental glomerulosclerosis (FSGS), MesPGN and minimal change disease (MCD) 45% (n/N=43/95) were steroid-resistant, and 54% (n/N=51/95) were steroid-sensitive. There was no significant association between any race group and steroid response. Patients with FSGS were more likely to be black, while MCD was more common in mixedrace patients (p=0.04). There was no difference in the likelihood of being mixed race or black between patients with FSGS and MesPGN (p=0.472). Conclusion. MesPGN was the most common histopathological subtype found in our study. There was no significant association between race and steroid response. Patients with FSGS were more likely to be black than mixed race when compared with MCD patients. Race was not otherwise significantly associated with any histopathological subtype. [ABSTRACT FROM AUTHOR]

Steroid-resistant nephrotic syndrome (SRNS) is the most severe form of childhood nephrotic syndrome with an increased risk of progression to chronic kidney disease stage 5. Research endeavors to date have identified more than 80 genes that are associated with SRNS. Most of these genes regulate the structure and function of the podocyte, the visceral epithelial cells of the glomerulus. Although individuals of African ancestry have the highest prevalence of SRNS, especially those from Sub-Saharan Africa (SSA), with rates as high as 30–40% of all cases of nephrotic syndrome, studies focusing on the characterization and understanding of the genetic basis of SRNS in the region are negligible compared with Europe and North America. Therefore, it remains unclear if some of the variants in SRNS genes that are deemed pathogenic for SRNS are truly disease causing, and if the leading causes of monogenic nephrotic syndrome in other populations are the same for children in SSA with SRNS. Other implications of this lack of genetic data for SRNS in the region include the exclusion of children from the region from clinical trials aimed at identifying potential novel therapeutic agents for this severe form of nephrotic syndrome. This review underlines a need for concerted efforts to advance the genetic basis of SRNS in children in SSA. Such endeavors will complement global efforts at understanding the genetic basis of nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Aim: The earlier the onset of proteinuria, the higher the incidence of genetic forms. Therefore, we aimed to analyse the spectrum of monogenic proteinuria in Egyptian children presenting at age <2 years. Methods: The results of 27‐gene panel or whole‐exome sequencing were correlated with phenotype and treatment outcomes in 54 patients from 45 families. Results: Disease‐causing variants were identified in 29/45 (64.4%) families. Mutations often occurred in three podocytopathy genes: NPHS1, NPHS2 and PLCE1 (19 families). Some showed extrarenal manifestations. Additionally, mutations were detected in 10 other genes, including novel variants of OSGEP, SGPL1 and SYNPO2. COL4A variants phenocopied isolated steroid‐resistant nephrotic syndrome (2/29 families, 6.9%). NPHS2 M1L was the single most common genetic finding beyond the age of 3 months (4/18 families, 22.2%). Biopsy results did not correlate with genotypes (n = 30). On renin–angiotensin–aldosterone system antagonists alone, partial and complete remission occurred in 3/24 (12.5%) patients with monogenic proteinuria each, whereas 6.3% (1/16) achieved complete remission on immunosuppression. Conclusion: Genotyping is mandatory to avoid biopsies and immunosuppression when proteinuria presents at age <2 years. Even with such a presentation, COL4A genes should be included. NPHS2 M1L was prevalent in Egyptian children (4 months–2 years) with proteinuria, demonstrating precision diagnostic utility. [ABSTRACT FROM AUTHOR]

Background: Nephrotic syndrome occurring as a complication of immune tolerance therapy for inhibitors in hemophilia B is well recognized. It is also known to occur in association with factor borne infections, especially hepatitis C. This is the first case report of nephrotic syndrome occurring in a child receiving prophylactic factor VIII in the absence of inhibitors of hepatitis infection. However, the pathophysiology of this phenomenon is poorly understood. Case presentation: A 7-year Sri Lankan boy diagnosed with severe hemophilia A on weekly factor VIII prophylaxis was diagnosed with three episodes of nephrotic syndrome, a condition in which there is leakage of plasma protein into urine. He had three episodes of nephrotic syndrome, all of which responded well to 60 mg/m2 daily dose of oral steroids, achieving remission within 2 weeks of starting daily prednisolone. He has not developed inhibitors for factor VIII. His hepatitis screening remained negative. Conclusions: There is a possible link between factor therapy for hemophilia A and nephrotic syndrome, which can be a T-cell-mediated immune response. This case also highlights the importance of monitoring for renal involvement in patients treated with factor replacement. [ABSTRACT FROM AUTHOR]

Therapeutic options with immunosuppressive agents for glomerular diseases have widened with refinements to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines from 2012 to 2021. However, international guidelines do not necessarily match the reality in each country. Expensive therapies such as rituximab and calcineurin inhibitors are sometimes inaccessible to patients with refractory nephrotic syndrome due to cost or regulations. Under the Japanese medical insurance system, rituximab is accessible but still limited to steroid-dependent patients who developed idiopathic nephrotic syndrome in childhood. Based on international KDIGO guidelines and other national guidelines, possible applications of immunosuppressive agents for nephrotic syndrome are comprehensively examined in this review. While rituximab has become the mainstay of immunosuppressive therapy for nephrotic syndrome, clinical trials have indicated that options such as cyclophosphamide, calcineurin inhibitors, and mycophenolate mofetil would be preferable. Given the rising number of patients with nephrotic syndrome worldwide, KDIGO guidelines mention the need for further consideration of cost-effectiveness. If the new option of rituximab is to be the first choice in combination with steroids for nephrotic syndrome, its cost-effectiveness should also be verified. Among the few studies examining the cost-effectiveness of treatments for nephrotic syndrome, administration of rituximab to young adults has been shown to be cost-beneficial, at least in Japan. However, further large-scale studies involving multiple facilities are needed to verify such findings. Network meta-analyses have concluded that the efficacy of rituximab remains controversial and confirmation through high-quality studies of large cohorts is needed. To this end, the mechanisms of action underlying immunosuppressive agents, both old and new, need to be understood and experience must be accumulated to evaluate possible effects and side effects. [ABSTRACT FROM AUTHOR]

Nephrotic Syndrome (NS) patients are prone to develop deep venous thrombosis as a complication. But it is unusual to present initially with multiple venous thrombosis and pulmonary artery thrombosis before the diagnosis of NS. Here, we present 60 years old female patient with a known history of diabetes mellitus who presented with shortness of breath and lower limb edema for 2 weeks. CT angiography showed thromboembolism at the right main pulmonary artery and its bronchus intermedius, lower and segmental with right lower lobe small pulmonary infarction and inferior vena cava (IVC) thrombosis extending in both renal veins, right common and left common iliac vein, moderate ascites. Her 24-hour urinary protein was 6.7g. a diagnosis of NS was reached and she was admitted to the ward. Anticoagulation with heparin and warfarin, methyl prednisone, and furosemide was initiated. After she become clinically stable, she was discharged with oral medications. Awareness of the complication of nephrotic syndrome is important not only to nephrologists but to all physicians. Using contrast-enhanced computed tomography to diagnose multiple venous and pulmonary arterial thrombosis is critical. Additionally, it is known that steroid-resistant NS, like membranous glomerulonephritis, are more susceptible to the complication of thromboembolism than steroid-sensitive NS. Contrast venography is used to diagnose DVT. CTPA is the gold standard test for pulmonary embolism. [ABSTRACT FROM AUTHOR]

Background: Minimal change disease (MCD) has been shown to be a common histological presentation in children presenting with nephrotic syndrome (NS) in developed countries. In Africa, information on clinical and histological characteristics of paediatric NS is scarce. This study assessed the characteristics and histological subtypes of NS. Methods: This was a prospective study that consecutively indexed children aged 2-16 years with the diagnosis of NS who were referred to the largest tertiary teaching hospital, Lusaka, Zambia. Thirteen children presenting with NS were biopsied under ultrasound guidance after ethical approval. The primary outcome of the study was to describe the histological characteristics of paediatric NS. Results: Thirteen children of African descent with a median age of onset of NS of 9.25 years (2.0-15.0)were enrolled in the study. The histopathologic lesions were as follows; four had MCD, four had focal segmental glomerulosclerosis (FSGS), one had immune complex mediated glomerulonephritis (ICMN) and four were inconclusive. Haematuria was present in eight out of 13 patients (61.5%) and hypertension was present in five of 13 patients (38.0%). Three children did not have either haematuria or hypertension. Ten of the 13 participants had primary steroid resistance. Conclusion: This study has demonstrated the need to perform a pre-treatment renal biopsy in paediatric patients presenting with NS in view of the atypical presentation, variable histopathologic findings, and unpredictable response to steroid therapy. [ABSTRACT FROM AUTHOR]

Objective: To predict the role of clinical risk factors and urinary ß2-microglobulin levels as a biomarker for steroid-resistant nephrotic syndrome. Study Design: Quasi-experimental study. Place and Duration of Study: Paediatric Nephrology Department, Sindh Institute of Urology and Transplantation, Karachi Pakistan, from Jun 2019 to Nov 2020. Methodology: All children (3 months to 12 years) with either first episode or relapse of the nephrotic syndrome were included. A stored urine sample was used on 100 patients with steroid-sensitive (group-1) and 35 patients with steroid-resistant nephrotic syndrome (group-2). In addition, histopathology of all patients with steroid-resistant nephrotic syndrome was recorded. Results: Both groups and those who had focal segmental glomerulosclerosis were compared and analysed to evaluate the predictability of steroid response. There was a significant association in both groups for microscopic haematuria, hypertension, heavy proteinuria (urine spot protein to creatinine ratio >10 g/g) and increased ß2-microglobulin levels (> 3× normal) as individual risk factors (p<0.01). The sensitivity of ß2-microglobulin levels was 78% and a positive predictive value of 80%. Multivariate regression analysis on steroid-resistant nephrotic syndrome as a group did not confer a higher risk; however, for children with focal segmental glomerulosclerosis, the likelihood of steroid unresponsiveness was significantly higher for the same parameters. Conclusion: The addition of biomarker measurement and known clinical risk factors helped predict steroid-resistant focal segmental glomerulosclerosis. However, further studies are warranted before these results can be generalized. [ABSTRACT FROM AUTHOR]

Introduction: Renal biopsy is an important diagnostic procedure in pediatric nephrology. Although considered as an invasive method, numerous renal diseases cannot be definitively diagnosed and treated without it. Objectives: The aim of this study was histopathological study of renal biopsy results in children of 6 months to 18 years old. Patients and Methods: In this retrospective cross-sectional study, the available data from children who had undergone kidney biopsy between 2007 and the end of 2017 were evaluated. Demographic data, indications of biopsy, the outcome of patients, biopsy complications and histopathologic findings were collected using a checklist. Finally, data were presented as frequency and percentages. Results: The most common cause of biopsy in children was nephrotic syndrome (43.7%). Focal segmental glomerulosclerosis (FSGS) with 39 cases (32.7%) had the highest frequency in examined biopsies. In the long-term follow-up, 71 children (59.7%) cured, 7 (5.9%) died, 25 (21.0%) continued treatment, 6 (5.0%) underwent a kidney transplant surgery, and the outcome of 10 children (8.8%) was unknown. While 6.7% of patients were diagnosed with complications of biopsy, the most frequent of them was hematuria. There was no case of death or nephrectomy and only one patient needed packed RBC transfusion. Conclusion: Nephrotic syndrome was the most common indication for kidney biopsy. FSGS had the highest frequency in examined biopsies. [ABSTRACT FROM AUTHOR]

Background: Steroid resistant nephrotic syndrome (SRNS), while uncommon in children, is associated with significant morbidity. Calcineurin inhibitors (CNIs) remain the first line recommended therapy for children with non-genetic forms of SRNS, but some children fail to respond to them. Intravenous (IV) cyclophosphamide (CTX) has been shown to be effective in Asian-Indian children with difficult to treat SRNS (SRNS-DTT). Our study evaluated the outcome of IV CTX treatment in North American children with SRNS-DTT.Methods: Retrospective review of the medical records of children with SRNS-DTT treated with IV CTX from January 2000 to July 2019 at our center. Data abstracted included demographics, histopathology on renal biopsy, prior and concomitant use of other immunosuppressive agents and serial clinical/laboratory data. Primary outcome measure was attainment of complete remission (CR).Results: Eight children with SRNS-DTT received monthly doses (median 6; range 4-6) of IV CTX. Four (50%) went into CR, 1 achieved partial remission and 3 did not respond. Three of the 4 responders had minimal change disease (MCD). Excluding the 1 child who responded after the 4th infusion, the median time to CR was 6.5 (range 0.5-8) months after completion of IV CTX infusions. Three remain in CR at a median of 8.5 years (range: 3.7-10.5 years) after completion of CTX; one child relapsed and became steroid-dependent. No infections or life-threatening complications related to IV CTX were observed.Conclusions: IV CXT can induce long term remission in North-American children with MCD who have SRNS-DTT. [ABSTRACT FROM AUTHOR]

Background: Nephrotic syndrome is a common glomerular disease in children with a relapsing course that leads to complications and steroid-related toxicities. In Ethiopia, data on the outcomes of steroid therapy in pediatric nephrotic syndrome patients are limited. Objective: The aim of the study was to assess the treatment outcomes of pediatric nephrotic syndrome patients in Ayder Specialized Comprehensive and Mekelle General Hospitals. Methods: A retrospective study was conducted among children treated for nephrotic syndrome from 2010 to 2017 in Ayder Comprehensive Specialized and Mekelle General Hospitals. Univariate and multivariate logic regression analyses were performed to identify determinants of treatment outcome with a p-value < 0.05 considered statistically significant. Results: A total of 159 pediatric patients treated for nephrotic syndrome in both hospitals were included in this study. The mean age of participants at the initial diagnosis was 5.21 ± 2.66 years. Most of the patients 150 (94.3%) achieved remission within 4 weeks of steroid therapy. Among initial responders, the majority of the patients 117 (78%) encountered relapses of which 65 (40.9%) were developed frequent relapse/steroid-dependent nephrotic syndrome. Also, the majority of patients 102 (64.5%) encountered steroid-related toxicities. The predictors of frequent relapse/steroid-dependent nephrotic syndrome were age of ≤ 6 years (AOR=3.16; p=0.00), hematuria (AOR=6.74; p=0.00), infection (AOR=3.28; p=0.01), acute renal failure (AOR=6.09; p=0.01), serum albumin below 1.5g/dl (8.38, p=0.01) and lack of remission within 2 weeks (AOR=3.69; p=0.00). Conclusion: Most of the pediatric NS patients treated in ACSH and MGH have achieved remission with initial to steroid therapy. However, there was a higher relapse rate and steroid-related toxicities among pediatric NS patients who achieved remission. Early age at diagnosis, hematuria, reduced GFR, infection, and remission time were the independent predictors of the frequent relapsing/steroid-dependent nephrotic disease course. [ABSTRACT FROM AUTHOR]

Background. First-line treatment for paediatric nephrotic syndrome, a chronic disease characterised by proteinuria, hypoalbuminaemia and oedema, is corticosteroid therapy. An association between African ethnicity and steroid resistance has been reported, but published data from sub-Saharan Africa are limited and lack consensus on the prevalence of steroid-resistant disease. Objective. We aimed to describe a cohort of paediatric patients with nephrotic syndrome, determine the frequency of steroid resistance, and investigate factors associated with steroid resistance at Hospital Central de Maputo, Mozambique. Methods. A retrospective chart review was performed for paediatric patients (1 - 14 years old) admitted with nephrotic syndrome between 2010 and 2015 with at least one follow-up visit by 31 March 2016. Patients with HIV or malaria were excluded. Descriptive statistics and frequencies disaggregated by treatment response were produced. Associations of treatment response with sociodemographic, clinical and laboratory variables were investigated by appropriate univariable statistical tests. Results. Twenty-eight patients met inclusion criteria and were characterised as having steroid-sensitive or steroid-resistant nephrotic syndrome based on response to an initial corticosteroid regimen. There were 15 boys (53.6%) and 13 girls (46.4%), with a median age of 5.5 years. Fifteen (53.6%) were steroid-sensitive, and 13 (46.4%) were steroid-resistant. Steroid-resistant patients had significantly lower diastolic blood pressure (p=0.004), lower serum haemoglobin (p=0.003), lower serum albumin (p=0.03) and higher platelet counts (p=0.008) compared with sensitive cases. Only 4 (30.8%) steroid-resistant patients received a kidney biopsy. Conclusion. Given the relatively high occurrence of steroid resistance in this study, expanding access to kidney biopsy and second-line medications for paediatric patients not in remission after an initial course of corticosteroid therapy is needed to meet the current standard of care. Factors associated with steroid resistance need to be studied prospectively in larger cohorts of Mozambican children. [ABSTRACT FROM AUTHOR]

Steroid-resistant nephrotic syndrome (SRNS) remains a challenge for paediatric nephrologists. SRNS is viewed as a heterogeneous disease entity including immune-based and monogenic aetiologies. Because SRNS is rare, treatment strategies are individualized and vary among centres of expertise. Calcineurin inhibitors (CNI) have been effectively used to induce remission in patients with immune-based SRNS; however, there is still no consensus on treating children who become either CNI-dependent or CNI-resistant. Rituximab is a steroid-sparing agent for patients with steroid-sensitive nephrotic syndrome, but its efficacy in SRNS is controversial. Recently, several novel monoclonal antibodies are emerging as treatment option, but their efficacy remains to be seen. Non-immune therapies, such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, have been proven efficacious in children with SRNS and are recommended as adjuvant agents. This review summarizes and discusses our current understandings in treating children with idiopathic SRNS. [ABSTRACT FROM AUTHOR]

Background: Recent reports from small studies in West Africa suggest that Black children may have high rate of steroid sensitivity nephrotic syndrome (SSNS) contrary to long held knowledge. Herein, we determined the proportion of children with idiopathic nephrotic syndrome (INS) who achieved complete remission with steroid therapy and identified factors associated with complete remission. Methods: We reviewed the medical records of 241 children with INS in two centres in Lagos from 2010 to 2019. We extracted demographic data, clinical features, laboratory values at the time of diagnosis, and receipt and response to steroids and other immunosuppressants. Results: The median (interquartile range) age at diagnosis of INS was 5.1 (3.0–8.7) years and boys were 60.2% of the study population. Children with SSNS made up 85.9% (n = 207) of the study cohort. Among those aged 0–5 years, 92.6%were SSNS compared with 69.2% in those aged 11–17 years at the time of diagnosis. In addition, the proportion of children with SSNS increased from 73.8% between year 2010 and 2012 to 88.4% afterwards. Also, children with SSNS had lower serum creatinine (0.44 vs 0.70; p<0.001) and higher estimated glomerular filtration rate (101 vs 74.3 ml/min/1.73 m2; p = 0.008) at the time of diagnosis than those with steroid resistant nephrotic syndrome (SRNS). Conclusion: Among Black children in Lagos, the proportion with SSNS is comparable to proportions described in children of Asian and European descent. Furthermore, children with SSNS had lower serum creatinine and higher glomerular filtration rate than those with SRNS. [ABSTRACT FROM AUTHOR]

Background: Thrombosis is a potentially life‐threatening nephrotic syndrome (NS) complication. We have previously demonstrated that hypercoagulopathy is proportional to NS severity in rat models and that pioglitazone (Pio) reduces proteinuria both independently and in combination with methylprednisolone (MP), a glucocorticoid (GC). However, the effect of these treatments on NS‐associated hypercoagulopathy remains unknown. We thus sought to determine the ability of Pio and GC to alleviate NS‐associated hypercoagulopathy. Methods: Puromycin aminonucleoside‐induced rat NS was treated with sham, Low‐ or High‐dose MP, Pio, or combination (Pio + Low‐MP) and plasma was collected at day 11. Plasma samples were collected from children with steroid‐sensitive NS (SSNS) and steroid‐resistant NS (SRNS) upon presentation and after 7 weeks of GC therapy. Plasma endogenous thrombin potential (ETP), antithrombin (AT) activity, and albumin (Alb) were measured using thrombin generation, amidolytic, and colorimetric assays, respectively. Results: In a rat model of NS, both High‐MP and Pio improved proteinuria and corrected hypoalbuminemia, ETP and AT activity (p <.05). Proteinuria (p =.005) and hypoalbuminemia (p <.001) were correlated with ETP. In childhood NS, while ETP was not different at presentation, GC therapy improved proteinuria, hypoalbuminemia, and ETP in children with SSNS (p <.001) but not SRNS (p =.330). Conclusions: Both Pio and GC diminish proteinuria and significantly alleviate hypercoagulopathy. Both Pio and MP improved hypercoagulopathy in rats, and successful GC therapy (SSNS) also improved hypercoagulopathy in childhood NS. These data suggest that even a partial reduction in proteinuria may reduce NS‐associated thrombotic risk. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence rates of the common histopathologic subtypes of childhood nephrotic syndrome associated with steroid resistance appear to be changing globally. In Sub Saharan Africa (SSA), the trend is similar over the past few decades. Aim: This systematic review aims to determine the current prevalence rates of the histopathologic subtypes associated with childhood steroid-resistant nephrotic syndrome (SRNS) in SSA. Methods: A search of the PubMed, Google and African Journals Online databases was conducted from January to December 2018 using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow-chart to identify relevant articles which met the aim of the systematic review. A qualitative synthesis and descriptive analysis of the extracted data were then conducted. The mean values for the prevalence rates of the reported histopathologic subtypes were calculated. A meta-analysis was not done due to few numbers of studies reviewed. The review is registered with PROSPERO, number CRD42018111916. Results: In the West African sub-region, the currently reported histopathologic subtypes associated with childhood nephrotic syndrome are focal segmental glomerulosclerosis (FSGS), minimal-change nephropathy (MCN), membrano-proliferative glomerulonephritis (MPGN), membranous nephropathy (MN) and mesangial proliferative glomerulonephritis (MesPGN). The picture is the same in South Africa. More importantly, the predominant histopathologic lesions associated with steroid resistance are FSGS (West Africa) and MCN/FSGS (South Africa), with mean prevalence rates of 57.2% and 36.1% respectively. Conclusion: The prevalence of FSGS is currently high in childhood nephrotic syndrome in SSA. This histopathologic subtype remains the commonest lesion associated with SRNS in this part of the globe. [ABSTRACT FROM AUTHOR]

The prevalence of childhood steroid-resistant nephrotic syndrome (SRNS) ranges from 35% to 92%. This steroid resistance among Nigerian children also reflects underlying renal histopathology, revealing a rare minimal-change disease and a varying burden of membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis (FSGS). FSGS tends to progress to end-stage kidney disease, which requires dialysis and/or renal transplantation. While knowledge of the molecular basis of NS is evolving, recent data support the role of mutant genes that otherwise maintain the structural and functional composition of the glomerular filtration barrier to account for many monogenic forms of FSGS. With the advent of next-generation sequencing, >39 genes are currently associated with SRNS, and the number is likely to increase in the near future. Monogenic FSGS is primarily resistant to steroids, and this foreknowledge obviates the need for steroids, other immunosuppressive therapy, and renal biopsy. Therefore, a multidisciplinary collaboration among cell biologists, molecular physiologists, geneticists, and clinicians holds prospects of fine-tuning the management of SRNS caused by known mutant genes. This article describes the genetics of NS/SRNS in childhood and also gives a narrative review of the challenges and opportunities for molecular testing among children with SRNS in Nigeria. For these children to benefit from genetic diagnosis, Nigeria must aspire to have and develop the manpower and infrastructure required for medical genetics and genomic medicine, leveraging on her existing experiences in genomic medicine. Concerted efforts can be put in place to increase the number of enrollees in Nigeria's National Health Insurance Scheme (NHIS). The scope of the NHIS can be expanded to cater for the expensive bill of genetic testing within or outside the structure of the National Renal Care Policy proposed by Nigerian nephrologists. [ABSTRACT FROM AUTHOR]

Background: Calcineurin inhibitors (CNIs) are commonly given to transplant recipients of kidneys and other solid organs and to patients with immune disorders, such as steroid-resistant nephrotic syndrome, steroid-dependent nephrotic syndrome, and frequent relapse nephrotic syndrome. Although CNIs remain the most effective available immunosuppressant agent, there is clinical concern regarding possible long-term nephrotoxicity. This concern is especially significant in children who have a longer life expectancy and greater growth rate.Data sources: In this review, we analyzed the literatures to identify original articles that examined use of CNIs in children who received organ transplantation and nephropathy to assess the available evidence of their nephrotoxicity. PubMed, Elsevier, and Tompson ISI Web of Knowledge were searched for identifying relevant papers.Results: Clinical research supports the presence of CNI-related nephrotoxicity. However, some researchers have questioned the prevalence and seriousness of chronic CNIs nephrotoxicity, especially because the pathological lesions typically associated with long-term CNI use are nonspecific. Many researchers have focused on early markers of CNI nephrotoxicity, and the methods that may help prevent and manage nephrotoxicity.Conclusions: Future research should focus on investigating early markers of CNI nephrotoxicity and strategies for improved immunosuppressant therapy, and developing alternative treatments. CNI-mediated nephrotoxicity should always be taken seriously in clinic. [ABSTRACT FROM AUTHOR]

Background: Kidney disease is an important extra-hepatic manifestation of hepatitis B virus (HBV) infection. However, there is paucity of recent literature on kidney disease in children and adolescents with HBV infection from several parts of sub-Saharan Africa including Nigeria. Objective: To review the pattern of kidney disease in hepatitis B surface antigen (HBsAg)-positive children and adolescents seen at a tertiary hospital in south-west Nigeria. Methods: A retrospective study was undertaken of HBsAg-seropositive children with kidney disease managed at University College Hospital, Ibadan, from January 2004 to December 2015. Patients were identified from the paediatric nephrology unit admissions and the renal histology registers. Results: 24 children and adolescents were studied, 17 of whom were male (70.8%), and the median age was 10.0 years (range 3–15). Ten (41.7%) had nephrotic syndrome, five (20.8%) had non-nephrotic glomerulonephritis, five (20.8%) were in end-stage renal disease (ESRD), including a patient with posterior urethral valves, and four had acute kidney injury secondary to acute tubular necrosis. Renal histology was available for 10 patients: nine had nephrotic syndrome associated with minimal change disease in six, focal segmental glomerulosclerosis in two and one had membanoproliferative glomerulonephritis. The patient with non-nephrotic glomerulonephritis had diffuse global sclerosis. Conclusion: The pattern of kidney disease in HBV-positive children demonstrated a predominance of nephrotic syndrome, followed by non-nephrotic glomerulonephritis, ESRD and acute kidney injury. Better diagnostic facilities and treatment are required. Prevention of HBV infection by universal childhood immunisation is the ultimate goal. [ABSTRACT FROM AUTHOR]

This descriptive and comparative review examines the changing epidemiology, treatment, renal and patient outcome of childhood nephrotic syndrome (NS) in tropical Africa (TpAfr). In the 1960s to 1980s, corticosteroid-resistant non-minimal change disease (nMCD) including quartan malaria nephropathy (QMN) was the dominant renal histopathology type. The overall incidence of NS was 0.35–1.34% of hospital admissions. Median age at onset of NS ranged between 4.0 and 12.0 years while the mean (SD) age range was 5.8 (3.8) to 10.3 (4.8) years across studies. The male: female ratio was 1.6:1.0. The overall mean (SD) incidence of idiopathic minimal change disease (MCD) [21.6 (18.6%)] compared with idiopathic nMCD [59.1 (25.7%)] demonstrates significant dominance of the latter (p= 0.0001). Post-1989, the following mean (SD) incidences of histopathological types were: MCD 20.4 (17.7%), focal segmental glomerulosclerosis 39.0 (26.3%), membranoproliferative glomerulonephritis 25.4 (16.8%), proliferative glomerulonephritis 16.7 (27.0%) and membranous nephropathy 7.4 (4.5%). While the mean (SD) proportion of steroid resistance (SR) [73.5 (19.2%)] was significantly greater than the mean complete remission (CR) [26.5 (19.2%)] during 1960-1989 (p=0.005), mean (SD) SR [27.4 (25.3%)] was significantly lower than mean (SD) CR [66.1 (28.0%)] post-1989 (p < 0.001). Unlike QMN, hepatitis B virus, HIV infection, sickle cell disease and systemic lupus erythematosus are now increasingly being associated with NS in TpAfr. Mean (SD) renal survival post-1989 was 58.3 (37.0%) while all-cause mortality was 9.8%. Children with NS now survive better than before, reflecting improved access to healthcare and transition to a clinical pattern favouring idiopathic NS and increased sensitivity to corticosteroids. [ABSTRACT FROM PUBLISHER]

This is a randomized, parallel group, active-controlled trial to compare the efficacy of intravenous cyclophosphamide (IVCP) with oral cyclophosphamide (OCP) in patients with steroid-resistant nephrotic syndrome (SRNS) in children. Fifty consecutive children with idiopathic SRNS were biopsied and then randomized to receive either OCP at a dose of 2 mg/kg/day for 12 weeks or IVCP at a dose of 500 mg/m²/month for 6 months. Both groups received tapering doses of oral steroids. The response was evaluated in terms of induction of complete remission (CR) or partial remission (PR), time to remit, and side effects. The groups were followed up to determine the duration of remission, percentage of patients who remain in sustained remission for more than 1 year after completion of therapy, change in steroid response status, progression to chronic kidney disease stage 3 or more. Of the fifty patients, OCP was given to 25 children and IVCP to 25 children. The demographic data, histopathology, biochemical profile, and duration of follow-up in the two groups were comparable. The rates of induction of CR were 52% versus 44% and of PR were 8% versus 8% in the intravenous (IV) and oral group, respectively. Time to remit was shorter with OCP than IVCP (53 days vs. 84.4 days). Incidence of side effects (both major and minor) was 36% in IVCP versus 20% in OCP group. The actuarial cumulative sustained remission in our study was 12% in IVCP compared with 16% in OCP at 1 year after completion of therapy. Twelve percent children in both the groups exhibited restoration of steroid sensitivity. Thus, in our study, overall, more than half of SRNS patients showed initial response to cyclophosphamide, but only one-fourth patients had sustained remission on follow-up. OCP and IVCP were equally efficacious and safe in idiopathic SRNS in children. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome (NS) is one of the most common causes of chronic kidney disease in children. Mostly, NS is controlled by steroids. In spite of this, 10% to 20% of the patients have steroid resistant NS (SRNS), and the rest have steroid sensitive NS (SSNS). Eighty-seven children with NS (66 SSNS; 21SRNS) were retrospectively studied within the past 10 years in Taif region of Saudi Arabia. Regarding outcome, 66 (76%) patient responded to the steroid therapy, while 21 (24%) patients characterize as SRNS. Out of 66 SSNS, 25 children revealed complete remission, 26 were diagnosed as steroid dependent, and 15 were identified as frequent relapses. Among 21 SRNS biopsied patients, focal segmental glomerulosclerosis was the most common histological patterns of NS followed by the membranoproliferative glomerulonephritis pattern, which is significantly different from other studies performed in the Kingdom of Saudi Arabia. Out of 21 SRNS patients, 13 developed chronic kidney disease, 4 got end-stage renal disease, and 4 patients died. [ABSTRACT FROM AUTHOR]

Hepatitis B virus is a well described cause of nephrotic syndrome (NS) worldwide, the typical lesion being membranous glomerulonephropathy. HBV associated NS has been successfully treated with intravenous alpha interferon (IFN), an anti-viral agent. In recent times there have been reports of treatment with lamivudine, an orally administered nucleoside analogue inhibitor of HBV DNA polymerase in Caucasian children. Data is however limited and it's actual efficacy and safety in children is yet to be determined. We present the case of an 8-year-old Nigerian boy with NS and active hepatitis B virus infection. He went into remission 3 months after commencing oral lamivudine which he had for a year with no significant side effects observed. He remains in remission 3 years later. This, to our knowledge is the first report in literature of successful treatment in an African child. [ABSTRACT FROM AUTHOR]

Background: Cyclosporine A and tacrolimus (TAC) are often used as a second-line treatment for children with refractory nephrotic syndrome (NS). This study was undertaken to investigate the efficacy and safety of Tacrobell®, a locally produced generic form of TAC. Methods: This study was a one-year prospective, open-label, single-arm, multicenter trial. Fourty-four children with steroid-dependent NS (SDNS) and 33 children with steroid-resistant NS (SRNS) were enrolled. The primary endpoints were defined as the remission rates, whereas the secondary endpoints were recognized as the duration of remission and adverse effects of TAC. Results: After one-year treatment, 34 (77.3%) of the 44 patients with SDNS were in complete remission, and 6 (13.6%) were in partial remission. Nineteen (43.2%) patients did not relapse during the study; for those who did relapse, the mean duration of remission was 4.6±2.9 months. The number of relapse episodes during the study period (0.90 per patient-year) was significantly lower than that in the preceding year (2.8 per patientyear). After treatment for 3 and 6 months, 12 (36.4%) of the 33 patients with SRNS were in remission, and after treatment for 12 months, the number of patients had increased to 13 (39.4%). The mean time to achieve remission was 4.0±3.2 months. After remission (duration, 3.7±2.7 months), 12 (54.5%) of 22 patients relapsed. The fasting blood glucose and blood pressure levels during the therapy were similar to those at the time of study entry. Conclusions: Treatment with Tacrobell® was effective and safe for children with refractory NS. The efficacy of this generic form of TAC was better than that of the original TAC formula. [ABSTRACT FROM AUTHOR]