Alport syndrome (AS) is the second common monogenic cause of end-stage kidney disease (ESKD) worldwide and is caused by defective type 4 collagen due to pathogenic variants of COL4A3, COL4A4, or COL4A5. Type 4 collagen also exists in the eyes and ears, and thus ocular defects and hearing loss occur in AS. The understanding of AS has expanded over the past two decades due to greater availability of genetic testing and research on genotype-phenotype correlation. Patients previously diagnosed with idiopathic steroid resistant nephrotic syndrome or ESKD of unknown etiology may now be diagnosed as AS if pathogenic COL4A3-5 variants are identified. Some carriers of heterozygous COL4A3-5 variants may now be classified into females with X-linked AS or autosomal dominant AS, if there are typical pathologic changes in the glomerular basement membrane or if there is proteinuria and progression of kidney disease. Lastly, it has been recommended that renin-angiotensin-aldosterone system inhibition be started as soon as possible for selected AS patients for its long-term protective effect against kidney function deterioration. The purpose of this review is to introduce these important concepts to general pediatricians and pediatric nephrologists.

Nephrotic syndrome is a condition in which the glomeruli of the kidney leak large amounts of protein from the blood into the urine. Most children who present with their first episode of nephrotic syndrome achieve remission with corticosteroids. Children who fail to respond to corticosteroids in the first episode of nephrotic syndrome (initial resistance) or develop resistance after one or more responses to corticosteroids (delayed resistance) may be treated with immunosuppressive agents, including calcineurin inhibitors (cyclosporin or tacrolimus), and with non-immunosuppressive agents, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. However, response to these agents is limited, so newer agents, including anti-CD20 antibodies (rituximab, ofatumumab) and dual endothelin-angiotensin receptor antagonists (sparsentan), are being assessed for efficacy and safety. This is an update of a review first published in 2004 and updated in 2006, 2010, 2016 and 2019. To evaluate the benefits and harms of different interventions used in children with idiopathic nephrotic syndrome, who do not achieve remission following four weeks or more of daily corticosteroid therapy. The Cochrane Kidney and Transplant (CKT) Information Specialist searched the CKT Register of Studies to 28 January 2025 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE and Embase, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. We included randomised controlled trials (RCTs) and quasi-RCTs that compared different immunosuppressive or non-immunosuppressive agents with placebo, prednisone or another agent given orally or parenterally in children aged three months to 18 years with steroid-resistant nephrotic syndrome (SRNS). We included studies that enrolled children and adults, in which paediatric data could not be separated from adult data. Two review authors independently screened the search results, determined study eligibility, assessed risk of bias and extracted study data. We expressed dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with 95% CIs. We used a random-effects model to pool data, and GRADE to assess the certainty of the evidence. The main outcomes of interest were treatment response (complete, partial, or complete or partial remission), kidney failure and adverse events. We included 29 studies (1248 evaluated children). Sixteen studies were at low risk of bias for sequence generation and allocation concealment. Seven and 21 studies were at low risk of performance and detection bias, respectively. Sixteen, 15 and 15 studies were at low risk of attrition bias, reporting bias and other bias, respectively. Compared with placebo, corticosteroid or no treatment, cyclosporin may increase the number who achieve complete remission (RR 3.50, 95% CI 1.09 to 11.20; 4 studies, 74 children) or complete or partial remission (RR 3.15, 95% CI 1.04 to 9.57; 4 studies, 74 children) by two to six months (low-certainty evidence). It is uncertain whether cyclosporin reduces the likelihood of kidney failure or increases the likelihood of worsening hypertension or infection (very low-certainty evidence). Compared with intravenous cyclophosphamide, calcineurin inhibitors may increase the number with complete remission (RR 3.43, 95% CI 1.84 to 6.41; 2 studies, 156 children) and complete or partial remission (RR 1.98, 95% CI 1.25 to 3.13; 2 studies, 156 children) at three to six months (low-certainty evidence), and probably reduces the number with treatment failure (no response, serious infection, persistently elevated creatinine) and medications ceased due to adverse events (moderate-certainty evidence), with little or no increase in serious infections (moderate-certainty evidence). Kidney failure was not reported. Tacrolimus may make little or no difference to the number who achieve complete, or complete or partial remission at six and 12 months compared with cyclosporin, but may reduce the number who relapse during treatment (RR 0.22, 95% CI 0.06 to 0.90; 1 study, 34 children) or the number with worsening hypertension (low-certainty evidence). Hypertrichosis and gingival hyperplasia probably increased with cyclosporin. Kidney failure was not reported. Compared with mycophenolate mofetil (MMF) and dexamethasone, cyclosporin probably makes little or no difference to complete, partial, or complete or partial remission (moderate-certainty evidence), and may make little or no difference to kidney failure, serious infection requiring hospitalisation or hypertension (low-certainty evidence). Among children who have achieved complete remission, tacrolimus compared with MMF may increase the number who maintain complete, partial, or complete or partial response for 12 months, but may make little or no difference to serious adverse events and serious infection (low-certainty evidence). Oral cyclophosphamide plus prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (low-certainty evidence) and has uncertain effects on adverse events. Kidney failure was not reported. Compared with oral cyclophosphamide plus intravenous dexamethasone, intravenous cyclophosphamide may make little or no difference to complete, partial, or complete or partial remission at six months. There may be little or no difference in bacterial infections; however, hypertension may decrease (all low-certainty evidence). Kidney failure was not reported. It is uncertain whether rituximab/cyclosporin/prednisolone compared with cyclosporin/prednisolone increases the likelihood of remission or reduces adverse events because the certainty of the evidence is very low. Kidney failure was not reported. Calcineurin inhibitors may increase the likelihood of complete or partial remission compared with placebo/no treatment or cyclophosphamide. For other regimens, it remains unclear whether the interventions alter outcomes because the certainty of the evidence is low. Further adequately powered, well-designed RCTs are needed to evaluate other regimens for children with idiopathic SRNS. Since SRNS represents a spectrum of diseases, future studies should enrol children from better-defined groups of people with SRNS.

To determine the clinico-pathological features and long-term outcome of secondary steroid-resistant nephrotic syndrome treated with steroids and calcineurin inhibitors. The retrospective cohort study was conducted at the Sindh Institute of Urology and Transplant, Karachi, in June and July 2023, and comprised data from January 1, 2008, to December 31, 2020, of children aged 1-18 years who developed steroid resistance after initial sensitivity to steroids with at least 1-year of follow-up. Demographics as well as time taken to secondary steroid response were documented. Renal biopsy of all patients with secondary steroid resistance had been performed. Eventual outcomes after treatment with calcineurin inhibitors based on the degree of proteinuria and serum albumin levels were used to categorise complete remission, partial remission and no response. Kidney function, as determined by estimated glomerular filtration rate, was recorded. Data was analysed using SPSS 22. Of the 1,000 patients who underwent renal biopsy for steroid resistance, 48(4.8%) had idiopathic steroid-resistant nephrotic syndrome; 32(66.7%) males, 16(33.3%) females and median age of 5 years (interquartile range: 4-7.3 years). Median age at diagnosis of nephrotic syndrome was 5 years (interquartile range: 3.6-7.3 years). The median time from nephrotic syndrome to secondary steroid-resistant nephrotic syndrome was 23 months (interquartile range: 8.75-44.5 months). Biopsy results at diagnosis showed that 27(56.3%) had minimal change disease. The mean follow-up time was 6.1±3.2 years. Of the 43(89.5%) patients who received cyclosporin for 1 year, 29(67%) obtained complete remission, 5(12%) attained partial remission and no response was seen in 9(21%) patients. Majority of the children had minimal change disease at the time of diagnosis of secondary steroid-resistant nephrotic syndrome. The long-term response with calcineurin inhibitors was favourable at 1 year.

Idiopathic steroid resistant nephrotic syndrome (SRNS) has variable outcomes in children. The primary objective of the present study was to assess the cumulative remission rate and the secondary objectives were to assess factors affecting the remission status, kidney function survival, and adverse effects of medications. One hundred fourteen patients with SRNS were included. Calcineurin inhibitor-based treatment protocol along with prednisolone and angiotensin-converting enzyme inhibitor were used, and patients were followed over 5 years. Median age was 4.5 years; 53.5% of cases were between 1 to 5 years of age. Sixty-two patients (54.4%) were at initial stage and 52 (45.6%) were at a late SRNS stage. Median eGFRcr was 83.5 mL/min/1.73m2 at presentation. Of the 110 patients, 63 (57.3%) achieved remission [complete remission 30 (27.3%), partial remission 33 (30%)], and 47 (42.7%) had no remission. Kidney function survival was 87.3% and 14 cases (12.7%) had progression to CKD (G3-8, G4-3, G5-1, and G5D-2). Median duration of follow up was 36 months (IQR 24, 60). Age of onset, cyclosporine/tacrolimus, eGFRcr, and histopathology (MCD/FSGS) did not affect remission. Similarly, remission status in addition to age of onset, drug protocol, and histopathology did not significantly affect kidney function during a period of 5 years. Hypertension, cushingoid facies, short stature, cataract, and obesity were observed in 37.7, 29.8, 25.5, 17.5, and 0.7% of cases, respectively. About half of the cases achieved remission. Age of onset of disease, cyclosporine/tacrolimus use, and histopathological lesion neither affected remission status nor short-term kidney function survival in SRNS. A síndrome nefrótica idiopática córtico-resistente (SNICR) apresenta desfechos variáveis em crianças. O objetivo principal deste estudo foi avaliar a taxa de remissão cumulativa. Os objetivos secundários foram avaliar fatores que afetam status de remissão, sobrevida da função renal e efeitos adversos de medicamentos. Foram incluídos 114 pacientes com SNCR. Utilizou-se protocolo de tratamento baseado em inibidores de calcineurina juntamente com prednisolona e inibidor da enzima conversora de angiotensina. Os pacientes foram acompanhados durante 5 anos. A idade mediana foi 4,5 anos; 53,5% dos casos tinham entre 1 e 5 anos. 62 pacientes (54,4%) estavam em estágio inicial; 52 (45,6%) em estágio tardio da SNCR. A TFGecr mediana foi 83,5 mL/min/1,73 m2 na apresentação. Dos 110 pacientes, 63 (57,3%) alcançaram remissão [remissão completa 30 (27,3%), remissão parcial 33 (30%)], e 47 (42,7%) não apresentaram remissão. A sobrevida da função renal foi 87,3%; 14 casos (12,7%) progrediram para DRC (G3-8, G4-3, G5-1, G5D-2). A duração mediana do acompanhamento foi 36 meses (IIQ 24, 60). Idade no início, ciclosporina/tacrolimus, TFGecr e histopatologia (DLM/GESF) não afetaram a remissão. Igualmente, status de remissão, além da idade no início, protocolo de medicamentos e histopatologia não afetaram significativamente a função renal por 5 anos. Observou-se hipertensão, fácies cushingoide, baixa estatura, catarata e obesidade em 37,7; 29,8; 25,5; 17,5; e 0,7% dos casos, respectivamente. Aproximadamente metade dos casos alcançou remissão. Idade no início, uso de ciclosporina/tacrolimus e lesão histopatológica não afetaram o status de remissão nem a sobrevida da função renal a curto prazo na SNICR.

Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome (NS) of different etiologies is critical for early clinical guidance. We employed whole-exome sequencing (WES) to detect monogenic causes of NS in a multicenter cohort of 637 patients. In this study, a genetic cause was identified in 30.0% of the idiopathic steroid-resistant nephrotic syndrome (SRNS) patients. Other than congenital nephrotic syndrome (CNS), there were no significant differences in the incidence of monogenic diseases based on the age at manifestation. Causative mutations were detected in 39.5% of patients with focal segmental glomerulosclerosis (FSGS) and 9.2% of those with minimal change disease (MCD). In terms of the patterns in patients with different types of steroid resistance, a single gene mutation was identified in 34.8% of patients with primary resistance, 2.9% with secondary resistance, and 71.4% of children with multidrug resistance. Among the various intensified immunosuppressive therapies, tacrolimus (TAC) showed the highest response rate, with 49.7% of idiopathic SRNS patients achieving complete remission. Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern, and only 31.4% of patients with monogenic disease achieved a partial remission on TAC. During an average 4.1-year follow-up, 21.4% of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease (ESRD). Collectively, this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients, especially those with primary and/or multidrug resistance.