In steroid-resistant nephrotic syndrome that meets the strict definition, monogenic variants less common than previously reported

In steroid-resistant nephrotic syndrome that meets the strict definition, monogenic variants less common than previously reported | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article In steroid-resistant nephrotic syndrome that meets the strict definition, monogenic variants less common than previously reported Yuta Ichikawa, Nana Sakakibara, China Nagano, Yuta Inoki, Yu Tanaka, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3995397/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Aug, 2024 Read the published version in Pediatric Nephrology → Version 1 posted 5 You are reading this latest preprint version Abstract Background In patients with steroid-resistant nephrotic syndrome (SRNS), the presence of monogenic variants influences therapeutic strategies. Large cohort studies reported the detection of monogenic variants in approximately 30% of patients with SRNS. However, these cohorts included many patients such as asymptomatic proteinuria who did not meet the strict diagnostic criteria for pediatric nephrotic syndrome (NS). Therefore, we investigated the proportion of causative monogenic variants detected in patients who strictly met the diagnostic criteria of SRNS and explored their clinical characteristics. Methods We examined pediatric SRNS cases with genetic analysis conducted in our hospital. Cases satisfying all of the following criteria were included: 1. age at onset 1–18 years, 2. serum albumin at onset ≤ 2.5 g/dl, and 3. no complete remission after 4 weeks of steroid monotherapy. Results The proportion of detected monogenic variants was 12% (22/185) among all patients. The proportion was only 7% (9/129) in patients with edema at disease onset compared with 38% (9/24) in those without (p < 0.0001). Monogenic variants were rare in patients with acute kidney injury associated with NS (1% [1/11]) or a history of complete remission (4% [2/51]). Conclusions Our study revealed a monogenic cause in 12% of individuals with strictly defined SRNS, a much smaller proportion than previously reported. The presence or absence of edema at the onset was an important factor to distinguish SRNS with monogenic cause from SRNS without. Our results provide further evidence of the SRNS types attributable to monogenic causes. Steroid resistant nephrotic syndrome Monogenic variants Edema Acute kidney injury associated with nephrotic syndrome Complete remission Figures Figure 1 Introduction Nephrotic syndrome (NS) is an umbrella term for glomerular filtration barrier dysfunction resulting in generalized edema because of heavy proteinuria and hypoalbuminemia. Per year, 2.0–6.5 per 100,000 children develop this syndrome [ 1 , 2 ]. Approximately 90% of pediatric NS is categorized as idiopathic nephrotic syndrome (INS) [ 3 ], and 10–15% of these are steroid-resistant nephrotic syndrome (SRNS) without complete remission after 4–6 weeks of steroid therapy (60 mg/m 2 or 2 mg/kg) [ 4 ]. In SRNS with immunological causes, combination therapy of steroid pulse therapy and cyclosporine A has shown favorable outcomes with an efficacy rate of more than 80% [ 5 ], and the combination with rituximab has also been suggested in recent years to be effective [ 6 , 7 ]. However, in SRNS associated with a monogenic variant, immunosuppressive therapy is ineffective in almost all cases [ 8 , 9 ]. Thus, it is important to distinguish monogenic from immunological SRNS, but this often proves difficult in clinical practice. Genetic analysis is essential to decide the treatment strategy [ 4 ], but not all patients with SRNS can immediately undergo genetic analyses. Based on analyses of large cohorts in Japan and other countries, genetic etiologies can be identified in about 30% of patients with SRNS [ 10 – 13 ]. However, these cohorts included cases that did not meet the International Study of Kidney Disease in Children (ISKDC) criteria of INS [ 14 ] and included asymptomatic proteinuria without nephrotic range hypoalbuminemia, familial focal segmental glomerulosclerosis (FSGS), congenital NS (onset before 3 months), and infantile NS (onset before 1 year). From a clinical perspective, monogenic SRNS represents less than 30% of all cases with SRNS, but surprisingly, the proportion of causative variants detected in strictly defined pediatric SRNS remains unclear. In this study, we investigated the proportion of causative monogenic variants detected in properly diagnosed SRNS and what clinical manifestations are associated with monogenic SRNS. Materials and methods Patients This study included pediatric patients diagnosed with SRNS between 1 and 18 years of age who underwent comprehensive gene screening between March 2016 and October 2022. Patients screened before December 2018 have already been reported by our group in a study about comprehensive genetic diagnosis of patients with severe proteinuria [ 10 ]. Children with congenital or infantile NS were excluded from the current study. Patients with serum albumin > 2.5 g/dl at onset or unknown serum albumin levels at onset were also excluded (Online Resource 1). Definitions In this study, SRNS was redefined as a serum albumin concentration ≤ 2.5 g/dl at onset and no complete remission after 4 weeks of treatment with 60 mg/m 2 /day of prednisolone, according to the ISKDC criteria [ 15 , 16 ]. Family history was defined as the presence of any type of urine abnormality or kidney disease in the parents or siblings of the study participants. History of temporary dialysis due to acute kidney injury associated with NS (NS-AKI) was defined as a prior dialysis due to NS-AKI with subsequent recovery of kidney function leading to weaning from dialysis. Chronic kidney disease (CKD) stage 5 was defined as a progressed stage of CKD with kidney replacement therapy (hemodialysis, peritoneal dialysis, or kidney transplantation). Complete remission was defined as dipstick-negative protein in morning urine or a morning urine protein-to-creatinine ratio < 0.2 g/gCr for 3 consecutive days. Assessment of clinical findings The following items were extracted from questionnaires obtained from the local doctors of the patients: (1) age at onset, (2) age at genetic analysis, (3) sex, (4) edema at onset, (5) family history, (6) extrarenal complications, (7) history of temporary dialysis due to NS-AKI until the results of the genetic analysis were known, (8) CKD stage 5 until the results of the genetic analysis were known, (9) history of complete remission until the results of the genetic analysis were known, and (10) initial histopathological diagnosis. Genetic analysis Genetic analysis was performed as previously reported [ 17 ]. In brief, genomic DNA was isolated from peripheral blood leukocytes obtained from the participants and their families. For the custom next-generation sequencing panel targeting podocyte-related genes (Online Resource 2), samples were prepared using the Haloplex or Sure Select target enrichment system kit (Agilent Technologies, Santa Clara, CA, USA), in accordance with the manufacturer’s instructions. All indexed DNA samples were amplified by polymerase chain reaction and sequenced using the MiSeq platform (Illumina, San Diego, CA, USA). We performed custom array comparative genomic hybridization (aCGH) as previously reported [ 18 ] for one case. We conducted pair analysis using the SureCall application in this patient and suspected that this patient had a large heterozygous deletion including the NUP85 gene (chromosome 17, q25.1 partial deletion). We used the computational prediction software SIFT ( https://research.a-star.edu.sg/tag/sift/ ), PolyPhen-2 ( http://genetics.bwh.harvard.edu/pph2/ ), Mutation Taster ( https://www.mutationtaster.org/ ), and CADD ( https://cadd.gs.washington.edu/snv ) to classify variants as pathogenic, likely pathogenic, or of uncertain significance, according to the guidelines of the American College of Medical Genetics and Genomics [ 19 ]. Statistical analysis Results are presented as median and interquartile range (IQR). The chi-squared test or Fisher’s exact test was used to compare variables between each group. Wilcoxon’s test was used to compare median differences between each experimental group. Statistical analysis was performed using standard statistical software (JMP version 14 for Windows; SAS Institute, Cary, NC, USA). In all tests, p < 0.05 was considered statistically significant. Results In total, 185 patients met the inclusion criteria (Online Resource 1). The clinical characteristics of the patients are shown in Online Resource 3. The median age at onset was 3 years (IQR, 2.0–10.5 years), and the median age at the time of genetic analysis was 5 years (IQR, 1.0–7.0 years). The male:female ratio was 10.0:7.6. Causative monogenic variants were identified in 12% (22 of 185) patients; WT1 gene variants had the highest frequency with 6 cases (Table 1 ). The genotype details of the 22 cases in which disease-causing variants were identified are shown in Online Resource 4, and the details of the aCGH results in the patient with suspected large deletion in NUP85 is shown in Online Resource 5. The proportions of detected causative variants by age group (Fig. 1 ) were 5% at 1 year of age, 12% at 2 years of age, and 21% at 3 years of age. Table 1 Genes with disease-causing variants in 185 patients with steroid-resistant nephrotic syndrome Causative gene n WT1 6 TRPC6 3 COL4A4 1 NPHS1 2 PLCE1 2 SMARCAL1 2 ACTN4 1 ARHGAP24 1 INF2 1 LAMB2 1 NUP85 1 NUP93 1 Causative variant not detected 163 The clinical phenotypes of patients with and without variants are compared in Table 2 . The groups with and without identified variants significantly differed in sex (p = 0.0455), presence of edema at onset (p < 0.0001), and history of complete remission (p = 0.01). The proportion of monogenic variants was only 7% (9 of 129) in patients with edema at disease onset but 38% (9 of 24) in those without edema at onset. However, no significant difference in the age at onset, family history, extrarenal complications, history of temporary dialysis due to NS-AKI, history of CKD stage 5, and initial histopathological diagnosis was found between the group with identified variants and that without. Notably, monogenic causes were rare in patients with NS-AKI (1% [1 of 11]) or those with a history of complete remission (4% [2 of 51]). Table 2 Comparison of clinical phenotypes between patients with and without variants in the analyzed genes Clinical phenotype Total Patients with variants Patients without variants p value Age at onset (years) a 3 (2.0–10.5) 4 (2.0–7.0) 3 (1.0–7.0) 0.2948 Male sex, % (n/N) 57% (105/185) 36% (8/22) 60% (97/163) 0.0455 Absence of edema, % (n/N) 16% (24/153) 50% (9/18) 11% (15/135) < 0.0001 Family history, % (n/N) 2% (3/185) 5% (1/22) 1% (2/163) 0.3175 Extrarenal complications, % (n/N) 17% (32/185) 23% (5/22) 17% (27/163) 0.5541 NS-AKI with temporary dialysis, % (n/N) 2% (4/185) 0% (0/22) 2% (4/163) > 0.9999 CKD stage 5, % (n/N) 9% (17/185) 18% (4/22) 8% (13/163) 0.1250 Complete remission, % (n/N) 19% (35/185) 5% (1/22) 21% (34/163) 0.0100 Initial histopathologic diagnosis, % (n/N) 0.2258 FSGS 50% (76/153) 71% (12/17) 47% (64/136) MGA 41% (62/153) 24% (4/17) 43% (58/136) DMS 2% (3/153) 6% (1/17) 1% (2/136) DMP 8% (12/153) 0% (0/17) 9% (12/136) a Median (interquartile range) Abbreviations: CKD, chronic kidney disease; DMP, diffuse mesangial proliferation; DMS, diffuse mesangial sclerosis; FSGS, focal segmental glomerular sclerosis; MGA, minor glomerular abnormalities; NS-AKI, acute kidney injury in nephrotic syndrome. Discussion This study showed that monogenic variants in patients meeting the strict SRNS definition account for only 12%, i.e., they are less common than previously reported. The results also demonstrated that the presence of edema is an important parameter to differentiate between SRNS types with a monogenic cause and those without. A recent report from the United Kingdom identified causative variants in 10% of non-syndromic SRNS, excluding congenital and infantile NS [ 20 ]. Although their study did not examine serum albumin levels, the patient population in their study might be similar to ours. The proportion of causative variants detected at 1 year of age was surprisingly 5% possibly due to the high incidence of INS at 1 year of age. Monogenic variants are generally detected with a high probability in congenital and infantile NS; by contrast, the probability of a monogenic cause was very low at 1 year of age in our study. In a previous large cohort from the US, the proportion of families with detected monogenic cause at 1, 2, and 3 years of age remained almost unchanged at approximately 25% [ 11 ], while in the present study, the proportion according to age at onset was higher at 3 years of age. This difference may be related to urine screening of 3-year-olds during checkups in Japan. As in our study a certain number of cases with monogenic causes were found even beyond school age, it should be considered that monogenic SRNS is not limited to a specific age group. The most important point of this study is that the detection of monogenic variants was low (7%) in typical cases with edema at onset but very high (38%) in atypical cases without edema at onset. Our group has previously reported that in a cohort of patients with severe proteinuria, significantly fewer patients with monogenic variants showed edema than those without [ 10 ], but it included several patients without hypoalbuminemia. The present study shows, for the first time, that in a cohort of only patients with hypoalbuminemia, those with monogenic variants had a significantly reduced frequency of edema. In patients with congenital analbuminemia, edema is rare, possibly due to edema-preventive mechanisms, including mitigating effects on the oncotic gradient, a reduction in the hydrostatic blood pressure gradient, and a decrease in the capillary permeability of proteins [ 21 ]. Moreover, patients with congenital NS can often escape after some time an albumin-dependent status despite hypoalbuminemia [ 22 ]. Patients with monogenic variants are less likely to present with edema probably because edema-compensatory mechanisms play a role in chronic or slowly progressive hypoalbuminemia. In addition to edema, a significant sex difference was observed between the study groups. The significantly lower detection rate of gene abnormalities in males might be due to the higher incidence of INS in male patients. Furthermore, a significant difference was observed regarding a history of complete remission. Similar to the findings of a previous report [ 23 ], our results confirmed that monogenic variants were usually not identified in cases with a history of complete remission, except for two cases with remission after cyclosporine A administration (one case each with a WT1 and a COL4A4 variant). Remission of patients with WT1 variants has previously been reported [ 9 ], and the case Neph573 with a COL4A4 variant was considered to be coincidentally complicated by INS because COL4A4 variants do not usually lead to NS. Although no significant difference was observed in other factors, probably due to the small number of cases, some important findings should be highlighted. Monogenic variants were generally not identified in cases with NS-AKI that required temporary dialysis except for one case with a COL4A4 variant (Neph573) that was considered to be coincidentally complicated by INS because COL4A4 variants do not usually lead to NS and therapy led to complete remission in this patient. The reason why SRNS with monogenic variants is less likely to be accompanied by NS-AKI seems to be that NS develops slowly. In addition, the prevalence of monogenic variants was in this study not particularly high in patients with CKD stage 5. Based on these findings, some cases with CKD stage 5 include immunologically induced SRNS, providing the potential for improving kidney outcomes with more intensive immunosuppressive therapy, such as rituximab. Regarding the initial histopathologic diagnosis, a high proportion (71%) of monogenic variants was found to be FSGS in this study, similar to 63–74% reported in previous publications [ 10 – 13 ]. However, an initial histopathological diagnosis of minor glomerular abnormalities should not lead to the assumption of a non-monogenic cause because minor glomerular abnormalities may change to FSGS over the course of the disease. Especially in younger patients, the histology might be evaluated in the early stage of the disease. This study has several limitations. First, not all pediatric patients diagnosed with SRNS underwent genetic analysis. The population referred to our hospital for genetic analysis might be biased towards complicated cases in which local doctors suspect monogenic causes. In practice, the proportion of monogenic causes seems to be much lower. Second, some of the cases without monogenic variants might include cases with genetic abnormalities that cannot be detected by our panels, such as deep intronic variants or genes with no established pathogenicity. Third, the timing of genetic analysis varied among patients; in some cases, genetic analysis was performed immediately after the diagnosis of SRNS, whereas in others, genetic analysis was performed after reaching CKD stage 5. In the end, even in cases where monogenic variants were identified, most patients received additional immunosuppressive therapy (steroid pulse therapy, cyclophosphamide, rituximab, cyclosporine A, tacrolimus, mizoribine, or mycophenolate mofetil) until the results of the genetic analysis were known. This suggests that determining the presence or absence of genetic abnormalities from clinical history alone is challenging. Although it is ideal for all patients with suspected SRNS to undergo genetic analysis promptly, cases with edema at disease onset should be more aggressively considered for additional immunosuppressive treatment. Conversely, in patients without edema, additional immunosuppressive treatment should be considered more carefully. We hope that our results may help pediatric nephrologists in the decision-making for SRNS therapy. Declarations Acknowledgments We thank all of the study patients. We also extend our sincere thanks to the participating doctors for providing clinical information. Finally, we would like to thank Editage (www.editage.jp) for English language editing. Author contributions YIc, NS, CN, YIn, YT, CU, HK, AK, SI, TH, KI, and KN conceived the study and performed the genetic analyses; YIc and NS drafted the manuscript; and KN reviewed the manuscript. All the authors have read and approved the final manuscript. Funding Our study received no specific grant from any funding agency in the public, commercial, or not-for-profit sections. Availability of data and material Data from this study can be obtained from the corresponding authors on reasonable request. Ethics approval All procedures involving humans were reviewed and approved by the Institutional Review Board of Kobe University Graduate School of Medicine (IRB approval number 301) and were performed in accordance with the Helsinki Declaration of 1964 and its later amendments. Consent to participate/Consent to publish Written informed consent was obtained from all patients or their parents before genetic analysis. Consent for publication was not required because the study was retrospective. Conflict of interest The authors declare no competing interest. References Schlesinger ER, Sultz HA, Mosher WE, Feldman JG (1968) The nephrotic syndrome. Its incidence and implications for the community. 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Kidney Int 91:937–947. https://doi.org/10.1016/j.kint.2016.10.013 Supplementary Files ESM1.docx ESM2.docx ESM3.xlsx ESM4.docx ESM5.docx Cite Share Download PDF Status: Published Journal Publication published 02 Aug, 2024 Read the published version in Pediatric Nephrology → Version 1 posted Editorial decision: Major Revisions Needed 04 Apr, 2024 Reviewers agreed at journal 05 Mar, 2024 Reviewers invited by journal 27 Feb, 2024 Editor assigned by journal 27 Feb, 2024 First submitted to journal 26 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3995397","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":275498665,"identity":"8029edd2-c72b-4259-a514-bb6500053ebf","order_by":0,"name":"Yuta Ichikawa","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-5926-1203","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":true,"prefix":"","firstName":"Yuta","middleName":"","lastName":"Ichikawa","suffix":""},{"id":275498666,"identity":"46707e8c-411e-4985-aa24-cec7accac5f4","order_by":1,"name":"Nana Sakakibara","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Nana","middleName":"","lastName":"Sakakibara","suffix":""},{"id":275498667,"identity":"02a679a9-e9f8-4bcb-ae9d-14827ac257ac","order_by":2,"name":"China Nagano","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"China","middleName":"","lastName":"Nagano","suffix":""},{"id":275498668,"identity":"e7619e45-5e2f-4a60-a00b-6deda366ce1c","order_by":3,"name":"Yuta Inoki","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Yuta","middleName":"","lastName":"Inoki","suffix":""},{"id":275498669,"identity":"4b2f9068-fbef-481a-ba3b-b818f85d703e","order_by":4,"name":"Yu Tanaka","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Tanaka","suffix":""},{"id":275498670,"identity":"821a3d47-56a7-4ff0-b625-f755a26ae276","order_by":5,"name":"Chika Ueda","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Chika","middleName":"","lastName":"Ueda","suffix":""},{"id":275498671,"identity":"b0e23bc6-5661-4b79-a742-13e380db4513","order_by":6,"name":"Hideaki Kitakado","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Hideaki","middleName":"","lastName":"Kitakado","suffix":""},{"id":275498672,"identity":"78426b2f-122f-4076-9384-7403f2710759","order_by":7,"name":"Atsushi Kondo","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Kondo","suffix":""},{"id":275498673,"identity":"cb8d205e-ab9e-4998-98d0-c1a298ff18ee","order_by":8,"name":"Shingo Ishimori","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Ishimori","suffix":""},{"id":275498674,"identity":"07a8eb0e-6900-4055-9188-7177b8aa3750","order_by":9,"name":"Tomoko Horinouchi","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Horinouchi","suffix":""},{"id":275498675,"identity":"c25915a9-397a-4394-a545-ae5ae4ed4cfd","order_by":10,"name":"Kazumoto Iijima","email":"","orcid":"","institution":"Hyogo Prefectural Kobe Children's Hospital: Hyogo Kenritsu Kodomo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Kazumoto","middleName":"","lastName":"Iijima","suffix":""},{"id":275498676,"identity":"99d27361-0d29-4f37-b0d0-16f04495aa17","order_by":11,"name":"Kandai Nozu","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Kandai","middleName":"","lastName":"Nozu","suffix":""}],"badges":[],"createdAt":"2024-02-28 02:38:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3995397/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3995397/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00467-024-06468-5","type":"published","date":"2024-08-02T15:58:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":52029510,"identity":"0962acf3-cf6f-4e46-9491-e5b5b71ee658","added_by":"auto","created_at":"2024-03-05 16:18:27","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":205028,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of monogenic variants by age at onset. Black and gray bars show whether causative variants were detected or not, respectively. The rates were lower at 1 year (5%) and 2 years (12%) of age but peaked at 3 years of age (21%). The rate was again lower for those over 13 years of age, but the rates in the age groups 4–6 and 7–12 years were relatively high. Abbreviation: y.o., years old\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3995397/v1/468f82d3ab6ab3990fb84edb.jpeg"},{"id":61794369,"identity":"dc2b850e-fb9a-4b2e-bbee-fcf095382941","added_by":"auto","created_at":"2024-08-05 16:18:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":600383,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3995397/v1/aa352e39-e864-40d4-94f4-91b83f6286d3.pdf"},{"id":52029513,"identity":"b32c691b-bf49-4ddc-9af7-906e446ff8aa","added_by":"auto","created_at":"2024-03-05 16:18:27","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":121191,"visible":true,"origin":"","legend":"","description":"","filename":"ESM1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3995397/v1/eaf14f9a2c2682c3783f3b63.docx"},{"id":52029514,"identity":"0dfedd7b-4306-4c42-80ee-82cb2c45a2a5","added_by":"auto","created_at":"2024-03-05 16:18:27","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":30843,"visible":true,"origin":"","legend":"","description":"","filename":"ESM2.docx","url":"https://assets-eu.researchsquare.com/files/rs-3995397/v1/7633090d2ba327beaa37d2c5.docx"},{"id":52029515,"identity":"b13b0002-9700-4123-8dea-476f6f279523","added_by":"auto","created_at":"2024-03-05 16:18:28","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":27933,"visible":true,"origin":"","legend":"","description":"","filename":"ESM3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3995397/v1/6e15d60bf6ad43d46e4d060d.xlsx"},{"id":52029516,"identity":"08634358-cfb5-46fa-ba89-de65d38f521f","added_by":"auto","created_at":"2024-03-05 16:18:28","extension":"docx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":34850,"visible":true,"origin":"","legend":"","description":"","filename":"ESM4.docx","url":"https://assets-eu.researchsquare.com/files/rs-3995397/v1/29f27e9ab5d2a1e754e40819.docx"},{"id":52029512,"identity":"dadbd466-f3e2-4c60-af5d-71adbd84e34d","added_by":"auto","created_at":"2024-03-05 16:18:27","extension":"docx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":236522,"visible":true,"origin":"","legend":"","description":"","filename":"ESM5.docx","url":"https://assets-eu.researchsquare.com/files/rs-3995397/v1/6d6819b7bd85d9e9732dda08.docx"}],"financialInterests":"","formattedTitle":"In steroid-resistant nephrotic syndrome that meets the strict definition, monogenic variants less common than previously reported","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNephrotic syndrome (NS) is an umbrella term for glomerular filtration barrier dysfunction resulting in generalized edema because of heavy proteinuria and hypoalbuminemia. Per year, 2.0\u0026ndash;6.5 per 100,000 children develop this syndrome [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Approximately 90% of pediatric NS is categorized as idiopathic nephrotic syndrome (INS) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and 10\u0026ndash;15% of these are steroid-resistant nephrotic syndrome (SRNS) without complete remission after 4\u0026ndash;6 weeks of steroid therapy (60 mg/m\u003csup\u003e2\u003c/sup\u003e or 2 mg/kg) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In SRNS with immunological causes, combination therapy of steroid pulse therapy and cyclosporine A has shown favorable outcomes with an efficacy rate of more than 80% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and the combination with rituximab has also been suggested in recent years to be effective [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, in SRNS associated with a monogenic variant, immunosuppressive therapy is ineffective in almost all cases [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Thus, it is important to distinguish monogenic from immunological SRNS, but this often proves difficult in clinical practice. Genetic analysis is essential to decide the treatment strategy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], but not all patients with SRNS can immediately undergo genetic analyses.\u003c/p\u003e \u003cp\u003eBased on analyses of large cohorts in Japan and other countries, genetic etiologies can be identified in about 30% of patients with SRNS [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, these cohorts included cases that did not meet the International Study of Kidney Disease in Children (ISKDC) criteria of INS [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] and included asymptomatic proteinuria without nephrotic range hypoalbuminemia, familial focal segmental glomerulosclerosis (FSGS), congenital NS (onset before 3 months), and infantile NS (onset before 1 year). From a clinical perspective, monogenic SRNS represents less than 30% of all cases with SRNS, but surprisingly, the proportion of causative variants detected in strictly defined pediatric SRNS remains unclear.\u003c/p\u003e \u003cp\u003eIn this study, we investigated the proportion of causative monogenic variants detected in properly diagnosed SRNS and what clinical manifestations are associated with monogenic SRNS.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003ePatients\u003c/p\u003e \u003cp\u003eThis study included pediatric patients diagnosed with SRNS between 1 and 18 years of age who underwent comprehensive gene screening between March 2016 and October 2022. Patients screened before December 2018 have already been reported by our group in a study about comprehensive genetic diagnosis of patients with severe proteinuria [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Children with congenital or infantile NS were excluded from the current study. Patients with serum albumin\u0026thinsp;\u0026gt;\u0026thinsp;2.5 g/dl at onset or unknown serum albumin levels at onset were also excluded (Online Resource 1).\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eDefinitions\u003c/strong\u003e \u003cp\u003eIn this study, SRNS was redefined as a serum albumin concentration\u0026thinsp;\u0026le;\u0026thinsp;2.5 g/dl at onset and no complete remission after 4 weeks of treatment with 60 mg/m\u003csup\u003e2\u003c/sup\u003e/day of prednisolone, according to the ISKDC criteria [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Family history was defined as the presence of any type of urine abnormality or kidney disease in the parents or siblings of the study participants. History of temporary dialysis due to acute kidney injury associated with NS (NS-AKI) was defined as a prior dialysis due to NS-AKI with subsequent recovery of kidney function leading to weaning from dialysis. Chronic kidney disease (CKD) stage 5 was defined as a progressed stage of CKD with kidney replacement therapy (hemodialysis, peritoneal dialysis, or kidney transplantation). Complete remission was defined as dipstick-negative protein in morning urine or a morning urine protein-to-creatinine ratio\u0026thinsp;\u0026lt;\u0026thinsp;0.2 g/gCr for 3 consecutive days.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eAssessment of clinical findings\u003c/p\u003e \u003cp\u003eThe following items were extracted from questionnaires obtained from the local doctors of the patients: (1) age at onset, (2) age at genetic analysis, (3) sex, (4) edema at onset, (5) family history, (6) extrarenal complications, (7) history of temporary dialysis due to NS-AKI until the results of the genetic analysis were known, (8) CKD stage 5 until the results of the genetic analysis were known, (9) history of complete remission until the results of the genetic analysis were known, and (10) initial histopathological diagnosis.\u003c/p\u003e \u003cp\u003eGenetic analysis\u003c/p\u003e \u003cp\u003eGenetic analysis was performed as previously reported [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In brief, genomic DNA was isolated from peripheral blood leukocytes obtained from the participants and their families. For the custom next-generation sequencing panel targeting podocyte-related genes (Online Resource 2), samples were prepared using the Haloplex or Sure Select target enrichment system kit (Agilent Technologies, Santa Clara, CA, USA), in accordance with the manufacturer\u0026rsquo;s instructions. All indexed DNA samples were amplified by polymerase chain reaction and sequenced using the MiSeq platform (Illumina, San Diego, CA, USA).\u003c/p\u003e \u003cp\u003eWe performed custom array comparative genomic hybridization (aCGH) as previously reported [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] for one case. We conducted pair analysis using the SureCall application in this patient and suspected that this patient had a large heterozygous deletion including the \u003cem\u003eNUP85\u003c/em\u003e gene (chromosome 17, q25.1 partial deletion).\u003c/p\u003e \u003cp\u003eWe used the computational prediction software SIFT (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://research.a-star.edu.sg/tag/sift/\u003c/span\u003e\u003cspan address=\"https://research.a-star.edu.sg/tag/sift/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), PolyPhen-2 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://genetics.bwh.harvard.edu/pph2/\u003c/span\u003e\u003cspan address=\"http://genetics.bwh.harvard.edu/pph2/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), Mutation Taster (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.mutationtaster.org/\u003c/span\u003e\u003cspan address=\"https://www.mutationtaster.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and CADD (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cadd.gs.washington.edu/snv\u003c/span\u003e\u003cspan address=\"https://cadd.gs.washington.edu/snv\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to classify variants as pathogenic, likely pathogenic, or of uncertain significance, according to the guidelines of the American College of Medical Genetics and Genomics [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eResults are presented as median and interquartile range (IQR). The chi-squared test or Fisher\u0026rsquo;s exact test was used to compare variables between each group. Wilcoxon\u0026rsquo;s test was used to compare median differences between each experimental group. Statistical analysis was performed using standard statistical software (JMP version 14 for Windows; SAS Institute, Cary, NC, USA). In all tests, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn total, 185 patients met the inclusion criteria (Online Resource 1). The clinical characteristics of the patients are shown in Online Resource 3. The median age at onset was 3 years (IQR, 2.0\u0026ndash;10.5 years), and the median age at the time of genetic analysis was 5 years (IQR, 1.0\u0026ndash;7.0 years). The male:female ratio was 10.0:7.6.\u003c/p\u003e \u003cp\u003eCausative monogenic variants were identified in 12% (22 of 185) patients; \u003cem\u003eWT1\u003c/em\u003e gene variants had the highest frequency with 6 cases (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The genotype details of the 22 cases in which disease-causing variants were identified are shown in Online Resource 4, and the details of the aCGH results in the patient with suspected large deletion in \u003cem\u003eNUP85\u003c/em\u003e is shown in Online Resource 5. The proportions of detected causative variants by age group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) were 5% at 1 year of age, 12% at 2 years of age, and 21% at 3 years of age.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGenes with disease-causing variants in 185 patients with steroid-resistant nephrotic syndrome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCausative gene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eWT1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTRPC6\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCOL4A4\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNPHS1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePLCE1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSMARCAL1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eACTN4\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eARHGAP24\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eINF2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eLAMB2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNUP85\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNUP93\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCausative variant not detected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e163\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe clinical phenotypes of patients with and without variants are compared in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The groups with and without identified variants significantly differed in sex (p\u0026thinsp;=\u0026thinsp;0.0455), presence of edema at onset (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and history of complete remission (p\u0026thinsp;=\u0026thinsp;0.01). The proportion of monogenic variants was only 7% (9 of 129) in patients with edema at disease onset but 38% (9 of 24) in those without edema at onset. However, no significant difference in the age at onset, family history, extrarenal complications, history of temporary dialysis due to NS-AKI, history of CKD stage 5, and initial histopathological diagnosis was found between the group with identified variants and that without. Notably, monogenic causes were rare in patients with NS-AKI (1% [1 of 11]) or those with a history of complete remission (4% [2 of 51]).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of clinical phenotypes between patients with and without variants in the analyzed genes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical phenotype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients with \u003c/p\u003e \u003cp\u003evariants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePatients without variants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at onset (years)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2.0\u0026ndash;10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.0\u0026ndash;7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1.0\u0026ndash;7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.2948\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex, % (n/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57% (105/185)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36% (8/22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60% (97/163)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0455\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsence of edema, % (n/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16% (24/153)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50% (9/18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11% (15/135)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history, % (n/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2% (3/185)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5% (1/22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1% (2/163)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.3175\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtrarenal complications, % (n/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17% (32/185)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23% (5/22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17% (27/163)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.5541\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNS-AKI with temporary dialysis, % (n/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2% (4/185)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0% (0/22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2% (4/163)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD stage 5, % (n/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9% (17/185)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18% (4/22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8% (13/163)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.1250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete remission, % (n/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19% (35/185)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5% (1/22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21% (34/163)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial histopathologic diagnosis, % (n/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.2258\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFSGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50% (76/153)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71% (12/17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47% (64/136)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41% (62/153)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24% (4/17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43% (58/136)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2% (3/153)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6% (1/17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1% (2/136)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8% (12/153)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0% (0/17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9% (12/136)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003eMedian (interquartile range)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: CKD, chronic kidney disease; DMP, diffuse mesangial proliferation; DMS, diffuse mesangial sclerosis; FSGS, focal segmental glomerular sclerosis; MGA, minor glomerular abnormalities; NS-AKI, acute kidney injury in nephrotic syndrome.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study showed that monogenic variants in patients meeting the strict SRNS definition account for only 12%, i.e., they are less common than previously reported. The results also demonstrated that the presence of edema is an important parameter to differentiate between SRNS types with a monogenic cause and those without.\u003c/p\u003e \u003cp\u003eA recent report from the United Kingdom identified causative variants in 10% of non-syndromic SRNS, excluding congenital and infantile NS [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Although their study did not examine serum albumin levels, the patient population in their study might be similar to ours. The proportion of causative variants detected at 1 year of age was surprisingly 5% possibly due to the high incidence of INS at 1 year of age. Monogenic variants are generally detected with a high probability in congenital and infantile NS; by contrast, the probability of a monogenic cause was very low at 1 year of age in our study. In a previous large cohort from the US, the proportion of families with detected monogenic cause at 1, 2, and 3 years of age remained almost unchanged at approximately 25% [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], while in the present study, the proportion according to age at onset was higher at 3 years of age. This difference may be related to urine screening of 3-year-olds during checkups in Japan. As in our study a certain number of cases with monogenic causes were found even beyond school age, it should be considered that monogenic SRNS is not limited to a specific age group.\u003c/p\u003e \u003cp\u003eThe most important point of this study is that the detection of monogenic variants was low (7%) in typical cases with edema at onset but very high (38%) in atypical cases without edema at onset. Our group has previously reported that in a cohort of patients with severe proteinuria, significantly fewer patients with monogenic variants showed edema than those without [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], but it included several patients without hypoalbuminemia. The present study shows, for the first time, that in a cohort of only patients with hypoalbuminemia, those with monogenic variants had a significantly reduced frequency of edema.\u003c/p\u003e \u003cp\u003eIn patients with congenital analbuminemia, edema is rare, possibly due to edema-preventive mechanisms, including mitigating effects on the oncotic gradient, a reduction in the hydrostatic blood pressure gradient, and a decrease in the capillary permeability of proteins [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Moreover, patients with congenital NS can often escape after some time an albumin-dependent status despite hypoalbuminemia [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Patients with monogenic variants are less likely to present with edema probably because edema-compensatory mechanisms play a role in chronic or slowly progressive hypoalbuminemia.\u003c/p\u003e \u003cp\u003eIn addition to edema, a significant sex difference was observed between the study groups. The significantly lower detection rate of gene abnormalities in males might be due to the higher incidence of INS in male patients. Furthermore, a significant difference was observed regarding a history of complete remission. Similar to the findings of a previous report [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], our results confirmed that monogenic variants were usually not identified in cases with a history of complete remission, except for two cases with remission after cyclosporine A administration (one case each with a \u003cem\u003eWT1\u003c/em\u003e and a \u003cem\u003eCOL4A4\u003c/em\u003e variant). Remission of patients with \u003cem\u003eWT1\u003c/em\u003e variants has previously been reported [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and the case Neph573 with a \u003cem\u003eCOL4A4\u003c/em\u003e variant was considered to be coincidentally complicated by INS because \u003cem\u003eCOL4A4\u003c/em\u003e variants do not usually lead to NS.\u003c/p\u003e \u003cp\u003eAlthough no significant difference was observed in other factors, probably due to the small number of cases, some important findings should be highlighted. Monogenic variants were generally not identified in cases with NS-AKI that required temporary dialysis except for one case with a \u003cem\u003eCOL4A4\u003c/em\u003e variant (Neph573) that was considered to be coincidentally complicated by INS because \u003cem\u003eCOL4A4\u003c/em\u003e variants do not usually lead to NS and therapy led to complete remission in this patient. The reason why SRNS with monogenic variants is less likely to be accompanied by NS-AKI seems to be that NS develops slowly. In addition, the prevalence of monogenic variants was in this study not particularly high in patients with CKD stage 5. Based on these findings, some cases with CKD stage 5 include immunologically induced SRNS, providing the potential for improving kidney outcomes with more intensive immunosuppressive therapy, such as rituximab.\u003c/p\u003e \u003cp\u003eRegarding the initial histopathologic diagnosis, a high proportion (71%) of monogenic variants was found to be FSGS in this study, similar to 63\u0026ndash;74% reported in previous publications [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, an initial histopathological diagnosis of minor glomerular abnormalities should not lead to the assumption of a non-monogenic cause because minor glomerular abnormalities may change to FSGS over the course of the disease. Especially in younger patients, the histology might be evaluated in the early stage of the disease.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, not all pediatric patients diagnosed with SRNS underwent genetic analysis. The population referred to our hospital for genetic analysis might be biased towards complicated cases in which local doctors suspect monogenic causes. In practice, the proportion of monogenic causes seems to be much lower. Second, some of the cases without monogenic variants might include cases with genetic abnormalities that cannot be detected by our panels, such as deep intronic variants or genes with no established pathogenicity. Third, the timing of genetic analysis varied among patients; in some cases, genetic analysis was performed immediately after the diagnosis of SRNS, whereas in others, genetic analysis was performed after reaching CKD stage 5.\u003c/p\u003e \u003cp\u003eIn the end, even in cases where monogenic variants were identified, most patients received additional immunosuppressive therapy (steroid pulse therapy, cyclophosphamide, rituximab, cyclosporine A, tacrolimus, mizoribine, or mycophenolate mofetil) until the results of the genetic analysis were known. This suggests that determining the presence or absence of genetic abnormalities from clinical history alone is challenging.\u003c/p\u003e \u003cp\u003eAlthough it is ideal for all patients with suspected SRNS to undergo genetic analysis promptly, cases with edema at disease onset should be more aggressively considered for additional immunosuppressive treatment. Conversely, in patients without edema, additional immunosuppressive treatment should be considered more carefully. We hope that our results may help pediatric nephrologists in the decision-making for SRNS therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eWe thank all of the study patients. We also extend our sincere thanks to the participating doctors for providing clinical information. Finally, we would like to thank Editage (www.editage.jp) for English language editing.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eYIc, NS, CN, YIn, YT, CU, HK, AK, SI, TH, KI, and KN conceived the study and performed the genetic analyses; YIc and NS drafted the manuscript; and KN reviewed the manuscript. All the authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eFunding\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study received no specific grant from any funding agency in the public, commercial, or not-for-profit sections.\u003c/p\u003e\n\u003cp\u003eAvailability of data and material\u003c/p\u003e\n\u003cp\u003eData from this study can be obtained from the corresponding authors on reasonable request.\u003c/p\u003e\n\u003cp\u003eEthics approval\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll procedures involving humans were reviewed and approved by the Institutional Review Board of Kobe University Graduate School of Medicine (IRB approval number 301) and were performed in accordance with the Helsinki Declaration of 1964 and its later amendments.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent to participate/Consent to publish\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all patients or their parents before genetic analysis. Consent for publication was not required because the study was retrospective.\u003c/p\u003e\n\u003cp\u003eConflict of interest\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchlesinger ER, Sultz HA, Mosher WE, Feldman JG (1968) The nephrotic syndrome. Its incidence and implications for the community. Am J Dis Child 116:623\u0026ndash;632\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKikunaga K, Ishikura K, Terano C, Sato M, Fumiyo K, Hamasaki Y, Sakaki S, Iijima K, Norishige Y, Nakanishi K, Nakazato H, Matsuyama T, Ando T, Ito S, Honda M, Japanese Pediatric Survey Holding Information of NEphrotic syndrome (JP-SHINE) study of the Japanese Study Group of Renal Disease in Children (2017) High incidence of idiopathic nephrotic syndrome in East Asian children: a nationwide survey in Japan (JP-SHINE study). 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Kidney Int 91:937\u0026ndash;947. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.kint.2016.10.013\u003c/span\u003e\u003cspan address=\"10.1016/j.kint.2016.10.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Steroid resistant nephrotic syndrome, Monogenic variants, Edema, Acute kidney injury associated with nephrotic syndrome, Complete remission","lastPublishedDoi":"10.21203/rs.3.rs-3995397/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3995397/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIn patients with steroid-resistant nephrotic syndrome (SRNS), the presence of monogenic variants influences therapeutic strategies. Large cohort studies reported the detection of monogenic variants in approximately 30% of patients with SRNS. However, these cohorts included many patients such as asymptomatic proteinuria who did not meet the strict diagnostic criteria for pediatric nephrotic syndrome (NS). Therefore, we investigated the proportion of causative monogenic variants detected in patients who strictly met the diagnostic criteria of SRNS and explored their clinical characteristics.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe examined pediatric SRNS cases with genetic analysis conducted in our hospital. Cases satisfying all of the following criteria were included: 1. age at onset 1\u0026ndash;18 years, 2. serum albumin at onset\u0026thinsp;\u0026le;\u0026thinsp;2.5 g/dl, and 3. no complete remission after 4 weeks of steroid monotherapy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe proportion of detected monogenic variants was 12% (22/185) among all patients. The proportion was only 7% (9/129) in patients with edema at disease onset compared with 38% (9/24) in those without (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Monogenic variants were rare in patients with acute kidney injury associated with NS (1% [1/11]) or a history of complete remission (4% [2/51]).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur study revealed a monogenic cause in 12% of individuals with strictly defined SRNS, a much smaller proportion than previously reported. The presence or absence of edema at the onset was an important factor to distinguish SRNS with monogenic cause from SRNS without. Our results provide further evidence of the SRNS types attributable to monogenic causes.\u003c/p\u003e","manuscriptTitle":"In steroid-resistant nephrotic syndrome that meets the strict definition, monogenic variants less common than previously reported","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-05 16:18:22","doi":"10.21203/rs.3.rs-3995397/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2024-04-04T07:27:26+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-03-05T19:56:18+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-27T21:37:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-27T09:06:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2024-02-26T22:19:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4786a8cc-852b-4762-8724-fe40be616795","owner":[],"postedDate":"March 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-05T16:14:56+00:00","versionOfRecord":{"articleIdentity":"rs-3995397","link":"https://doi.org/10.1007/s00467-024-06468-5","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2024-08-02 15:58:06","publishedOnDateReadable":"August 2nd, 2024"},"versionCreatedAt":"2024-03-05 16:18:22","video":"","vorDoi":"10.1007/s00467-024-06468-5","vorDoiUrl":"https://doi.org/10.1007/s00467-024-06468-5","workflowStages":[]},"version":"v1","identity":"rs-3995397","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3995397","identity":"rs-3995397","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}