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Assessment of the true impact of therapeutic interventions is a challenge in the absence of universal, standardized definitions for clinical trial endpoints in children with kidney diseases. Steroid-resistant nephrotic syndrome (SRNS) is a difficult kidney disease to treat, with unremitting disease progressing to kidney failure. Currently, available therapies result in suboptimal cure rates. Clinical trials with innovative, targeted treatments will likely be conducted for this disease in the foreseeable future. An international consortium of the IPNA Best Practices and Standards Committee and the Pediatric Nephrology Expert Group of the conect4children (c4c) network developed through consensus, standardized, internationally acceptable definitions for trial outcomes for SRNS. The endpoint definitions were formulated for use with urine protein to creatinine ratios and estimated glomerular filtration rates. Definitions of complete remission, partial remission, non-remission of disease, reduction in proteinuria, kidney disease progression, kidney failure, and composite kidney outcome were refined using an iterative process until a consensus was achieved., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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).)

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: Despite the burden of human immunodeficiency virus (HIV) disease in Southern Africa, there have been few reports of HIV-related nephropathy in children. This study outlines the spectrum of HIV-1-related kidney diseases of children in KwaZulu-Natal, South Africa., Methods: A review of the clinical presentation, laboratory and histopathological findings of children diagnosed with HIV-related nephropathy., Results: Forty-nine out of 71 children (1-16 years old) with HIV-1 related nephropathy underwent kidney biopsy. The most common histopathological finding was focal segmental glomerulosclerosis (FSGS), which was present in 32 (65.3%) children; 13 (26.5%) having collapsing glomerulopathy and 19 (38.8%) classic FSGS. The majority of patients showed haematological (86.4%) and electrolyte abnormalities (69.4%). Renal impairment was present in 41% of patients on initial presentation. However, end-stage kidney disease was present in only 4% of these patients. All patients were treated with highly active anti-retroviral therapy (HAART), the majority (79.6%) showed decreased proteinuria with 38.8% having complete remission., Conclusions: This study, one of the largest series of children reported from Africa, demonstrates that nephrotic syndrome due to HIV-associated nephropathy (HIVAN) is the commonest presentation of HIV-related nephropathy in childhood. Highly active anti-retroviral therapy in combination with angiotensin-converting enzyme antagonists is highly effective in decreasing proteinuria and preserving renal function.

HIV infection remains one of the leading causes of morbidity and mortality worldwide, especially in children living in resource-limited settings. Although the World Health Organization (WHO) recently recommended antiretroviral therapy (ART) initiation upon diagnosis regardless of the number of CD4, ART access remains limited, especially in children living in sub-Saharan Africa (SSA). HIV-infected children who do not receive appropriate ART are at increased risk of developing HIV-associated nephropathy (HIVAN). Although due to genetic susceptibility, SSA is recognized to be the epicenter of HIVAN, limited information is available regarding the burden of HIVAN in children living in Africa. The present review discusses the information available to date on the prevalence, pathogenesis, risk factors, diagnosis, and management of HIVAN in children, focusing on related challenges in a resource-limited setting., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

The burden of chronic kidney disease (CKD) in children in developing countries remains unknown, due to the lack of a national data-reporting system. We undertook a retrospective study of all children < 16 years old in our hospital, which is the tertiary referral centre for children with complex kidney disorders, to analyse the spectrum of CKD (stages 2-5) from 1994-2006. Six hundred and fifty-three children with kidney disorders were screened for CKD; 286 (44.0%) were < 5 years old. Of these, 177 (62%) were male, 202 (70.6%) were black, 77 (26.9%) were Indian, five (1.8%) were mixed race and two (0.7%) were white. One hundred and twenty-six children had CKD (stages 2-5); 55 (43.7%) were < 5 years olds; 41 (74.5%) were male. There were 71 (56.3%) that were > 5 years old, 42 (59.2%) were male. The commonest cause of CKD (stages 2-5) in all children was nephrotic syndrome, comprising 30.9% in children < 5 years old and 40.8% in children > 5 years old. Within the observation period of 11 years, end-stage kidney disease was diagnosed in 20 children; only nine had been on long-term dialysis, and seven qualified for transplantation. Five (25%) children had died, four from sepsis during dialysis and one from tuberculosis after receiving a transplant. We concluded that lack of resources, late referrals, and high cost of renal replacement therapy in developing countries leads to poor outcome in CKD.

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.

Human leucocyte antigen (HLA) associations have been reported in children with hepatitis B virus (HBV) associated membranous nephropathy (MN). In a previous study, we found an association with HLA DQB1*0603 in black children with HBVMN. To determine whether HLA DQB1*0603 predisposes to HBV carriage and development of abnormal proteinuria, we studied 70 family members of 14 children with HBVMN positive for HLA DQB1*0603. HBV was determined using third generation ELISA, slot-blot hybridisation, and nested polymerase chain reaction. HLA class I antigens were determined using a two-staged lymphocytotoxic test whereas class II antigen typing was done using sequence-specific primers. Abnormal proteinuria was defined by a protein/creatinine ratio > or =0.2. Associations of HLA DQB1*0603 with HBV carriage and abnormal proteinuria were determined using the mean probability ratio (LOD scores). Forty-seven (67%) family members were positive for HBV infection. Nineteen (27%) had abnormal range proteinuria. LOD scores in the study subjects with DQB1*0603 who were HBV negative versus those with DQB1*0603 who were HBV positive was not significant (anti-log sum =2.0559 and average 0.23). When a similar calculation was made for abnormal proteinuria, there were no significant findings (anti-log sum =3.8587 and average 0.43). This lack of association of HLA DQB1*0603 with either HBV carriage or abnormal proteinuria in family members suggests that additional factors may play a role in predisposing children to chronic HBV carriage and the development of MN. We therefore conclude that the main effect of HLA DQB1*0603 that distinguishes family members from HBVMN is the degree of proteinuria, which is a reflection of the severity of glomerular basement membrane damage in the latter.

Membranous glomerulonephritis is a recognized complication of hepatitis B virus infection, especially in children, and an occasional complication of hepatitis C virus infection. Co-infection with the two viruses has not previously been described in membranous glomerulonephritis. We report five black African children with membranous glomerulonephritis who were co-infected with hepatitis B and C viruses. Proof of hepatitis B virus infection was obtained using serological and molecular detection methods. Hepatitis C virus infection was demonstrated using reverse transcription to convert viral RNA to cDNA followed by amplification of the cDNA using a double round of the polymerase chain reaction with confirmation by Southern hybridization and nucleotide sequencing. The clinical, biochemical, immunological, and pathological characteristics of the co-infected children, as well as the natural history of the disease, did not differ from those in 24 children with hepatitis B virus-associated membranous glomerulonephritis. Of the 24 family and household contacts of the five co-infected children, 7 were infected with hepatitis B virus, 1 with hepatitis C virus, and none with both viruses. It is not known whether infection with the two viruses was acquired simultaneously or sequentially. Thus, black children with membranous glomerulonephritis are occasionally co-infected with hepatitis B and C viruses. The resulting disease appears to be no more severe than that in children infected with hepatitis B virus alone.

The efficacy of interferon (IFN) in the treatment of hepatitis B virus (HBV)-associated nephropathy in black children has not been established. Twenty-four black children with biopsy-proven HBV-associated nephropathy were recruited into the study during the period April 1997 to June 1999. Five defaulted treatment and were excluded from the primary analysis. IFNalpha 2b was administered for 16 weeks. Response to treatment was defined as loss of HBeAg, decrease in proteinuria, and prevention of deterioration in renal and liver function. A control group of 20 patients was followed up for the same period. Ten (52.6%) of the treated children responded with clearance of HBeAg by 40 weeks. None cleared HBsAg. All responders showed remission of proteinuria, 90% maintained normal renal function and 1 (10%) showed improvement of renal function. HBV DNA levels decreased in this group. Nine patients did not clear HBeAg; none showed remission of proteinuria, and two showed deterioration of renal function. Liver enzymes rose during treatment but subsequently declined irrespective of response to therapy. No serious side effects were encountered. Only 5% of controls showed spontaneous clearance of HBeAg, and none had remission of proteinuria. Black children with HBV-associated nephropathy show accelerated clearance of HBeAg with remission of proteinuria following treatment with IFNalpha 2b. IFNalpha 2b was well tolerated.

Hepatitis B virus (HBV)-related membranous nephropathy (MN) is prominent in secondary nephrotic syndromes (NS) in Africa, but the features of this disease and the spectrum of associated glomerulopathies have not been adequately documented in black children. HBV was detected in 93 children with NS included in this study. In 70 patients the histological type was membranous; 46 were followed for a mean of 3.4 years (range 1-11 years). Spontaneous elimination of both HBsAg and HBeAg occurred in 10 (21.7%) patients; 16 (34.8%) cleared HBeAg alone. Co-existing liver disease occurred in 18 (25.7%) and hypocomplementemia (C3,C4) in 47.1% and 11.4% of children, respectively. Sixty-five (92.9%) patients had normal renal function, 1 (1.4%) impaired renal function, 3 (4.3%) chronic renal insufficiency, and 1 (1.4%) end-stage renal disease at last hospital visit. Twelve patients were in remission, all having cleared HBeAg. HBVMN was clinically indistinguishable from 24 children with idiopathic MN, although biochemical characteristics were different. This report delineates the natural history of HBV infection in black South African children with NS, the majority of whom have MN. Disease remission in HBVMN parallels elimination of HBV antigens, particularly HBeAg. Comparison of HBVMN with idiopathic MN revealed clinically indistinguishable characteristics but unexplained biochemical differences.

We report 81 of 107 cases of hemolytic uremic syndrome (HUS), admitted between July 1994 and February 1996, following an outbreak of Shigella dysenteriae type 1 dysentery in Kwazulu/Natal. All patients, excluding 1, were black with a mean age of 38 months (range 1-121); 50 (61.7%) were males. The mean duration of dysentery was 11.3 days (range 1-41) and HUS 15 days (range 1-91). Most patients had acute oliguric renal failure (90.1%), 42 (51.6%) required peritoneal dialysis. Complications included encephalopathy 30 (37.0%), convulsions 12 (14.8%) and hemiplegia 2 (2.3%), gastrointestinal perforation 8 (9.9%), protein losing enteropathy 26 (32.1%), toxic megacolon 4 (4.9%), rectal prolapse 5 (6.2%), hepatitis 11 (13.6%), myocarditis 5 (6.2%), congestive cardiac failure 3 (3.7%), cardiomyopathy 3 (3.7%), infective endocarditis 1 (1.2%), septicemia 15 (18.5%), disseminated intravascular coagulation 17 (21%). Leukemoid reactions were found in 74 (91.3%) patients, hyponatremia in 56 (69.1%), and hypoalbuminemia in 67 (82.7%). Stool culture for Shigella dysenteriae type I was positive in only 7 (8.6%) patients; Shiga toxin assays were not performed. Outcome was as follows: recovery 32 (39.5%), impaired renal function 8 (9.9%), chronic renal failure 26 (32.1%), end-stage renal disease 1 (1.2%), and death 14 (17.3%) patients.

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.

Seven children with steroid-resistant focal segmental glomerulosclerosis (SR-FGS) were placed on a therapeutic protocol of methylprednisolone (MP), oral prednisone (pred) and oral cyclophosphamide (CYC) given over 16 months (regimen A). Another 5 children with SR-FGS were treated with a shorter course of intravenous CYC (monthly doses over 6 months), intravenous MP (3 consecutive daily doses) and oral pred 2 mg/kg (alternate days) (regimen B). With regimen A, 1 child had a short remission, and in the others, oedema subsided, the urine protein/ creatinine ratio decreased, haematuria disappeared and the estimated glomerular filtration rate (GFR) increased. The observation period was 21-42 months and the drugs were well tolerated. With regimen B, 2 patients went into complete remission, 1 had partial remission, 1 failed to respond and another died because of severe concurrent infections. In the responding children, oedema cleared, the urine protein/ creatinine ratio decreased, haematuria disappeared and the GFR rose. The follow-up was between 3 and 34 months. Minor side effects were alopecia and transient hypertension. Both regimens improved the quality of life of most children. Compared with regimen A, regimen B is six times less costly with a quarter of the number of hospital visits. These observations may be of value in designing appropriate multicentre controlled trials, which have been advocated recently, for the rational and optimum management of SR-FGS.

Background: Caregivers of children with chronic kidney disease (CKD) in low resource settings must provide complex medical care at home while being burdened by treatment costs often paid out-of-pocket. We hypothesize that caregiver burden in our low resource setting is greater than reported from high income countries and is associated with frequent catastrophic healthcare expenditure (CHE)., Methods: We conducted a mixed-methods study of primary caregivers of children with advanced CKD (stage 3b-5) in our private-sector referral hospital in a low resource setting. We assessed caregiver burden using the Pediatric Renal Caregiver Burden Scale (PRCBS) and measured financial burden by calculating the proportion of caregivers who experienced CHE (monthly out-of-pocket healthcare expenditure exceeding 10% of total household monthly expenditure). We performed a qualitative reflexive thematic analysis of caregiver interviews to explore sources of burden., Results: Of the 45 caregivers included, 35 (78%) had children on maintenance dialysis (25 PD, 10 HD). Mean caregiver burden score was 141 (± 17), greater than previously reported. On comparative analysis, PRCBS scores were higher among caregivers of children with kidney failure (p = 0.005), recent hospitalization (p = 0.03), non-earning caregivers (p = 0.02), caring for > 2 dependents (p = 0.009), and with high medical expenditure (p = 0.006). CHE occurred in 43 (96%) caregivers of whom 37 (82%) paid out-of-pocket. The main themes derived relating to caregiver burden were severe financial burden, mental stress and isolation, and perpetual burden of concern., Conclusion: Parents of children with CKD experienced severe caregiver burden with frequent CHE and relentless financial stress indicating an imminent need for social support interventions., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Intravenous steroid pulses (SP) are successfully used for the treatment of patients with idiopathic nephrotic syndrome (INS) resistant to oral prednisone., Methods: We performed a retrospective analysis of all patients in the three pediatric nephrology centers of the Paris region from 2002 to 2022 who were resistant to a 30-day course of oral prednisone and who received SP for their first INS flare and analyzed their disease course over 4 years., Results: Forty-seven patients (17 girls), median age 3.4 years, were analyzed. Of them, 68% reached remission within 7 days of SP. No significant short-term side effects were noted. Half of the patients started immunosuppressive treatment immediately after their first remission and 62% of them relapsed at least once, whereas all the patients who did not receive immunosuppressive treatment since their first remission relapsed. Among the SP-sensitive patients, 75% needed calcineurin inhibitor (CNI) or B-cell depletion during their disease course to achieve stable remission. Forty-two percent of the whole cohort received B-cell-depleting agents. Among the 15 SP-resistant patients, all received CNI. Twelve/fifteen patients reached remission. After 4 years, 68% among the SP-sensitive patients and 87% of SP-resistant patients still had an active disease., Conclusions: SP are helpful to obtain rapid remission in pediatric INS patients resistant to oral steroids. However, as most SP-sensitive patients need immunosuppressive drugs, mainly CNI and B-cell-depleting agents it could be interesting to discuss the possibility to start CNI directly after the 30-day course of prednisone instead of SP., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

It is well known that minimal change disease (MCD) and focal segmental glomerulosclerosis are the most common histopathology findings in children with idiopathic nephrotic syndrome. Moreover, several studies demonstrated that MCD is associated with high steroid-responsiveness and a low incidence of kidney failure, suggesting that routine kidney biopsy is not warranted. Over time, the indications for performing a kidney biopsy have become increasingly stringent, aiming to limit unnecessary invasive procedures in the paediatric population. The most recent guidelines state that a kidney biopsy is not usually necessary at disease onset. Still, it should be performed in case of atypical features suggestive of systemic diseases or glomerulonephritis and in case of steroid-resistance, to assess the different differential diagnoses, regardless of patient age. Moreover, it has been shown that the best prognostic marker in childhood nephrotic syndrome is response to treatment and that kidney histology is not accurate in predicting prognosis. Furthermore, a kidney biopsy is not necessary to predict the relapsing course. Notably, kidney biopsy is an invasive procedure and may lead to significant complications. Finally, novel non-invasive biomarkers have been validated or are in the process of being approved to guide differential diagnoses and thus limit the need for kidney biopsies in patients with typical nephrotic syndrome. In the following sections, we aim to explain why initiating steroid treatment as the initial approach in teenagers with typical nephrotic syndrome is a reasonable strategy. Additionally, we explore how kidney biopsy indications may be alleviated in this population., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Kidney biopsy plays a crucial role in the diagnosis and management of several glomerular diseases. While it is generally considered a routine and safe procedure in children, it should be conducted with the primary objective of addressing the following question: do the prognosis and treatments vary based on the findings of kidney biopsy? In children presenting with idiopathic nephrotic syndrome (INS), guidelines suggest to consider kidney biopsy for individuals older than 12 years, primarily due to the possible increased incidence of different glomerulonephritis compared to younger patients, who predominantly manifest with minimal change disease. However, these guidelines also advocate for uniform therapeutic strategies, typically steroids, irrespective of the age or histological findings. Whether the age of more than 12 years may be a recommendation for performing kidney biopsy at presentation of INS is debatable. Instead, kidney biopsy could be reserved for steroid-resistant cases. On the other hand, when kidney biopsy is performed in INS, particularly in focal segmental glomerulosclerosis, histology may reveal additional lesions, that are strongly associated with a poorer response to treatment and worse clinical outcomes. Therefore, current guidelines on treatments of nephrotic syndrome may appear overly restrictive, despite the relevant findings provided by kidney biopsy. Therefore, in the present manuscript, which is part of a pro-con debate on the management of nephrotic syndrome in adolescents, we emphasize the potential role of performing a kidney biopsy before initiating corticosteroid treatment., (© 2024. The Author(s).)

Primary glomerular diseases are rare entities. This has hampered efforts to better understand the underlying pathobiology and to develop novel safe and effective therapies. NEPTUNE is a rare disease network that is focused on patients of all ages with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. It is a longitudinal cohort study that collects detailed demographic, clinical, histopathologic, genomic, transcriptomic, and metabolomic data. The goal is to develop a molecular classification for these disorders that supersedes the traditional pathological features-based schema. Pediatric patients are important contributors to this ongoing project. In this review, we provide a snapshot of the children and adolescents enrolled in NEPTUNE and summarize some key observations that have been made based on the data accumulated during the study. In addition, we describe the development of NEPTUNE Match, a program that aims to leverage the multi-scalar information gathered for each individual patient to provide guidance about potential clinical trial participation based on the molecular characterization and non-invasive biomarker profile. This represents the first organized effort to apply principles of precision medicine to the treatment of patients with primary glomerular disease. NEPTUNE has proven to be an invaluable asset in the study of glomerular diseases in patients of all ages including children and adolescents., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Dyslipidemia is an important and modifiable risk factor for CVD in children with CKD., Methods: In a cross-sectional study of baseline serum lipid levels in a large prospective cohort study of children with stage 3-5 (predialysis) CKD, frequencies of abnormal lipid levels and types of dyslipidemia were analyzed in the entire cohort and in subpopulations defined by fasting status or by the presence of nephrotic range proteinuria. Associated clinical and laboratory characteristics were determined by multivariable linear regression analysis., Results: A total of 681 patients aged 12.2 ± 3.3 years with a mean eGFR of 26.9 ± 11.6 ml/min/1.73 m 2 were included. Kidney diagnosis was classified as CAKUT in 69%, glomerulopathy in 8.4%, and other disorders in 22.6% of patients. Nephrotic range proteinuria (defined by a urinary albumin/creatinine ratio > 1.1 g/g) was present in 26.9%. Dyslipidemia was found in 71.8%, and high triglyceride (TG) levels were the most common abnormality (54.7%). Fasting status (38.9%) had no effect on dyslipidemia status. Except for a significant increase in TG in more advanced CKD, lipid levels and frequencies of dyslipidemia were not significantly different between CKD stages. Hypertriglyceridemia was associated with younger age, lower eGFR, shorter duration of CKD, higher body mass index (BMI-SDS), lower serum albumin, and higher diastolic blood pressure., Conclusions: Dyslipidemia involving all lipid fractions, but mainly TG, is present in the majority of patients with CKD irrespective of CKD stage or fasting status and is significantly associated with other cardiovascular risk factors., (© 2024. The Author(s).)

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: Acute post-streptococcal glomerulonephritis (APSGN) is a common cause of acute kidney injury (AKI) in children; however, in a small subgroup, the presentation is one of rapidly progressive glomerulonephritis (RPGN) deteriorating kidney function associated with severe oligo-anuria or a mixed nephritic-nephrotic picture. This study reviewed potential clinical and laboratory factors which may assist the treating clinician to identify patients at high risk of severe disease., Methods: All kidney biopsies for APSGN performed between 1996 and 2020 were obtained from a departmental biopsy database. Clinical and laboratory data were extracted from the patients' clinical records. Kidney biopsies were reviewed and scored independently by a renal histopathologist., Results: Thirty of 53 (56.6%) patients had stage 3 AKI at initial presentation with a median estimated glomerular filtration rate (eGFR) 27 (IQR 11-41), falling to 20 ml/min/1.73 m 2 (IQR 13.3-43) at time of biopsy. Patients who had either a pre-biopsy eGFR < 35 ml/min/1.73 m 2 or a ≥ 25% fall in eGFR between admission and biopsy were more likely to have glomerular crescents (p = 0.004). Multivariate regression analysis and receiver operating curve showed the pre-biopsy eGFR most accurately predicted glomerular crescents (p = 0.047, ROC 0.757). There were no significant predictors of nephrotic proteinuria or nephrotic syndrome during the acute phase., Conclusions: Severe APSGN is associated with a pronounced reduction in eGFR. Calculation of eGFR in this small group of patients may assist in identifying which patient should have an urgent kidney biopsy to facilitate a more accurate clinical diagnosis and management plan., (© 2023. 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.)

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.)

Background: We aimed to determine the prevalence of hypoalbuminemia in STEC-HUS patients with hemorrhagic colitis (HC) and whether serum albumin level (SAL), leukocyte count, hematocrit and serum sodium level (SSL) are prognostic markers of HC, central nervous system disease (CNSd) and/or dialysis requirement and evaluate if hypoalbuminemia is associated with fecal protein losses., Methods: We prospectively evaluated STEC-HUS patients treated at our institution from 9/2011 to 2/2019, analyzing the presence of HC, CNSd and dialysis requirement and SAL, SSL, leukocytes, hematocrit and α1-antitrypsin clearance., Results: We evaluated 98 patients, with mean age of 33.3 months. SAL ≤ 29.5 g/l, > 24,600 leukocytes/mm 3 and hematocrit > 30% behave as independent prognostic markers for HC. SAL ≤ 28 g/l, > 25,200 leukocytes/mm 3 and hematocrit > 30% behave as prognostic markers for CNSd. SAL ≤ 31.6 g/l, > 13,800 leukocytes/mm 3 , hematocrit > 18.9% and hyponatremia (≤ 132 mEq/l) behave as prognostic markers for dialysis requirement. However, in multivariate logistic regression models, only hypoalbuminemia behaved as a risk factor for HC, CNSd and dialysis. α1-antitrypsin clearance was performed in 69 patients and was high in 9/69 (13%), only 4 with HC. No significant association was observed between α1-antitrypsin clearance and albuminemia (χ 2 = 0.1076, p = 0.7429) as well as α1-antitrypsin clearance and HC (χ 2 = 1.7892, p = 0.1810)., Conclusions: Almost all patients with HC had hypoalbuminemia, which behaves as a risk factor for HC, CNSd and dialysis requirement. No significant association was observed between elevated α1-antitrypsin clearance and hypoalbuminemia nor between elevated α1-antitrypsin clearance and HC. These findings could be related to the small number of evaluated patients., (© 2021. IPNA.)

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.