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This article explores the duration of B-cell depletion in pediatric patients undergoing rituximab therapy for various nephrological conditions. The study reveals that the duration of B-cell depletion varies among individuals and that predicting this duration could enhance treatment effectiveness. Factors such as higher doses of rituximab and concomitant use of mycophenolate mofetil were associated with longer B-cell depletion. Additionally, a longer duration of B-cell depletion was linked to a potential decrease in the risk of clinical relapse in patients with nephrotic syndrome. The study emphasizes the importance of understanding the factors influencing B-cell depletion duration to optimize rituximab treatment. However, the study acknowledges limitations, including the lack of standardized immunophenotyping times and a relatively small number of patients using mycophenolate mofetil. Further research is needed to explore the relationship between mycophenolate mofetil and the risk of relapse in steroid-dependent nephrotic syndrome. [Extracted from the article]

This article explores the potential use of rituximab (RTX) as a treatment for minimal change disease (MCD), a type of kidney disorder. The study found that RTX showed promising results in achieving complete remission in patients with MCD, with some patients experiencing remission within a month of starting treatment. The study also observed improvements in kidney function and minimal side effects. However, the study acknowledges the need for further research to determine the optimal dosage and long-term effects of RTX in MCD treatment, as well as the limitations of a small sample size. [Extracted from the article]

The article discusses the challenges faced by clinicians in diagnosing and treating membranous nephropathy (MN), a leading cause of nephrotic syndrome. The discovery of multiple antigens associated with MN has expanded our understanding of the disease and its various subtypes. The article explores the implications of these discoveries for clinical practice, including the potential for targeted therapies such as chimeric antigen receptor T cell (CAR-T) therapy. However, the article also acknowledges the limitations and complexities of implementing these advancements in patient care. The authors suggest that specialized centers with expertise in MN may be beneficial for managing complex cases. [Extracted from the article]

This article examines the role of B cells in the development and treatment of primary podocytopathies, specifically minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). The study focuses on adults with new-onset nephrotic syndrome (NS) caused by primary podocytopathy and compares them to healthy controls. The findings indicate that B cell proportions differ between children and adults, and specific B cell subsets are associated with disease activity and predict response to steroid treatment. These findings have implications for targeted therapies for primary podocytopathies. However, more research is needed to confirm these results. [Extracted from the article]

Idiopathic nephrotic syndrome (INS) is the most frequent glomerular disease in childhood. Pediatr Nephrol 2020; 35: 1529 - 61. https://doi.org/10.1007/s00467-020-04519-1 Google Scholar Crossref Search ADS PubMed WorldCat 3 McKay AM, Parekh RS, Noone D. Therapeutic trials in difficult to treat steroid sensitive nephrotic syndrome: challenges and future directions. First, challenges in INS-specific biomarker discovery include determining the causality of observed changes, understanding their functional redundancy in INS mechanisms, and the geographic and ethnic heterogeneity of gut microbiota. [Extracted from the article]

Background Children with primary nephrotic syndrome (PNS) who relapse after glucocorticoid therapy are shown to have a decreased total proportion of butyrate-producing bacteria in the gut at onset. Glucocorticoid treatment changes the gut microbiota composition. It is unclear whether gut microbiota at remission right after therapy and gut bacteria other than butyrate-producing bacteria are associated with PNS relapse. Methods PNS relapse of paediatric patients within 1 year after glucocorticoid therapy was recorded. The gut microbiota composition, profiled with 16S rRNA gene V3–V4 region sequencing, was compared between relapsing and non-relapsing PNS children at onset before glucocorticoid treatment (preT group) and in PNS children at remission right after treatment (postT group), respectively. Results The gut microbiota composition of postT children significantly differed from that of preT children by having lower levels of Bacteroides, Lachnoclostridium, Flavonifractor , Ruminococcaceae UBA1819, Oscillibacter, Hungatella and Coprobacillus and higher levels of Ruminococcaceae UCG-013 and Clostridium sensu stricto 1 group. In the preT group, compared with non-relapsing patients, relapsing patients showed decreased Blautia, Dialister and total proportion of butyrate-producing bacteria and increased Oscillibacter, Anaerotruncus and Ruminococcaceae UBA1819. However, relapsing and non-relapsing postT children showed no difference in gut microbiota composition. Conclusions PNS relapse–associated gut microbiota dysbiosis at onset, which includes alterations of both butyrate-producing and non-butyrate-producing bacteria, disappeared right after glucocorticoid therapy. It is necessary to study the association of the longitudinal changes in the complete profiles of gut microbiota after glucocorticoid treatment with later PNS relapse. [ABSTRACT FROM AUTHOR]

A group of experts from the International Pediatric Nephrology Association (IPNA) has recently updated recommendations for steroid-resistant and steroid-sensitive nephrotic syndrome (SRNS and SSNS) in children [[1]]. Anti-CD20 monoclonal antibodies (rituximab) [[11]]: indicated in children >7-9 years of age with FRNS or SDNS who are not controlled on therapy after a course of treatment with at least one other steroid-sparing agent at an adequate dose, especially in case of non-adherence. Sequential rituximab therapy sustains remission of nephrotic syndrome but carries high risk of adverse effects. [Extracted from the article]

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

Paediatric idiopathic nephrotic syndrome (INS), commonly described histopathologically as minimal change disease, is one of the most common glomerular diseases in children [[1]]. We have shown here that urinary podocyte-derived LEVs can differentiate relapse and remission in children with INS and may act as early warning markers of disease. As such, we sought to quantify urinary podocyte-derived LEVs in a consecutively enrolled cohort of 14 paediatric patients with INS, all of whom contributed a relapse sample and a remission sample. [Extracted from the article]

Nephrotic syndrome (NS) is characterized by massive proteinuria; podocyte loss or altered function is a central event in its pathophysiology. Treatment with glucocorticoids is the mainstay of therapy, however, many patients experience one or multiple relapses and prolonged use may be associated with severe adverse effects. Recently the beneficial effects of glucocorticoids have been attributed to a direct effect on podocytes in addition to the well‐known immunosuppressive effects. The molecular effects of glucocorticoid action have been studied using animal and cell models of NS. This review provides a comprehensive overview of different molecular mediators regulated by glucocorticoids, including an overview of the model systems that were used to study them. Glucocorticoids are described to stimulate podocyte recovery by restoring pro‐survival signalling of slit diaphragm–related proteins and limiting inflammatory responses. Of special interest is the effect of glucocorticoids on stabilizing the cytoskeleton of podocytes, since these effects are also described for other therapeutic agents used in NS, such as cyclosporin. Current models provide much insight but do not fully recapitulate the human condition since the pathophysiology underlying NS is poorly understood. New and promising models include the glomerulus‐on‐a‐chip and kidney organoids, which have the potential to be further developed into functional NS models in the future. [ABSTRACT FROM AUTHOR]

Background The associations of focal segmental glomerulosclerosis (FSGS) histological variants with renal outcomes have rarely been investigated comprehensively by clinically relevant subgroups in this modern age. Methods Data on 304 (173 nephrotic and 131 non-nephrotic) patients with biopsy-confirmed FSGS from 2010 to 2013 were analyzed using the Japanese nationwide renal biopsy registry. The primary outcome was a composite of a 30% decline in estimated glomerular filtration rate or progression to end-stage kidney disease 5 years from the biopsy. We compared outcomes of FSGS variants according to the Columbia classification using survival analyses. Subgroup analyses were performed based on nephrotic syndrome (NS), immunosuppression and proteinuria remission (PR; proteinuria <0.3 g/day) during follow-up. Additionally, associations of NS, immunosuppression and PR with outcomes were examined for each variant. Results The distribution of variants was 48% (n = 145) FSGS not otherwise specified, 19% (n = 57) tip, 15% (n = 47) perihilar, 13% (n = 40) cellular and 5% (n = 15) collapsing. The outcome event occurred in 87 patients (29%). No significant differences in the outcome were found among the variants. Subgroup analyses yielded similar results. However, there was a trend toward improved outcome in patients with PR irrespective of variants [hazard ratio adjusted for histological variant and potential confounders (adjusted HR) 0.19 (95% confidence interval 0.10–0.34)]. NS was marginally associated with better outcome compared with non-NS [adjusted HR 0.50 (95% confidence interval 0.25–1.01)]. Conclusions FSGS variants alone might not have significant impacts on the renal outcome after 5 years, while PR could be predictive of improved renal prognosis for any variant. Specific strategies and interventions to achieve PR for each variant should be implemented for better renal outcomes. [ABSTRACT FROM AUTHOR]

Glucocorticoids have been a cornerstone of treatment for inflammatory and autoimmune kidney diseases for almost 70 years, yet it is fair to say, we still do not know how 'best' to use them. Significant adverse events are associated with their continued use, which contribute to premature patient mortality. Steroid avoidance or minimization is possible and has been tested in various glomerular diseases, as a result of novel agents or innovative regimens using established therapeutics. It is now time to seriously address our use of steroids and educate physicians on better ways of managing inflammatory kidney diseases. [ABSTRACT FROM AUTHOR]

BackgroundPrior small studies have suggested an association between low serum albumin and increased risk of venous thromboembolic (VTE) events in patients with nephrotic syndrome (NS).MethodsFrom a nationally representative prospective cohort of over 3 million US veterans with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m 2 , we identified 7037 patients with NS based on ICD-9 codes. Association between serum albumin and risk of incident VTE was assessed using Cox regression analysis with adjustments for age, gender, race, comorbidities, eGFR, body mass index and anticoagulant treatment.ResultsMean age was 57 ± 11 years, patients were 96% male, 32% African-American and 60% diabetic. There were a total of 158 VTE events over a median follow-up of 8.1 years; 16 events [absolute event rate (AER) 4.1%, event rate 8.5/1000 patient-years (PY)] in patients with albumin

Background Nephrotic syndrome is associated with an increased risk of venous thromboembolism (VTE). However, the risk factors of VTE in nephrotic syndrome, other than hypoalbuminemia and severe proteinuria, are not well established. Therefore we aimed to investigate the risk factors of VTE in patients with nephrotic syndrome. Methods This retrospective cohort study used data from a Japanese nationwide claims database. We identified patients ≥18 years of age hospitalized with nephrotic syndrome. Through multivariable logistic regression, we determined the risk factors of VTE in patients with nephrotic syndrome during hospitalization. Results Of the 7473 hospitalized patients with nephrotic syndrome without VTE, 221 (3.0%) developed VTE. In the VTE group, 14 (6.3%), 11 (5.0%) and 198 (89.6%) patients developed pulmonary embolism, renal vein thrombosis and deep vein thrombosis, respectively. We found that female sex {odds ratio [OR] 1.39 [95% confidence interval (CI) 1.05–1.85]}, body mass index (BMI) ≥30 [OR 2.01 (95% CI 1.35–2.99)], acute kidney injury [AKI; OR 1.67 (95% CI 1.07–2.62)], sepsis [OR 2.85 (95% CI 1.37–5.93)], lupus nephritis [OR 3.64 (95% CI 1.58–8.37)] and intravenous corticosteroids use [OR 2.40 (95% CI 1.52–3.80)] were associated with a significantly higher risk of developing VTE. Conclusions In patients with nephrotic syndrome, female sex, BMI ≥30, AKI, sepsis, lupus nephritis and intravenous corticosteroid use may help evaluate the risk of VTE. [ABSTRACT FROM AUTHOR]

BackgroundNephrotic syndrome (NS) leads to elevation of serum total and LDL cholesterol. This is largely due to impaired LDL clearance, which is caused by hepatic LDL receptor (LDLR) deficiency despite normal LDLR mRNA expression, pointing to a post-transcriptional process. The mechanism(s) by which NS causes LDLR deficiency is not known. By promoting degradation of LDLR, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and inducible degrader of the LDL receptor (IDOL) play a major role in post-translational regulation of LDLR. We, therefore, tested the hypothesis that LDLR deficiency despite its normal gene expression in NS may be due to upregulation of hepatic PCSK9 and IDOL.MethodsLDLR, IDOL and PCSK9 expressions and nuclear translocation of liver X receptor (LXR) that regulates IDOL expression were determined in the liver of rats with puromycin-induced NS and control (CTL) rats.ResultsCompared with the CTLs, the NS rats showed marked elevation of serum total and LDL cholesterol and a significant reduction in hepatic LDLR protein expression. This was accompanied by marked upregulation of hepatic PCSK9 and IDOL expressions and heightened LXR activation.ConclusionsLDLR deficiency, hypercholesterolemia and elevated plasma LDL in NS are associated with upregulation of PCSK9 and IDOL. Interventions targeting these pathways may be effective in the management of hypercholesterolemia and the associated cardiovascular and other complications of NS.

Background The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis. Methods We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN). Results Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = −0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = −0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively). Conclusions An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells. [ABSTRACT FROM AUTHOR]

Background Information on the epidemiology of idiopathic nephrotic syndrome (INS) in children, complications of INS and the side effects of steroid therapy is scarce. Methods The Japanese Pediatric Survey Holding Information of Nephrotic Syndrome, a nationwide cohort study, was conducted by the Japanese Study Group of Renal Disease in Children and enrolled 2099 children with newly diagnosed INS between 1 January 2010 and 31 December 2012. We conducted a follow-up study of the complications during the first onset and the patients' prognosis in this cohort. Results We obtained follow-up data on 999 children (672 males) with a median age at onset of 4.5 years [interquartile range (IQR) 2.8–9.4] and a median follow-up period of 4.1 years (IQR 2.5–5.1). At the first onset, 24% of patients experienced severe acute kidney injury (AKI), defined as a serum creatinine increase to a level two or more times the baseline. On logistic regression analysis, age, hematuria, severe hypoalbuminemia (serum albumin <1.0 g/dL) and severe bacterial infection were not independent factors, but female sex {hazard ratio [HR] 1.5 [95% confidence interval (CI) 1.1–1.7]} and hypertension [HR 4.0 (95% CI 2.6–6.0)] were significantly related to AKI. During the observation period, ocular hypertension requiring treatment occurred in 17.4% of patients, among which 0.4% received surgical treatment. Progression to frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome in 3 years was seen in 44.2% of the patients and was shown by the Cox regression analysis to be significantly related to younger age and days until remission at the first episode, but not to sex, hematuria, the minimum serum albumin level or AKI. Two patients died during the observation period. One patient showed progression to end-stage kidney disease. Conclusion Based on the results of a multicenter questionnaire survey, the overall survival and renal survival rates were found to be excellent. However, proper management of complications, particularly in AKI and ocular hypertension, is mandatory. [ABSTRACT FROM AUTHOR]

Low-density lipoprotein cholesterol (LDL-C) levels almost constantly increased in patients with nephrotic syndrome (NS). Protein convertase subtilisin/kexin type 9 (PCSK9) [accelerates LDL-receptor (LDL-R) degradation] is overexpressed by liver cells in NS. Their levels, correlated inversely to LDL-R expression and directly to LDL-C, seem to play a central role in hypercholesterolaemia in NS. Hypersynthesis resulting from sterol regulatory element-binding protein dysfunction, hyperactivity induced by c-inhibitor of apoptosis protein expressed in response to stimulation by tumour necrosis factor-α produced by damaged podocytes and hypo-clearance are the main possible mechanisms. Increased LDL-C may damage all kidney cell populations (podocytes, mesangial and tubular cells) in a similar manner. Intracellular cholesterol accumulation produces oxidative stress, foam cell formation and apoptosis, all favoured by local inflammation. The cumulative effect of cellular lesions is worsened proteinuria and kidney function loss. Accordingly, NS patients should be considered high risk and treated by lowering LDL-C. However, there is still not enough evidence determining whether lipid-lowering agents are helpful in managing dyslipidaemia in NS. Based on good efficacy and safety proved in the general population, therapeutic modulation of PCSK9 via antibody therapy might be a reasonable solution. This article explores the established and forthcoming evidence implicating PCSK9 in LDL-C dysregulation in NS. [ABSTRACT FROM AUTHOR]

Background Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis (FSGS) in populations with African ancestry. We determined the frequency of G1/G2 variants in steroid-resistant nephrotic syndrome (SRNS)/FSGS patients with African or French West Indies ancestry in France and its relationships with other SRNS genes. Methods In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped by direct Sanger sequencing and pathogenic mutations were screened by next-generation sequencing with a panel including 35 SRNS genes. Results The two risk allele [high-risk (HR)] genotypes were found in 43.1% (66/152) of subjects compared with 18.9% (106/562) in a control population (P < 0.0001): 33 patients homozygous for APOL1 G1 alleles, 4 homozygous for G2 and 29 compound heterozygous for G1 and G2. Compared with patients in the low-risk (LR) group, patients in the HR group were more likely to originate from the French West Indies than from Africa [45/66 (68.2%) versus 30/86 (34.9%); P < 0.0001]. There were more familial cases in the HR group [27 (41.5%) versus 8 (11.4%); P < 0.0001]. However, causative mutations in monogenic SRNS genes were found in only 1 patient in the HR group compared with 16 patients (14 families) in the LR group (P = 0.0006). At diagnosis, patients in the HR group without other mutations were more often adults [35 (53.8%) versus 19 (27.1%); P = 0.003] and had a lower estimated glomerular filtration rate (78.9 versus 98.8 mL/min/1.73 m2; P = 0.02). Conclusions The HR genotype is frequent in FSGS patients with African ancestry in our cohort, especially in those originating from the West Indies, and confer a poor renal prognosis. It is usually not associated with other causative mutations in monogenic SRNS genes. [ABSTRACT FROM AUTHOR]

AL amyloidosis (light chain; previously also called primary amyloidosis) is a systemic disease characterized by an amyloid deposition process affecting many organs, and which still has unsatisfactory survival of patients. The monoclonal light chains kappa (κ) or lambda (λ) or their fragments form the fibrils that deposit and accumulate in different tissues. Renal involvement is very frequent in AL amyloidosis and can lead to the development of nephrotic syndrome followed by renal failure in some cases. AL amyloidosis ultimately leads to destruction of tissues and progressive disease. With recent advances in the treatment, the importance of an early diagnosis of amyloidosis and correct assessment of its type is high. Histologic confirmation is based on Congo red detection of amyloid deposits in tissues but AL amyloidosis must also be distinguished from other systemic forms of amyloidoses with renal involvement, such as AA amyloidosis, amyloidosis with heavy chain deposition, fibrinogen Aα or ALECT2 (leukocyte chemotactic factor 2) deposition. Immunofluorescence (IF) plays a key role here. IF on formalin-fixed paraffin-embedded tissue after protease digestion, immunohistochemistry or laser microdissection with mass spectrometry should complete the diagnosis in unclear cases. Standard treatment with melphalan and prednisolone or with cyclophosphamide and dexamethasone has been replaced with newer drugs used for the treatment of multiple myeloma—bortezomib, carfilzomib and ixazomib or thalidomide, lenalidomide and pomalidomide. High-dose melphalan supported by autologous stem cell transplantation remains the therapeutic option for patients with low-risk status. These new treatment options prolong survival from months to years and improve the prognosis in a majority of patients. [ABSTRACT FROM AUTHOR]

Background Management of children with congenital nephrotic syndrome (CNS) is challenging. Bilateral nephrectomies followed by dialysis and transplantation are practiced in most centres, but conservative treatment may also be effective. Methods We conducted a 6-year review across members of the European Society for Paediatric Nephrology Dialysis Working Group to compare management strategies and their outcomes in children with CNS. Results Eighty children (50% male) across 17 tertiary nephrology units in Europe were included (mutations in NPHS1 , n  = 55; NPHS2 , n  = 1; WT1 , n  = 9; others, n  = 15). Excluding patients with mutations in WT1 , antiproteinuric treatment was given in 42 (59%) with an increase in S-albumin in 70% by median 6 (interquartile range: 3–8) g/L (P < 0.001). Following unilateral nephrectomy, S-albumin increased by 4 (1–8) g/L (P = 0.03) with a reduction in albumin infusion dose by 5 (2–9) g/kg/week (P = 0.02). Median age at bilateral nephrectomies (n  = 29) was 9 (7–16) months. Outcomes were compared between two groups of NPHS1 patients: those who underwent bilateral nephrectomies (n  = 25) versus those on conservative management (n  = 17). The number of septic or thrombotic episodes and growth were comparable between the groups. The response to antiproteinuric treatment, as well as renal and patient survival, was independent of NPHS1 mutation type. At final follow-up (median age 34 months) 20 (80%) children in the nephrectomy group were transplanted and 1 died. In the conservative group, 9 (53%) remained without dialysis, 4 (24%; P < 0.001) were transplanted and 2 died. Conclusion An individualized, stepwise approach with prolonged conservative management may be a reasonable alternative to early bilateral nephrectomies and dialysis in children with CNS and NPHS1 mutations. Further prospective studies are needed to define indications for unilateral nephrectomy. [ABSTRACT FROM AUTHOR]

Background Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France. Methods We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS. Results The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9–52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year. Conclusions Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients. [ABSTRACT FROM AUTHOR]

Background Alport syndrome (AS) and atypical hemolytic–uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. Methods We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. Results We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%). Conclusions We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria. [ABSTRACT FROM AUTHOR]

Background Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, ∼15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In ∼30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-α5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria. Methods To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation. Results In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably. Conclusion We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients. [ABSTRACT FROM AUTHOR]

Background Membranous nephropathy is among the most common causes of nephrotic syndrome worldwide, with a high healthcare burden. Treatment using the modified Ponticelli regimen (mPR) has remained the standard of care for decades, but newer therapies such as rituximab offer promising results with reduced side effects. The cost of this treatment, however, is perceived as a barrier to widespread use, especially in resource limited healthcare systems. Methods We developed a decision-analytic model to estimate the cost-effectiveness of rituximab versus the mPR from the perspective of the National Health Service in the UK over a 1 year, 5 year and lifetime horizon. Primary outcome is the cost-effectiveness of rituximab versus mPR at 5 years post-treatment. Secondary outcomes are cost-effectiveness at 1 and 10 years post-treatment and over a lifetime. Results At 1-year post-treatment, rituximab therapy dominates mPR. At 5 years post-treatment, rituximab therapy is cheaper than the Ponticelli regimen but at a loss of 0.014 quality-adjusted life years (QALYs) with an incremental cost-effectiveness ratio (ICER) of £95 494.13. Over a lifetime, rituximab remains the cheaper option with an incremental cost of −£5251.03 but with a reduced quality of life (incremental QALY of −0.512) giving an ICER of £10 246.09. Conclusions Our analysis indicates that rituximab has the potential to be a cost-effective treatment in the short and medium terms despite the high single-dose cost. This evaluation suggests that further research is warranted and highlights the need for a high-quality clinical trial to confirm the efficacy and cost-effectiveness of rituximab versus the current standard of care. [ABSTRACT FROM AUTHOR]

Background. Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation (KTx) in children. This can lead to delayed graft loss. As themanagement of children with recurrent FSGS is not well established, apheresis strategies could be a cornerstone to control the disease. Immunoadsorption (IA) is a recent apheresis therapy. There have been few studies examining IA in this setting.We report the results of IA for management of recurrent FSGS after KTx in children in France. Methods. We included all children treated with IA for early FSGS recurrence after KTx between January 2011 and June 2014 in France. We excluded genetic forms of FSGS. Patients' characteristics and technical data on IA were retrospectively collected. Recurrence was defined as nephrotic proteinuria during the post-transplantation period. Partial and complete remissions were defined when urine protein:creatinine ratios were less than 0.2 and 0.05 g/mmol, respectively. Results. Twelve patients, from six paediatric KTx units, presenting with FSGS recurrence between 0 and 21 days after KTx were treated with IA. Ten of 12 children were responders: 2 achieved partial remission and 8 complete remission. The decrease of proteinuria rapidly occurred within the first 10 sessions after initiating IA. After 3months of IA, two patients maintained remission without IA and eight became IA dependent. No severe side effects were reported. Conclusions. Our study reports on the efficacy of IA in the recurrence of FSGS after KTx in children. Further prospective controlled studies are required to confirm these results and to optimize themanagement of FSGS recurrence after paediatric KTx. [ABSTRACT FROM AUTHOR]

Background. Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add value to current classification of glomerulopathies. Methods. We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria. Results. IF was highly correlated with TA (P < 0.001) and II (P < 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P < 0.001). IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r| > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis. Conclusions. The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression. [ABSTRACT FROM AUTHOR]

Background. The optimal dosing and the efficacy of rituximab for primary membranous nephropathy (PMN) has not been established. This multicentric prospective study evaluates the efficacy and safety of low-dose rituximab (RTX) therapy in patients with PMN in clinical practice. Methods. Thirty-four consecutive patients with PMN and nephrotic syndrome were included and received RTX (375 mg/ m2) once (18 patients) or twice (16 patients). RTX was the firstline therapy for 19 (56%) and the second line for 15 (44%) patients. All patients were followed for 12 months after RTX and 24 for at least 18months (mean 23.9± 18.6 months). Results. At 12 months, 5 patients (14.7%) achieved complete response, 10 (29.4%) partial and 19 (55.8%) no response. Response occurred ~6 months after RTX. At 24 months, the clinical situation was unchanged: two non-responders achieved partial response and two responders relapsed. Responders had significantly higher baseline GFR and lower anti-PLA2R antibodies compared with non-responders. Outcome was similar between one or two doses of RTX (non-responders 55.5 versus 56%, respectively) and between patients who had received previous therapy versus those receiving RTX as first-line therapy (non-responders 40 versus 68%, respectively). In the 15 patients already treated, the response to RTX was comparable to that of previous therapies. Conclusion. Low-dose RTX obtains remission in <50% of PMN patients. Probably, higher doses and longer treatments are needed to induce andmaintain a response. The balance between the costs and benefits should guide the selection of the patient and the optimal dosage. [ABSTRACT FROM AUTHOR]

During chronic kidney disease (CKD), bone mineral metabolism is disturbed owing in part to the endogenous hormone fibroblast growth factor 23 (FGF23). Elevated FGF23 levels are seen in CKD patients. Current research has demonstrated that FGF23 directly modulates the immune response and host defense to bacterial infections. FGF23 also impairs the activation and recruitment of neutrophils, which are the main immune effector cells required for host defense against bacterial infections. In addition, while FGF23 levels reduce leukocyte recruitment and functions, inflammatory conditions may also--in a reverse fashion--contribute to elevated FGF23 levels in the circulation. In this context, altered hypoxia inducible factor 1a signaling and iron metabolism may contribute to intact FGF23 (iFGF23) production. This review examines evidence on the role of FGF23 in inflammation, immune cell function and recruitment as well as the regulation of FGF23 during inflammation and the clinical implications of this process for the immune system in individuals with CKD. Clinical observations and laboratory investigations indicate an important role of FGF23 in directly modulating leukocyte activation and recruitment behavior with consequences on host defense against bacterial infections. This novel observation may in part explain the increased infectious risk among patients with CKD. However, studies of FGF23 neutralization also revealed increased mortality after sustained administration over several weeks in rats. Thus, therapeutic interventions targeting FGF23 must be carefully evaluated. [ABSTRACT FROM AUTHOR]

Background: Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 (APOL1) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known. Methods: This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE).Results: Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m2; NEPTUNE: 74 versus 94 mL/min/1.73 m2). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: −18 versus −8% per year; NEPTUNE: −13 versus −3% per year). Conclusions: Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1-associated glomerular disease. Further study is needed to determine the generalizability of these findings. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterized by diffuse mesangial deposition of IgM. IgM nephropathy has been a controversial diagnosis since it was first reported, and there are few data identifying specific pathological features that predict the risk of progression of renal disease. Methods: We identified 57 cases of IgM nephropathy among 3220 adults undergoing renal biopsy at our institution. Biopsies had to satisfy the following three criteria to meet the definition of IgMnephropathy in this study: (i) dominant mesangial staining for IgM, (ii) mesangial deposits on electron microscopy (EM) and (iii) exclusion of systemic disease. Results: The median age was 42 years and 24 patients were male. Thirty-nine per cent of patients presented with the nephrotic syndrome, 49% presented with non-nephrotic proteinuria and 39% had eGFR <60 mL/min. The median post-biopsy follow-up was 40 months and serum creatinine had doubled in 31% by 5 years. Of histological parameters, glomerular sclerosis and tubular atrophy, but not mesangial proliferation, were risk factors for renal insufficiency. Thirty-nine per cent of nephrotic patients achieved complete remission, and outcome was significantly worse in those who did not respond to treatment. Focal segmental glomerulosclerosis was diagnosed in 80% of those undergoing repeat renal biopsy, despite ongoing mesangial IgM deposition. Conclusions: We propose criteria for a consensus definition of IgMnephropathy. [ABSTRACT FROM AUTHOR]

Background: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Previous genome-wide association studies (GWAS) of 300 000 genotyped variants identifiedMN-associated loci at HLA-DQA1 and PLA2R1. Methods: We used a combined approach of genotype imputation, GWAS, human leucocyte antigen (HLA) imputation and extension to other aetiologies of chronic kidney disease (CKD) to investigate genetic MN risk variants more comprehensively. GWAS using 9 million high-quality imputed genotypes and classical HLA alleles were conducted for 323 MN Europeanancestry cases and 345 controls. Additionally, 4960 patients with different CKD aetiologies in the German Chronic Kidney Disease (GCKD) study were genotyped for risk variants at HLA-DQA1 and PLA2R1. Results: In GWAS, lead variants in known loci [rs9272729, HLA-DQA1, odds ratio (OR) = 7.3 per risk allele, P = 5.9 × 10-27 and rs17830558, PLA2R1, OR =2.2, P = 1.9 × 10-8 ] were significantly associated with MN. No novel signals emerged in GWAS of X-chromosomal variants or in sexspecific analyses. Classical HLA alleles (DRB1*0301-DQA1* 0501-DQB1*0201 haplotype) were associated with MN but provided little additional information beyond rs9272729. Associations were replicated in 137 GCKD patients with MN (HLA-DQA1: P = 6.4 × 10-24 ; PLA2R1: P = 5.0 × 10-4 ). MN risk increased steeply for patients with high-risk genotype combinations (OR > 79). While genetic variation in PLA2R1 exclusively associated with MN across 19 CKD aetiologies, the HLA-DQA1 risk allele was also associated with lupus nephritis (P = 2.8 × 106 ), type 1 diabetic nephropathy (P = 6.9 × 105 ) and focal segmental glomerulosclerosis (P = 5.1 × 105 ), but not with immunoglobulin A nephropathy. Conclusions: PLA2R1 and HLA-DQA1 are the predominant risk loci for MN detected by GWAS. While HLA-DQA1 risk variants show an association with other CKD aetiologies, PLA2R1 variants are specific to MN. [ABSTRACT FROM AUTHOR]

Idiopathic membranous nephropathy (IMN) remains the most common cause of the nephrotic syndrome in adults and one of the leading identifiable causes of end-stage kidney disease. Prior to considering the best approach to treatment, three important components need to be considered. First, the natural history of the typical membranous patient today; second, the importance of identifying the causative factors; and third, the integration of the current data on the known autoantibody/antigen systems involved in IMN into the diagnosis and management of the patient. Combining this with information on the known indicators associated with a poor prognosis plus new data on surrogate markers that provide important clues that the treatment plan is correct has provided us with a more secure platform for choosing the right treatment for each patient. This already provides a more rational and precise approach to the use of our current therapeutic options. Even today, we can slow disease progression and in the future new approaches and new therapies are likely to lead to prevention of progression or even reversal of the injury in IMN, thereby leading to improved quality of life of our patients. [ABSTRACT FROM AUTHOR]

Focal segmental glomerulosclerosis (FSGS) is a lesion and not a disease. This conundrum is the crux of controversies regarding interventions to alter its natural history. In the broadest sense, the lesion can be primary (idiopathic), or secondary to a process originating outside the kidneys or to a genetic mutation. The organ-based target is the podocyte, and the mechanisms responsible for the podocytopathy are numerous and diverse. Recurrence of primary FSGS in renal allografts provides the best evidence for the existence of a circulating factor or factors, the nature of which remains uncertain. The separation of primary from secondary FSGS clinically and pathologically is challenging, but full-blown nephrotic syndrome and diffuse (universal) foot process effacement are strong signals for a primary form of FSGS. It is imperative that clinical trials designed to investigate therapeutic strategies for patients with a lesion of FSGS pay careful attention to the separation of primary from secondary forms of FSGS. This critical review provides a rationale and a process for helping to ensure that this is accomplished, such that clinical trials provide useful information and treatment responsiveness applicable to the primary forms of FSGS. [ABSTRACT FROM AUTHOR]

Background. People living with nephrotic syndrome (NS) need to develop an in-depth understanding of their condition in order to participate in treatment decisions, develop self-management skills and integrate illness into daily life. However, the learning needs of adult patients and parents of children with NS are unknown. We therefore explored patient and parent perspectives on learning needs related to NS as part of a larger study to develop a shared learning tool for NS. Methods. Qualitative data were collected using semistructured focus groups and individual interviews with adult patients (n = 22) and parents of children with NS (n = 25). Results. The complexity of NS and its treatment made decision making challenging, as patients/parents often had to assimilate information about a condition that is poorly understood. Specific informational needs related to understanding the diagnosis and treatment approaches as well as learning tomanageNS were identified. Difficulty in getting accurate information often made learning challenging. The importance of learning to monitor their condition, including understanding triggers that might precipitate a relapse, was highlighted, underscoring the need for individualized approaches to ensure unique learning needs are addressed. Conclusions. Our findings reveal some of the unique concerns of people with NS given its uncertain course and the limited information available specific to NS. These results suggest the need for shared communication between the patient/parents and providers to elicit the patient's/parents' understanding of NS and to support them in meeting their unique learning needs. [ABSTRACT FROM AUTHOR]

Background. Managing patients with nephrotic syndrome (NS) remains difficult for the practicing nephrologist. This often young patient population is faced with a debilitating, relapsing and remitting disease with non-specific treatment options that are often poorly tolerated. Clinicians managing these complex patients must attempt to apply disease-specific evidence while considering the individual patient's clinical and personal situation. Methods. We conducted qualitative interviews to ascertain the provider perspectives of NS, treatment options and factors that influence recommendations for disease management, and administered a survey to assess both facilitators and barriers to the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Results. When making treatment recommendations, providers considered characteristics of various treatments such as efficacy, side effects and evaluation of risk versus benefit, taking into account how the specific treatment fit with the individual patient. Time constraints and the complexity of explaining the intricacies of NS were noted as significant barriers to care. Although the availability of guidelines was deemed a facilitator to care, the value of the KDIGO guidelines was limited by the perception of poor quality of evidence. Conclusions. The complexity of NS and the scarcity of robust evidence to support treatment recommendations are common challenges reported by nephrologists. Future development and use of shared learning platforms may support the integration of best available evidence, patient/family preferences and exchange of information at a pace that is unconstrained by the outpatient clinic schedule. [ABSTRACT FROM AUTHOR]

Minimal change disease (MCD) is a pathological condition characterized by subtle glomerular lesions causing massive and reversible proteinuria that is usually steroid sensitive. Recurrence of symptoms of active disease following successful treatment (including proteinuria, oedema and oliguria) and steroid toxicity requires the use of other drugs to attain or maintain remission. Unresolved MCD is considered the initial step in the pathological pathway leading to focal and segmental glomerulosclerosis (FSGS). Historically, cyclophosphamide, chlorambucil, mycophenolate and calcineurin inhibitors have been utilized with success in MCD; however, the chronic nature of the disease and the toxicity of long-term use of these medications has pushed the development of new therapies. Synthetic corticotropin (adrenocorticotropic hormone) and anti-CD20 monoclonal antibodies, for example, are currently under investigation in clinical trials. In addition, these new interventions have dramatically impacted our understanding of the mechanisms of the disease. Phase II-IV clinical trials targeting new mechanisms and/or molecules are in progress. The list is long and includes drugs blocking the adaptive immune system (abatacept and anti-CD40 antibodies), as well as retinoids and the sialic acid precursor N-acetyl-D-mannosamine (ManNAc), two agents that affect the sieving properties of the glomerular basement membrane. Other drugs are being tested against FSGS and, if successful, could also be utilized againstMCD. Clinical trials currently in progress should furnish a proper solution to what appears to be a solvable problem. [ABSTRACT FROM AUTHOR]

Steroid-resistant nephrotic syndrome (SRNS) represents the second most frequent cause of chronic kidney disease in the first three decades of life. It manifests histologically as focal segmental glomerulosclerosis (FSGS) and carries a 33%risk of relapse in a renal transplant. No efficient treatment exists. Identification of single-gene (monogenic) causes of SRNS has moved the glomerular epithelial cell (podocyte) to the center of its pathogenesis. Recently, mutations in >30 recessive or dominant genes were identified as causing monogenic forms of SRNS, thereby revealing the encoded proteins as essential for glomerular function. These findings helped define protein interaction complexes and functional pathways that could be targeted for treatment of SRNS. Very recently, it was discovered that in the surprisingly high fraction of ~30%of all individuals who manifest with SRNS before 25 years of age, a causative mutation can be detected in one of the ~30 different SRNS-causing genes. These findings revealed that SRNS and FSGS are not single disease entities but rather are part of a spectrum of distinct diseases with an identifiable genetic etiology. Mutation analysis should be offered to all individuals who manifest with SRNS before the age of 25 years, because (i) it will provide the patient and families with an unequivocal cause-based diagnosis, (ii) it may uncover a form of SRNS that is amenable to treatment (e.g. coenzyme Q10), (iii) it may allow avoidance of a renal biopsy procedure, (iv) it will further unravel the puzzle of pathogenic pathways of SRNS and (v) it will permit personalized treatment options for SRNS, based on genetic causation in way of 'precision medicine'. [ABSTRACT FROM AUTHOR]