Protein-losing enteropathy as a new phenotype in atypical hemolytic uremic syndrome caused by CD46 gene mutation and recovery from chronic kidney failure by eculizumab treatment

Protein-losing enteropathy as a new phenotype in atypical hemolytic uremic syndrome caused by CD46 gene mutation and recovery from chronic kidney failure by eculizumab treatment | 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 Protein-losing enteropathy as a new phenotype in atypical hemolytic uremic syndrome caused by CD46 gene mutation and recovery from chronic kidney failure by eculizumab treatment Chunyan Wang, Jing Chen, Xinli Han, Manqing Sun, Xiaoyan Fang, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4019102/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Aug, 2024 Read the published version in Pediatric Nephrology → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathies. Genetic defects in complement alternative pathway have been identified in 60-70% of aHUS individuals. Eculizumab is recommended as first-line therapy. Methods : We collected clinical data of a pediatric aHUS case, who accompanied with protein-losing enteropathy (PLE). Genetic testing was performed. Related literatures of aHUS combined with PLE were reviewed. Results: A 15-year-old Chinese girl was diagnosed with aHUS at 3.7-year- old, and suffered with five episodes, she showed completely resolved with plasma treatment. Severe gastrointestinal symptoms and hypoalbuminemia presented after first episode and protein-losing enteropathy (PLE) was diagnosed. A novel homozygous CD46 variant was identified and FACS showed significantly decreased CD46 expression. She presented a recent relapse with persistent GI symptoms and headache, and progressed to chronic kidney failure, peritoneal dialysis was initiated. Eculizumab was given after 8 months of last recurrence. Surprisingly, PLE was cured, Afterwards, dialysis could be discontinued, eGFR recovered to 44.8ml/min/1.73㎡. Review of literatures indicated PLE with thrombosis was caused by CD55 variants with a mechanism of hyperactivation of complement system. We firstly reported an aHUS case with PLE caused by CD46 variants, both symptoms of PLE and aHUS improved significantly in our case and cases reported with CD55 variants treated with eculizumab, which indicates PLE as a new symptom of aHUS in our case with CD46 variants. Conclusions: Our case expands phenotype of aHUS caused by CD46 mutation, and provide evidence of efficiency of eculizumab after a long chronic kidney failure phase. atypical hemolytic uremic syndrome protein-losing enteropathy new phenotype chronic kidney failure eculizumab recovery Figures Figure 1 Figure 2 Introduction Hemolytic uremic syndrome (HUS) is a rare, life-threatening thrombotic microangiopathies (TMA), which was defined with a triad of microangiopathic hemolytic anemia, thrombocytopenia, and kidney impairment[ 1 ]. The majority of HUS cases were secondary to Escherichia coli serotypes or other bacteria that produce Shiga-like toxin (Stx)[ 2 ], atypical hemolytic uremic syndrome (aHUS) contribute only around 10 percent of all HUS cases, majority were caused by uncontrolled complement activation in the alternative pathway (AP)[ 3 ]. Genetic defects or anti-CFH antibodies in complement AP have been identified in 60–70% aHUS individuals[ 4 , 5 ] most commonly caused by genes complement factor H (CFH, approximately 25%), then membrane cofactor protein ( CD46 ; 10%), others including complement factor I (CFI, 6%), factor B (CFB, 2%), thrombomodulin (THBD, 5%), and C3 (5–10%)[ 6 , 7 ]. Anti-factor H autoantibodies contribute to 5–13% of cases, which has been reported related to deletions of CFHR1-5 [ 8 ]. The majority causative variants in AP were reported as heterozygousity and with variable penetrance, only 20–30% of patients report a family history of HUS[ 7 ]. The CD46 gene located in the Regulators of Complement Activation (RCA) gene cluster, 1q32[ 9 ], CD46, also known as membrane cofactor protein (MCP), is ubiquitously expressed on most cells (except erythrocytes), especially highly expressed on kidney cells[ 10 ], it acts as a C3b and C4b binding protein of human peripheral blood cells and kidney cells, which regulates complement activation by serving as a cofactor for the factor I-mediated cleavage of C3b and C4b that are deposited on host cells[ 11 ]. CD46 has four complement control protein (CCP) modules that house the sites for complement interaction. CD46 mutation was first identified in aHUS cases in 2003[ 12 ], to date, over 100 variants in CD46 gene have been found in aHUS cases, 95% varaints located in CCP domain. these variants can be heterozygosity or homozygousity, CD46 variants have been implied to cause reduction of CD46 expression or abnormal function with normal expression[ 7 , 13 ]. aHUS Individuals with CD46 variants showed high replase rate, but a quite favorable long-term kidney outcome[ 7 ]. Eculizumab, a humanized monoclonal antibody as the complement C5-inhibitor by blocking the cleavage of C5 into C5a and C5b and subsequently the assembly of C5b-C9, endothelial injury is prevented, has been approved the treatment of aHUS patients[ 14 ], It is highly effective for treating acute episodes and preventing the replases, and significantly improved the long-term outcome of kidney. Therefore, eculizumab is recommended as first-line and long-term therapy of aHUS individuals, but it just be aprroved in mainland, China[ 3 ]. Here, we describe an aHUS case with 6 episodes, gastrointestinal (GI) symptoms (vomiting, nausea, and intermittent abdominal pain) and hypoalbuminemia presented after the first episode and protein-losing enteropathy (PLE) was diagnosed based on endoscopy, and treated with intermittent infusion of albumin. We identified a homozygous variant in CD46 gene and further tested CD46 expression. Plasma exchange (PE) and plasma infusion (PI) were given, no remission showed in kidney function, and peritoneal dialysis were initialed. Eculizumab was started after 8 months of last recurrence episode, the long-term kidney outcome was summarized. We also reviewed the literatures of aHUS and PLE. Materials and Methods 2.1 Clinical details The study was approved by Ethics Committee of the Children’s Hospital of Fudan University. The informed consent was obtained by the subject’s guardian. All clinical data of this patient was collected and further analyzed. 2.2. Detection of CFI, CFH, anti-CFH autoantibody and sC5b-9 by ELISA The concentrations of CFI and CFH, and sC5b-9 before and after eculizumab treatment in plasma were detected by ELISA. The plasma CFH autoantibodies were also detected by ELISA. 2.3 Genetic testing Thrombotic microangiopathy (TMA) related genes were collected and targeted gene sequencing (TGS) is performed for screening the genetic cause of our individual in 2014. We further performed whole-genome sequencing (WGS) involving a sequential diagnosis strategy for individual in 2023 because the emerging new phenotypes of protein-losing enteropathy, retinal abnormality, and decreased hearing were demonstrated in our individual. Whole-exon sequencing (WES) and chromosomal microarray analysis are firstly conducted, if a disease-causing variant or copy number variations (CNVs) was detected, the genotype-phenotype correlation was re-assessed, and the final decision is made by at least two geneticists and three pediatric nephrologists. If no disease-causing variants or CNVs were identified, WGS (30X) was performed to explore the likely disease-causing variant in intron regions, chromosomal abnormality, and mitochondrial variants. All likely disease-causing variants we identified were confirmed by Sanger sequencing. Deep whole-exome sequencing (WES, 100X) was performed by Chgene (Beijing Chigene Translational Medicine Research Center Co., Ltd, 100875, Beijing) as previously described [15]. The potential copy-number variants (CNVs) identified by WES were further confirmed by chromosomal microarray analysis (CMA) and confirmed by real-time polymerase chain reaction or PCR-based gel electrophoresis. 2.4 Protein structure prediction The SWISS-MODEL server and PyMOL were applicate to modeled the effects of three-dimensional structures between WT and Tyr189Asp mutant. Adaptive Poisson-Boltzmann Solver（APBS）in ChimeraX was used to analyze the change of electrostatic potential surfaces. To understand the effect on protein stability of the Tyr189Asp mutant, free energies (∆Gs) were calculated using the DUET sever. 2.5 Flow cytometry Expression of CD46 on peripheral blood mononuclear cells (PBMC). Briefly, 5ml of peripheral blood was used to isolate the BMC using for isolation of mononuclear cells by with ficoll. Heparinized peripheral blood was incubated in the dark at room temperature for 30 min with anti-CD45 (a PBMC marker) Ab (Biolegend) and either phycoerythrin-conjugated anti-CD46 Ab (anti-CD46, clone, Biolegend), or phycoerythrin-conjugate disotype control Ab (Biolegend). BD Fortessa X20 is implied for final detection. Bloods from unaffected mother and a normal healthy volunteer were used as controls. Fluorescence was expressed as corrected mean fluorescence units (cMFI). 2.6 Literature review We further reviewed literatures relationship between aHUS, thrombosis disease and PLE by searching English databases, including Pubmed, Emabse, Ovid, Cochrane Library, and Web of Science, the keywords include “atypical hemolytic syndrome”, “aHUS”, “protein-losing enteropathy”, We also searched the Chinese publications in Chinese databases, including Wanfang, China national knowledge infrastructure. Studies published in Chinese or English language were included. Case presentation Case report A 15-year-old Chinese girl with no remarkable family history was transferred to our hospital (21/06/2022) because she was diagnosed with aHUS without any improvement with treatment of plasma infusion (PI) and plasma exchange (PE) in another hospital. She was diagnosed aHUS with severe renal involvement at 3.7 years old (4/04/2012) and completely recovered after PI and PE. She suffered from persistent gastrointestinal (GI) symptoms (nausea, vomiting, abdominal pain, diarrhea, and edema) after 1.5 years of first episode. Laboratory testing showed severe hypoalbuminemia (17-21g/L, normal range 39-54g/L) and hypogammaglobulinemia (2-2.5g/L, normal range 5,52-11.46g/L). She had no history of proteinuria, cirrhosis, or congestive heart failure. The gastrointestinal endoscope was performed and showed lymphangiectasis. She suffered from enteric perforation and partial bowel resection, and anastomosis was operated. Histopathology of intestinal resections revealed extensive lymphangiectasia, taking the above results together, protein-losing enteropathy (PLE) was diagnosed. Edema was alleviated by intermittent albumin infusion, but GI symptoms (recurrent abdominal pain, diarrhea, abdominal distension and poor appetite) were not obviously improved during the follow-up. She had previously suffered five episodes of severe anemia and thrombocytopenia with slight renal involvement. All of these episodes had been treated with plasma and resolved completely of kidney function and routine blood test. Thrombotic microangiopathy related gene panel was sequenced in 2014, and a homozygous variant in complement regulatory protein CD46 was identified ( Fig 1 ), and the clinical features of our case was consistent with CD46 related aHUS features. Recent recurrence She had irregular menstruation in 04/2022 and took drospirenone and ethinylestradiol tablets on 21/04/2022, while recurrence of aHUS was demonstrated in 24 hours. She presented the clinical triad of thrombocytopenia, anemia, and acute kidney injury. Blood film revealed occasional schistocytes. She was admitted to the intensive care unit of the local hospital, and was treated with PE, PI,and 12 times of continuous renal replacement therapy (CRRT). However, she still showed severe anemia, thrombocytopenia, hypertension, elevated serum creatine, intermittent headache, and obviously reduced urine output. She was transferred to our hospital (06/21/2022). Physical examination showed chronic malnutrition. She was in below the 3% percentile for weight (34kg) and in the 50% percentile for height (162cm). Her blood pressure is 157/118mmHg (above P99th), and 24 hours urine output is around 300-500ml/d. Laboratory tests revealed anemia (69g/L), thrombocytopenia (135*109/L), and peripheral smear demonstrated 1.5-3% schistocytes, elevated lactate dehydrogenase [LDH, 658 U/L, normal range (180-430U/L)], acute kidney injury (serum creatine, 237umol/L), hypocomplementemia [C3, 0.5g/L, normal range(0.67-1.76g/L)], and normal ADAMTS13 activity(86%). The clinical diagnosis of aHUS was made. Anti-CFH autoantibodies, serum complement H and complement I were all in normal range. Other abnormal testing results included hypoalbuminemia (17g/L, normal range 39-54g/L), and hypogammaglobulinemia [2g/L, normal range (5.52-11.46g/L)]. Urine analysis showed proteinuria 1-2+. Extra-renal manifestation assessment showed that she still had persistent GI symptoms (nausea, vomiting and anorexia). Ophthalmologic examination demonstrated exudative retinal detachment in both eyes, which disappeared after the well-controlled blood pressure by anti-hypertensive drugs. She suffered from obvious intermittent headache (persistent after the well-controlled blood pressure). Magnetic resonance imaging (MRI) of brain is normal. Gastroscopy was performed again because of persistent gastrointestinal tract symptoms and the hypoalbuminemia, which demonstrated lymphatic dilatation. PE and intermittent HD was given, the laboratory testing showed normal homological parameters and C3 level during follow-up, however, the urine output reduced to 50-100ml/d, and elevated serum creatine (316umol/L, GFR18.5ml/min/1.73㎡). Automated peritoneal dialysis was initiated on 07/19/2022. Genetic testing Taking into consideration of new emerging phenotype (PLE, hearing loss, and exudative retinal detachment), we further performed whole-genome sequence analysis, the same homozygous variant in complement regulatory protein CD46 was identified ( Fig 1a-d ), this variant segregated recessively with disease and heterozygous parents were unaffected. This variant was absent from the gnomAD database and characterized as likely pathogenic based on ACMG criteria. The Tyr189 residue is located in complement control protein modules (CCP) ( Fig 1a ). To understand the effect of the missense change in the CCP domain on protein function, a mutant model was built through SWISS-MODEL and PyMOL, compared with Tyr189, mutant Asp189 showed a destroyed protein side chain but not the main chain, electrostatic surface potential changing from neutral to negative, and the computational energy calculation showed that Tyr189Asp mutant is predicted destabilizing for the protein( Fig 1e-f ). CD55 variants in exons or intron region were not identified, which was reported to cause PLE and thrombosis events. CD46 expression PBMCs from our individual, showed almost no CD46 staining by FACS. The Y189D homozygous mutant protein is not expressed on PBMCs. PBMCs from her mother, who carries only the heterozygous Y189D mutation, had 50% reduction in CD46 median fluorescence intensity compared with PBMCs from healthy controls ( Fig 1g ) Treatment of Eculizumab No improvement in renal function and urine output showed during the next 5 months with normal homological manifestation. Eculizumab was used because of the consistent impaired kidney function after 8 months of last aHUS episode since it was just approved and available in Mainland China. Surprisingly, GI symptoms and headache dramatically improved after the first dose of eculizumab. Serum albumin reached normal, renal function and urine output started to improve after two-month treatment. Afterwards, dialysis could be discontinued and eGFR recovered to 44.8 ml/min/1.73㎡ after ten-month treatment. ( Fig 2a ), urine output had back to normal (around 1500-to 2000ml/d) after 6 months of treatment. Review of literature PLE as a new phenotype in aHUS individuals with CD46 variants We reviewed the relationship between protein-losing enteropathy and aHUS individuals carried with CD46 variants. All reported individuals presented with typical clinical triad of thrombocytopenia, anemia, and acute kidney injury. No protein-losing enteropathy has been reported as a part of clinical phenotype in individuals with CD46 variants. We further reviewed relationship between protein-losing enteropathy and thrombotic microangiopathy individuals. To date, only 19 cases from 14 families were reported. The detailed information was summarized in Table 1 . PLE was considered as a trigger of HUS in two cases, as an accompanied phenotype in one case with eight distinct episodes of HUS, while the treatment and follow-up was not mentioned in literatures. In the other 16 cases of 11 families, PLE with thrombosis disease was reported. The genetic studying of these cases indicated to be caused by variants in CD55 gene with autosomal recessive inheritance mode. In these CD55 variants cases, the medium age of onset was 16.5 months (ranged from 6 months to 10 years), the most common clinical manifestation were gastrointestinal symptoms (diarrhea, abdominal pain, vomiting, hypoalbuminemia, hypogammaglobulinemia, and edema). PLE usually presented before thrombosis event in these cases. laboratory examination indicated the possible mechanism was complement hyperactivation, which finally leads to MAC-induced gastrointestinal injury. In 16 cases, 4 out of them was treated with corticosteroids/mesalazine/azathioprine/anti-TNF and 9 out of them were given supportive care. Three individuals passed away due to multiple complications and 10 cases showed persistent PLE symptoms during follow-up. The other 3 cases who were treated with eculizumab showed fast resolved GI symptoms and thrombosis ( Table 1 ). Discussion We herein reported a pediatric aHUS case with a homozygous CD46 variant, who presented with a new phenotype of protein-losing enteropathy. The CD46 variant (p.Y189D) is located in complement control protein modules (CCP) is predicted destabilizing for the protein. The homozygous mutant results a very low (almost 0%) level CD46 expression on PBMCs surface by FACS, heterozygous variant in her mother causes reduction of 50% CD46 expression comparing with normal individual. Drug-induced aHUS recurrence (drospirenone and ethinylestradiol tablets) demonstrated in our case. Treatment showed poor response to PE and PI. PD was initiated and eculizumab was started at chronic kidney failure stage (eight months after the last episode). Surprisingly, renal function was significant improved and PD was discontinued. Our patient also demonstrated complete remission of symptoms of PLE after eculizumab treatment. To our knowledge, our case firstly demonstrates that eculizumab can recover renal function in individual with a long-term chronic kidney failure depending on dialysis treatment (over 3 months). PLE has only been reported as a accompanied symptom in one case[16]. Early-onset PLE was also reported to be caused by hyperactivation of complement, which was induced by homozygous loss of function variants in CD55 gene[17]. To date, 16 cases with PLE were reported by homozygous variants in the gene encoding the complement regulatory protein CD55/decay accelerating factor (DAF) due to primary intestinal lymphangiectasia and bowel inflammation. Immunohistochemistry of duodenal biopsies revealed in-vivo terminal complement activation (membrane attack complex/C5b-9) in submucosal arterioles. Functional studies showed CD55 is a membrane-bound complement regulator that prevents the formation of new C3 and C5 convertases and accelerates their decay. Finally, it can protect host tissues from complement-induced damage during complement activation, that can explain an increased risk of thrombotic microangiopathy in CD55-defiency individuals[18]. In vitro studies, eculizumab suppressed C5a production on patient cells. Eculizumab was also implied in PLE individuals with CD55 variants and repaid clinical and laboratory responses were observed[18]. Our patient presented with aHUS and PLE. Homozygous CD46 variant was identified. We further analyzed variants in CD55 gene and no disease-causing variant was found Previous studies showed CD46 and CD55 are both complement regulatory proteins (Cregs) with structural and functional mimics. CD46 and CD55 are key molecules that regulate activation of the complement cascade, mostly at the C3 convertase step[19], loss of function of CD46 and CD55 cause overaction of AP. We consider PLE as accompanied symptom in our case mainly supported by the rapid response to the treatment of eculizumab, the reported evidence between PLE and hyperactivation of complement AP, and the similar function of CD46 and CD55 in regulation AP system Eculizumab is recommended as first-line therapy during acute episode without PE/PI[3]. Both hematological disease activity and kidney function showed rapidly remission. Tthe efficacy of chronic kidney stage has been reported in a few cases. The most late starting time of eculizumab was 85 days after diagnosis with unknown outcome[20]. In addition, Eculizumab was started 68 days after diagnosis in another case flowing prolonged PD, in which showed near-normal kidney function[21]. Taking all these cases together (including our case), it deserves to try to start eculizumab treatment in aHUS cases even they progressed to chronic kidney failure stage. Drug-induced TMA was first described in 1971[22] and the list of drugs potentially involved as causative for TMA are rapidly increasing in recent years. The possible mechanism of drug-induced including immune-mediated reactions and dose- or duration-related toxic reactions[23]. Chemotherapeutic drugs are the most common drugs in reported cases by review the literature. The suspected causative drug should be withdrawal as long as drug-induced aHUS is suspected. Other treatment included supportive care, plasma infusion, plasma exchange, and eculizumab ( Suplemental Table 1a-b ). Prioritized treatment is still controversial, by reviewing literature, we found that, comparing with plasma treatment, eculizumab showed rapidly remission, which can be explained by the evidence of hyperactivation of complement system[23]. However, conflicting results were reported in cases with gemcitabine-induced TMA treated with eculizumab[24, 25], more cohort studies should be performed to get more evidence in drug-induced aHUS. In summary, we firstly reported a new phenotype, protein-losing enteropathy, in an aHUS case with a novel homozygous variant in CD46 gene. The functional study showed this variant cause significant reduced expression of CD46 protein. The recent episode of our individual was drug-induced and showed no improvement of PE and PI treatment. Eculizumab was started after 8 months of acute episode. Chronic kidney failure recovered and PLE was also completely recovered. Our case expanded phenotype of CD46 gene related aHUS and provided evidence of efficiency of eculizumab in chronic kidney stage of aHUS case. Declarations Declaration of interest The authors report no conflicts of interest. Funding Hong xu is funded by National Natural Science Foundation (NSFC, 82170793). Qian Shen is funded by National Natural Science Foundation (NSFC, 82070686). Chunyan Wang is funded by National Natural Science Foundation (NSFC, 8190032071). Authors’ contributions All authors participated in the diagnostic procedures. Chen jing and Chunyan Wang analyzed and interpreted the patient’s data, Chen jing, Chunyan Wang and Xinli Han performed the literature review and drafted the manuscript, Qian Shen and Xu hong designed and supervised the study. All authors have read and approved the final manuscript. References Yoshida Y, Kato H, Ikeda Y, Nangaku M (2019) Pathogenesis of Atypical Hemolytic Uremic Syndrome. J Atheroscler Thromb 26:99-110. Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361:1676-1687. 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Mazzierli T, Allegretta F, Maffini E, Allinovi M (2022) Drug-induced thrombotic microangiopathy: An updated review of causative drugs, pathophysiology, and management. Front Pharmacol 13:1088031. Al Ustwani O, Lohr J, Dy G, Levea C, Connolly G, Arora P, Iyer R (2014) Eculizumab therapy for gemcitabine induced hemolytic uremic syndrome: case series and concise review. J Gastrointest Oncol 5:E30-33. Daviet F, Rouby F, Poullin P, Moussi-Frances J, Sallee M, Burtey S, Mancini J, Duffaud F, Sabatier R, Pourroy B, Grandvuillemin A, Grange S, Fremeaux-Bacchi V, Coppo P, Micallef J, Jourde-Chiche N (2019) Thrombotic microangiopathy associated with gemcitabine use: Presentation and outcome in a national French retrospective cohort. Br J Clin Pharmacol 85:403-412. Table Table1 Protein-Losing Enteropathy (PLE) and thrombosis disease Family ID Genetic Age of onset Thrombosis Treatment of original disease Comments Outcome PMID F1 CD55 p. Glu50Alafs*12 6m None Corticosteroids, mesalazine, azathioprine, anti-TNF In vitro studies, eculizumab suppressed C5a production on patient cells PLE persists, Frequent albumin infusion 28657829 F2 CD55 p. Gly37Alafs*24 6y None Corticosteroids, mesalazine, azathioprine, anti-TNF Underwent surgery for intestinal obstruction F3 CD55 p. Gly37Alafs*24 11m None Corticoteroids, mesalazine, azathioprine. Requires intermittent albumin infusion F4 CD55 p. Cys267Ser F4-1: 1y None None PLE persists, requires intermittent albumin infusion F4-2: 2y None Noe Asymptomatic with subclinical hypoproteinemia F4-3: NA None Noe Asymptomatic, mild hypogammaglobulinemia F4-4: NA Thrombosis and Cerebral Vascular Disease. Intra-abdominal and cerebral vasculopathies Steroids and azathioprine Persistent PLE Intestinal resection to remove obstruction. Died at 33YOA of thrombosis, cardiac arrhythmia, and respiratory distress syndrome following surgical intestinal resection. F5 CD55 p. Gly37Alafs*24 F5-1: 1y Multiple thrombi in mesenteric and hepatic veins and right atrium None Resection of localized lymphangiectasis led to an intermittent recovery of PLE. Requires intermittent albumin infusion F5-2: 10y None None Hypoalbuminemia alleviated after surgical resection of lymphangiectatic segments F5-3: 15m Thrombus in the vena cava superior None Persistent PLE. Patient passed away due to multiple complications. F6 CD55 c.287-1G>A 18m Multiple thrombi in IVC, heart, and pulmonary arteries None Severe PLE, frequent albumin infusion, unstable GI disease and thrombosis. Patient passed away due to thrombotic embolism. F7 CD55 p. Glu50Alafs*12 1y None None PLE persists, requires frequent albumin infusion F8 CD55 p. Thr123Asnfs*5 5y None None PLE persists requiring monthly albumin infusion F9 Negative 63y HUS None PLE was considered as a trigger of HUS Partial remission of renal function 31364428 F10 NM 23y HUS Not mentioned PLE accompanied during eight distinct episodes of HUS Not mentioned 9274848 F11 NM 17y HUS Not mentioned PLE was considered as a trigger of HUS Not mentioned 17514630 F12 CD55 p.Leu15Serfs∗46 1y11m Acrodermatitis Sinus vein thrombosis, SVC syndrome Supportive, Eculizumab Treatment regimen was adjusted from the PNH and aHUS protocols. Difference: an intensive maintenance phase, included 2 eculizumab infusions per week for 2 weeks followed by 3 weekly doses; thereafter, patients continue to receive a maintenance infusion every 2 weeks Resolved fast 30418410 F13 CD55 p.Leu15Serfs∗46 1y3m None Supportive, Eculizumab Resolved fast, weaned off gastrostomy and parenteral dietary supplementation F14 CD55 p.Leu15Serfs∗46 2.5y SVC syndrome (recurrent), central line thrombosis Somatostatins and corticosteroids, Eculizumab Resolved fast, weaned off gastrostomy and parenteral dietary supplementation Supplementary Files SuplementalTable1ab.docx Cite Share Download PDF Status: Published Journal Publication published 03 Aug, 2024 Read the published version in Pediatric Nephrology → Version 1 posted Reviewers agreed at journal 12 Mar, 2024 Reviewers invited by journal 07 Mar, 2024 Editor assigned by journal 07 Mar, 2024 First submitted to journal 05 Mar, 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. 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University","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Chen","suffix":""},{"id":277149002,"identity":"b20c12d9-c622-4f8a-8920-9fa43003897f","order_by":2,"name":"Xinli Han","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Xinli","middleName":"","lastName":"Han","suffix":""},{"id":277149003,"identity":"208a21e1-0522-492c-afe0-11062c124310","order_by":3,"name":"Manqing Sun","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Manqing","middleName":"","lastName":"Sun","suffix":""},{"id":277149004,"identity":"412305a7-cf19-4edd-a5c7-d9a238b63946","order_by":4,"name":"Xiaoyan Fang","email":"","orcid":"","institution":"Children's Hospital of Fudan 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University","correspondingAuthor":false,"prefix":"","firstName":"Zhiqing","middleName":"","lastName":"Zhang","suffix":""},{"id":277149008,"identity":"57ed729f-439d-4280-abb4-49ed173831c8","order_by":8,"name":"Xiaoshan Tang","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoshan","middleName":"","lastName":"Tang","suffix":""},{"id":277149009,"identity":"0e9a0116-9ac1-4ea2-89ab-05c7efcb23bc","order_by":9,"name":"Jiaojiao Liu","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Jiaojiao","middleName":"","lastName":"Liu","suffix":""},{"id":277149010,"identity":"38d243fe-2fec-4313-839d-7025430fe1e7","order_by":10,"name":"Rufeng Dai","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Rufeng","middleName":"","lastName":"Dai","suffix":""},{"id":277149011,"identity":"c624a4bb-a51b-489a-a4c1-1dd411c1baf4","order_by":11,"name":"Qian Shen","email":"","orcid":"","institution":"Children's Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Shen","suffix":""},{"id":277149012,"identity":"b1f4bf36-f58a-489b-a082-15b3be9c06a8","order_by":12,"name":"Hong Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAApUlEQVRIiWNgGAWjYBACAwYGxgeMDTA2kVqYDUjWwiZBmhZziRyzyp87tiU2sDdvk2CouUNYi2XPGbPbvGduJzbwHCuTYDj2jAiHHe8xu83YBtQCtA7owsNEaDnMY1b4E6RF/g2xWoC2MPCCbeEhVsuZY8XSQC3GbTxpxRYJx4jRciN540egw2T72Q9vvPGhhggtcMAGIhJI0DAKRsEoGAWjAA8AAABMOhxFZqK+AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-7617-0872","institution":"Children's Hospital of Fudan University","correspondingAuthor":true,"prefix":"","firstName":"Hong","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2024-03-06 03:11:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4019102/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4019102/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00467-024-06451-0","type":"published","date":"2024-08-03T15:56:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":52530667,"identity":"ead440f9-e9e0-40df-9318-9a70bab8b0e0","added_by":"auto","created_at":"2024-03-12 16:21:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":189622,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWhole exome sequencing identifies recessive variant in the gene CD46\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea. \u003c/strong\u003eExon structure of \u003cem\u003eCD46 \u003c/em\u003ecDNA. Positions of start codon, stop codon, and mutated nucleotides are indicated.\u003cstrong\u003e b. \u003c/strong\u003eDomain structure of the encoded protein CD46. Arrows indicate the positions of the mutated amino acid residues in families. \u003cstrong\u003ec. \u003c/strong\u003eEvolutionary conservation amongst orthologous proteins of CD46. The mutated amino acid residues in family is indicated with an arrowhead and a red box. \u003cstrong\u003ed. \u003c/strong\u003eSanger sequencing of the identified variant in individual and her parent. \u003cstrong\u003ee. \u003c/strong\u003eThe SWISS-MODEL server and PyMOL were applicate to modeled the effects of three-dimensional structures between WT and Tyr189Asp mutant. \u003cstrong\u003ef. \u003c/strong\u003eAdaptive Poisson-Boltzmann Solver（APBS）in ChimeraX was used to analyze the change of electrostatic potential surfaces. \u003cstrong\u003eg. \u003c/strong\u003eExpression of MCP on peripheral blood mononuclear cells (PBMC) by Flow cytometry.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4019102/v1/713dd33f5be8296abd033116.png"},{"id":52527652,"identity":"9d747a1d-30af-4328-a714-7aa4b4f0d5f9","added_by":"auto","created_at":"2024-03-12 16:13:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":129121,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTreatment and long-term follow-up of our aHUS individual\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea. \u003c/strong\u003eSerum and urine output changing during follow-up. \u003cstrong\u003eb. \u003c/strong\u003eSerum albumin changing during follow-up\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4019102/v1/5c4a3f3f06c08aca4690c4fe.png"},{"id":61793884,"identity":"50d2900e-452e-418e-ae36-aba7819e4ef9","added_by":"auto","created_at":"2024-08-05 16:16:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":888761,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4019102/v1/b8e64ace-7b7c-4047-9a31-d29444c64416.pdf"},{"id":52527649,"identity":"16ee8ac6-c509-4f23-b487-6ce1e4af8d44","added_by":"auto","created_at":"2024-03-12 16:13:48","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":26926,"visible":true,"origin":"","legend":"","description":"","filename":"SuplementalTable1ab.docx","url":"https://assets-eu.researchsquare.com/files/rs-4019102/v1/2dde77c597e4f6fa3306c1b3.docx"}],"financialInterests":"","formattedTitle":"Protein-losing enteropathy as a new phenotype in atypical hemolytic uremic syndrome caused by CD46 gene mutation and recovery from chronic kidney failure by eculizumab treatment","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHemolytic uremic syndrome (HUS) is a rare, life-threatening thrombotic microangiopathies (TMA), which was defined with a triad of microangiopathic hemolytic anemia, thrombocytopenia, and kidney impairment[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The majority of HUS cases were secondary to Escherichia coli serotypes or other bacteria that produce Shiga-like toxin (Stx)[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], atypical hemolytic uremic syndrome (aHUS) contribute only around 10 percent of all HUS cases, majority were caused by uncontrolled complement activation in the alternative pathway (AP)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Genetic defects or anti-CFH antibodies in complement AP have been identified in 60\u0026ndash;70% aHUS individuals[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] most commonly caused by genes complement factor H (CFH, approximately 25%), then membrane cofactor protein (\u003cem\u003eCD46\u003c/em\u003e; 10%), others including complement factor I (CFI, 6%), factor B (CFB, 2%), thrombomodulin (THBD, 5%), and C3 (5\u0026ndash;10%)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Anti-factor H autoantibodies contribute to 5\u0026ndash;13% of cases, which has been reported related to deletions of \u003cem\u003eCFHR1-5\u003c/em\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The majority causative variants in AP were reported as heterozygousity and with variable penetrance, only 20\u0026ndash;30% of patients report a family history of HUS[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe CD46 gene located in the Regulators of Complement Activation (RCA) gene cluster, 1q32[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], CD46, also known as membrane cofactor protein (MCP), is ubiquitously expressed on most cells (except erythrocytes), especially highly expressed on kidney cells[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], it acts as a C3b and C4b binding protein of human peripheral blood cells and kidney cells, which regulates complement activation by serving as a cofactor for the factor I-mediated cleavage of C3b and C4b that are deposited on host cells[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. CD46 has four complement control protein (CCP) modules that house the sites for complement interaction. CD46 mutation was first identified in aHUS cases in 2003[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], to date, over 100 variants in CD46 gene have been found in aHUS cases, 95% varaints located in CCP domain. these variants can be heterozygosity or homozygousity, CD46 variants have been implied to cause reduction of CD46 expression or abnormal function with normal expression[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. aHUS Individuals with CD46 variants showed high replase rate, but a quite favorable long-term kidney outcome[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEculizumab, a humanized monoclonal antibody as the complement C5-inhibitor by blocking the cleavage of C5 into C5a and C5b and subsequently the assembly of C5b-C9, endothelial injury is prevented, has been approved the treatment of aHUS patients[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], It is highly effective for treating acute episodes and preventing the replases, and significantly improved the long-term outcome of kidney. Therefore, eculizumab is recommended as first-line and long-term therapy of aHUS individuals, but it just be aprroved in mainland, China[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere, we describe an aHUS case with 6 episodes, gastrointestinal (GI) symptoms (vomiting, nausea, and intermittent abdominal pain) and hypoalbuminemia presented after the first episode and protein-losing enteropathy (PLE) was diagnosed based on endoscopy, and treated with intermittent infusion of albumin. We identified a homozygous variant in CD46 gene and further tested CD46 expression. Plasma exchange (PE) and plasma infusion (PI) were given, no remission showed in kidney function, and peritoneal dialysis were initialed. Eculizumab was started after 8 months of last recurrence episode, the long-term kidney outcome was summarized. We also reviewed the literatures of aHUS and PLE.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Clinical details\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by Ethics Committee of the Children\u0026rsquo;s Hospital of Fudan University. The informed consent was obtained by the subject\u0026rsquo;s guardian. All clinical data of this patient was collected and further analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2. Detection of CFI, CFH, anti-CFH autoantibody and sC5b-9 by ELISA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe concentrations of CFI and CFH, and sC5b-9 before and after eculizumab treatment in plasma were detected by ELISA. The plasma CFH autoantibodies were also detected by ELISA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Genetic testing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThrombotic microangiopathy (TMA) related genes were collected and targeted gene sequencing (TGS) is performed for screening the genetic cause of our individual in 2014.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe further performed whole-genome sequencing (WGS) involving a sequential diagnosis strategy for individual in 2023 because the emerging new phenotypes of protein-losing enteropathy, retinal abnormality, and decreased hearing were demonstrated in our individual. Whole-exon sequencing (WES) and chromosomal microarray analysis are firstly conducted, if a disease-causing variant or copy number variations (CNVs) was detected, the genotype-phenotype correlation was re-assessed, and the final decision is made by at least two geneticists and three pediatric nephrologists. If no disease-causing variants or CNVs were identified, WGS (30X) was performed to explore the likely disease-causing variant in intron regions, chromosomal abnormality, and mitochondrial variants. All likely disease-causing variants we identified were confirmed by Sanger sequencing.\u003c/p\u003e\n\u003cp\u003eDeep whole-exome sequencing (WES, 100X) was performed by Chgene (Beijing Chigene Translational Medicine Research Center Co., Ltd, 100875, Beijing) as previously described\u0026nbsp;[15].\u003c/p\u003e\n\u003cp\u003eThe potential copy-number variants (CNVs) identified by WES were further confirmed by chromosomal microarray analysis (CMA) and confirmed by real-time polymerase chain reaction or PCR-based gel electrophoresis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Protein structure prediction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe SWISS-MODEL server and PyMOL were applicate to modeled the effects of three-dimensional structures between WT and Tyr189Asp mutant. Adaptive Poisson-Boltzmann Solver（APBS）in ChimeraX was used to analyze the change of electrostatic potential surfaces. To understand the effect on protein stability of the Tyr189Asp mutant, free energies (∆Gs) were calculated using the DUET sever.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 Flow cytometry \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExpression of CD46 on peripheral blood mononuclear cells (PBMC). Briefly, 5ml of peripheral blood was used to isolate the BMC using for isolation of mononuclear cells by with ficoll. Heparinized peripheral blood was incubated in the dark at room temperature for 30 min with anti-CD45 (a PBMC marker) Ab (Biolegend) and either phycoerythrin-conjugated anti-CD46 Ab (anti-CD46, clone, Biolegend), or phycoerythrin-conjugate disotype control Ab (Biolegend). BD Fortessa X20 is implied for final detection. Bloods from unaffected mother and a normal healthy volunteer were used as controls. Fluorescence was expressed as corrected mean fluorescence units (cMFI).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.6 Literature review\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe further\u0026nbsp;reviewed literatures relationship between aHUS, thrombosis disease and PLE by searching English databases, including Pubmed, Emabse, Ovid, Cochrane Library, and Web of Science, the keywords include \u0026ldquo;atypical hemolytic syndrome\u0026rdquo;, \u0026ldquo;aHUS\u0026rdquo;, \u0026ldquo;protein-losing\u0026nbsp;enteropathy\u0026rdquo;, We also searched the Chinese publications in Chinese databases, including Wanfang, China national knowledge infrastructure. Studies published in Chinese or English language were included.\u0026nbsp;\u003c/p\u003e"},{"header":"Case presentation ","content":"\u003cp\u003e\u003cstrong\u003eCase report\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 15-year-old Chinese girl with no remarkable family history was transferred to our hospital (21/06/2022) because she was diagnosed with aHUS without any improvement with treatment of plasma infusion (PI) and plasma exchange (PE) in another hospital.\u003c/p\u003e\n\u003cp\u003eShe was diagnosed aHUS with severe renal involvement at 3.7 years old (4/04/2012) and completely recovered after PI and PE. She suffered from persistent gastrointestinal (GI) symptoms (nausea, vomiting, abdominal pain, diarrhea, and edema) after 1.5 years of first episode. Laboratory testing showed severe hypoalbuminemia (17-21g/L, normal range 39-54g/L) and hypogammaglobulinemia (2-2.5g/L, normal range 5,52-11.46g/L). She had no history of proteinuria, cirrhosis, or congestive heart failure. The gastrointestinal endoscope was performed and showed lymphangiectasis. She suffered from enteric perforation and partial bowel resection, and anastomosis was operated. Histopathology of intestinal resections revealed extensive lymphangiectasia, taking the above results together, protein-losing enteropathy (PLE) was diagnosed. Edema was alleviated by intermittent albumin infusion, but GI symptoms (recurrent abdominal pain, diarrhea, abdominal distension and poor appetite) were not obviously improved during the follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eShe had previously suffered five episodes of severe anemia and thrombocytopenia with slight renal involvement. All of these episodes had been treated with plasma and resolved completely of kidney function and routine blood test. Thrombotic microangiopathy related gene panel was sequenced in 2014, and a homozygous variant in complement regulatory protein CD46 was identified (\u003cstrong\u003eFig 1\u003c/strong\u003e), and the clinical features of our case was consistent with CD46 related aHUS features.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecent recurrence\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShe had irregular menstruation in 04/2022 and took drospirenone and ethinylestradiol tablets on 21/04/2022, while recurrence of aHUS was demonstrated in 24 hours. She presented the clinical triad of thrombocytopenia, anemia, and acute kidney injury. Blood film revealed occasional schistocytes. She was admitted to the intensive care unit of the local hospital, and was treated with PE, PI,and 12 times of continuous renal replacement therapy (CRRT). However, she still showed severe anemia, thrombocytopenia, hypertension, elevated serum creatine, intermittent headache, and obviously reduced urine output. She was transferred to our hospital (06/21/2022).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePhysical examination showed chronic malnutrition. She was in below the 3% percentile for weight (34kg) and in the 50% percentile for height (162cm). Her blood pressure is 157/118mmHg (above P99th), and 24 hours urine output is around 300-500ml/d. Laboratory tests revealed anemia (69g/L), thrombocytopenia (135*109/L), and peripheral smear demonstrated 1.5-3% schistocytes, elevated lactate dehydrogenase [LDH, 658 U/L, normal range (180-430U/L)], acute kidney injury (serum creatine, 237umol/L), hypocomplementemia [C3, 0.5g/L, normal range(0.67-1.76g/L)], and normal ADAMTS13 activity(86%). The clinical diagnosis of aHUS was made. Anti-CFH autoantibodies, serum complement H and complement I were all in normal range.\u003c/p\u003e\n\u003cp\u003eOther abnormal testing results included hypoalbuminemia (17g/L, normal range 39-54g/L), and hypogammaglobulinemia [2g/L, normal range (5.52-11.46g/L)]. Urine analysis showed proteinuria 1-2+. Extra-renal manifestation assessment showed that she still had persistent GI symptoms (nausea, vomiting and anorexia). Ophthalmologic examination demonstrated exudative retinal detachment in both eyes, which disappeared after the well-controlled blood pressure by anti-hypertensive drugs. She suffered from obvious intermittent headache (persistent after the well-controlled blood pressure). Magnetic resonance imaging (MRI) of brain is normal. Gastroscopy was performed again because of persistent gastrointestinal tract symptoms and the hypoalbuminemia, which demonstrated lymphatic dilatation. PE and intermittent HD was given, the laboratory testing showed normal homological parameters and C3 level during follow-up, however, the urine output reduced to 50-100ml/d, and elevated serum creatine (316umol/L, GFR18.5ml/min/1.73㎡). Automated peritoneal dialysis was initiated on 07/19/2022.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenetic testing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTaking into consideration of new emerging phenotype (PLE, hearing loss, and exudative retinal detachment), we further performed whole-genome sequence analysis, the same homozygous variant in complement regulatory protein CD46 was identified (\u003cstrong\u003eFig 1a-d\u003c/strong\u003e), this variant segregated recessively with disease and heterozygous parents were unaffected. This variant was absent from the gnomAD database and characterized as likely pathogenic based on ACMG criteria. The Tyr189 residue is located in complement control protein modules (CCP) (\u003cstrong\u003eFig 1a\u003c/strong\u003e). To understand the effect of the missense change in the CCP domain on protein function, a mutant model was built through SWISS-MODEL and PyMOL, compared with Tyr189, mutant Asp189 showed a destroyed protein side chain but not the main chain, electrostatic surface potential changing from neutral to negative, and the computational energy calculation showed that Tyr189Asp mutant is predicted destabilizing for the protein(\u003ca href=\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895874/figure/fig4/\" target=\"figure\"\u003e\u003cstrong\u003eFig 1e-f\u003c/strong\u003e\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCD55 variants in exons or intron region were not identified, which was reported to cause PLE and thrombosis events.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCD46 expression\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePBMCs from our individual, showed almost no CD46 staining by FACS. The Y189D homozygous mutant protein is not expressed on PBMCs. PBMCs from her mother, who carries only the heterozygous Y189D mutation, had 50% reduction in CD46 median fluorescence intensity compared with PBMCs from healthy controls (\u003ca href=\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895874/figure/fig4/\" target=\"figure\"\u003e\u003cstrong\u003eFig 1g\u003c/strong\u003e\u003c/a\u003e)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment of Eculizumab \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo improvement in renal function and urine output showed during the next 5 months with normal homological manifestation. Eculizumab was used because of the consistent impaired kidney function after 8 months of last aHUS episode since it was just approved and available in Mainland China. Surprisingly, GI symptoms and headache dramatically improved after the first dose of eculizumab. Serum albumin reached normal, renal function and urine output started to improve after two-month treatment. Afterwards, dialysis could be discontinued and eGFR recovered to 44.8 ml/min/1.73㎡\u0026nbsp;after ten-month treatment. (\u003cstrong\u003eFig 2a\u003c/strong\u003e), urine output had back to normal (around 1500-to 2000ml/d) after 6 months of treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReview of literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePLE as a new phenotype in aHUS individuals with CD46 variants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe reviewed the relationship between protein-losing enteropathy and aHUS individuals carried with CD46 variants. All reported individuals presented with typical clinical triad of thrombocytopenia, anemia, and acute kidney injury. No protein-losing enteropathy has been reported as a part of clinical phenotype in individuals with CD46 variants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe further reviewed relationship between protein-losing enteropathy and thrombotic microangiopathy individuals. To date, only 19 cases from 14 families were reported. The detailed information was summarized in \u003cstrong\u003eTable 1\u003c/strong\u003e. PLE was considered as a trigger of HUS in two cases, as an accompanied phenotype in one case with eight distinct episodes of HUS, while the treatment and follow-up was not mentioned in literatures. In the other 16 cases of 11 families, PLE with thrombosis disease was reported. The genetic studying of these cases indicated to be caused by variants in CD55 gene with autosomal recessive inheritance mode. In these CD55 variants cases, the medium age of onset was 16.5 months (ranged from 6 months to 10 years), the most common clinical manifestation were gastrointestinal symptoms (diarrhea, abdominal pain, vomiting, hypoalbuminemia, hypogammaglobulinemia, and edema). \u0026nbsp;PLE usually presented before thrombosis event in these cases. laboratory examination indicated the possible mechanism was complement hyperactivation, which finally leads to MAC-induced gastrointestinal injury. In 16 cases, 4 out of them was treated with corticosteroids/mesalazine/azathioprine/anti-TNF and 9 out of them were given supportive care. Three individuals passed away due to multiple complications and 10 cases showed persistent PLE symptoms during follow-up. The other 3 cases who were treated with eculizumab showed fast resolved GI symptoms and thrombosis (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion ","content":"\u003cp\u003eWe herein reported a pediatric aHUS case with a homozygous CD46 variant, who presented with a new phenotype of protein-losing enteropathy. The CD46 variant (p.Y189D) is located in complement control protein modules (CCP) is predicted destabilizing for the protein. The homozygous mutant results a very low (almost 0%) level CD46 expression on PBMCs surface by FACS, heterozygous variant in her mother causes reduction of 50% CD46 expression comparing with normal individual. Drug-induced aHUS recurrence (drospirenone and ethinylestradiol tablets) demonstrated in our case. Treatment showed poor response to PE and PI. PD was initiated and eculizumab was started at chronic kidney failure stage (eight months after the last episode). Surprisingly, renal function was significant improved and PD was discontinued. Our patient also demonstrated complete remission of symptoms of PLE after eculizumab treatment. To our knowledge, our case firstly demonstrates that eculizumab can recover renal function in individual with a long-term chronic kidney failure depending on dialysis treatment (over 3 months). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePLE has only been reported as a accompanied symptom in one case[16]. Early-onset PLE was also reported to be caused by hyperactivation of complement, which was induced by homozygous loss of function variants in CD55 gene[17]. To date, 16 cases with PLE were reported by homozygous variants in the gene encoding the complement regulatory protein CD55/decay accelerating factor (DAF) due to primary intestinal lymphangiectasia and bowel inflammation. Immunohistochemistry of duodenal biopsies revealed in-vivo terminal complement activation (membrane attack complex/C5b-9) in submucosal arterioles. Functional studies showed CD55 is a membrane-bound complement regulator that prevents the formation of new C3 and C5 convertases and accelerates their decay. Finally, it can protect host tissues from complement-induced damage during complement activation, that can explain an increased risk of thrombotic microangiopathy in CD55-defiency individuals[18]. In vitro studies, eculizumab suppressed C5a production on patient cells. Eculizumab was also implied in PLE individuals with CD55 variants and repaid clinical and laboratory responses were observed[18].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur patient presented with aHUS and PLE. Homozygous CD46 variant was identified. We further analyzed variants in CD55 gene and no disease-causing variant was found Previous studies showed CD46 and CD55 are both complement regulatory proteins (Cregs) with structural and functional mimics. CD46 and CD55 are key molecules that regulate activation of the complement cascade, mostly at the C3 convertase step[19], loss of function of CD46 and CD55 cause overaction of AP. We consider PLE as accompanied symptom in our case mainly supported by the rapid response to the treatment of eculizumab, the reported evidence between PLE and hyperactivation of complement AP, and the similar function of CD46 and CD55 in regulation AP system\u003c/p\u003e\n\u003cp\u003eEculizumab is recommended as first-line therapy during acute episode without PE/PI[3]. Both hematological disease activity and kidney function showed rapidly remission. Tthe efficacy of chronic kidney stage has been reported in a few cases. The most late starting time of eculizumab was 85 days after diagnosis with unknown outcome[20]. In addition, Eculizumab was started 68 days after diagnosis in another case flowing prolonged PD, in which showed near-normal kidney function[21]. Taking all these cases together (including our case), it deserves to try to start eculizumab treatment in aHUS cases even they progressed to chronic kidney failure stage.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDrug-induced TMA was first described in 1971[22]\u0026nbsp;and the list of drugs potentially involved as causative for TMA are rapidly increasing in recent years. The possible mechanism of drug-induced including immune-mediated reactions and dose- or duration-related toxic reactions[23]. Chemotherapeutic drugs are the most common drugs in reported cases by review the literature.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe suspected causative drug should be withdrawal as long as drug-induced aHUS is suspected. Other treatment included supportive care, plasma infusion, plasma exchange, and eculizumab (\u003cstrong\u003eSuplemental Table 1a-b\u003c/strong\u003e). Prioritized treatment is still controversial, by reviewing literature, we found that, comparing with plasma treatment, eculizumab showed rapidly remission, which can be explained by the evidence of hyperactivation of complement system[23]. However, conflicting results were reported in cases with gemcitabine-induced TMA treated with eculizumab[24, 25], more cohort studies should be performed to get more evidence in drug-induced aHUS.\u003c/p\u003e\n\u003cp\u003eIn summary, we firstly reported a new phenotype, protein-losing enteropathy, in an aHUS case with a novel homozygous variant in CD46 gene. The functional study showed this variant cause significant reduced expression of CD46 protein. The recent episode of our individual was drug-induced and showed no improvement of PE and PI treatment. Eculizumab was started after 8 months of acute episode. Chronic kidney failure recovered and PLE was also completely recovered. Our case expanded phenotype of CD46 gene related aHUS and provided evidence of efficiency of eculizumab in chronic kidney stage of aHUS case.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of interest\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The authors report no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHong xu is funded by National Natural Science Foundation (NSFC, 82170793). Qian Shen is funded by National Natural Science Foundation (NSFC, 82070686). Chunyan Wang is funded by National Natural Science Foundation (NSFC, 8190032071).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors participated in the diagnostic procedures. Chen jing and Chunyan Wang analyzed and interpreted the patient’s data, Chen jing, Chunyan Wang and Xinli Han performed the literature review and drafted the manuscript, Qian Shen and Xu hong designed and supervised the study. All authors have read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eYoshida Y, Kato H, Ikeda Y, Nangaku M (2019) Pathogenesis of Atypical Hemolytic Uremic Syndrome. J Atheroscler Thromb 26:99-110.\u003c/li\u003e\n \u003cli\u003eNoris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. 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Pediatr Nephrol 34:269-281.\u003c/li\u003e\n \u003cli\u003eGoodship TH, Cook HT, Fakhouri F, Fervenza FC, Fremeaux-Bacchi V, Kavanagh D, Nester CM, Noris M, Pickering MC, Rodriguez de Cordoba S, Roumenina LT, Sethi S, Smith RJ, Conference P (2017) Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a \u0026quot;Kidney Disease: Improving Global Outcomes\u0026quot; (KDIGO) Controversies Conference. Kidney Int 91:539-551.\u003c/li\u003e\n \u003cli\u003eFremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaime F, Dragon-Durey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S, Niaudet P, Deschenes G, Lebranchu Y, Zuber J, Loirat C (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8:554-562.\u003c/li\u003e\n \u003cli\u003eDurey MA, Sinha A, Togarsimalemath SK, Bagga A (2016) Anti-complement-factor H-associated glomerulopathies. 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Proc Natl Acad Sci U S A 100:12966-12971.\u003c/li\u003e\n \u003cli\u003eEsparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L, Lopez-Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S (2005) Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet 14:703-712.\u003c/li\u003e\n \u003cli\u003eWijnsma KL, Duineveld C, Wetzels JFM, van de Kar N (2019) Correction to: Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use. Pediatr Nephrol 34:741-742.\u003c/li\u003e\n \u003cli\u003eRao J, Liu X, Mao J, Tang X, Shen Q, Li G, Sun L, Bi Y, Wang X, Qian Y, Wu B, Wang H, Zhou W, Ma D, Zheng B, Shen Y, Chen Z, Luan J, Wang X, Wang M, Dang X, Wang Y, Wu Y, Hou L, Sun S, Li Q, Liu X, Bai H, Yang Y, Shao X, Li Y, Zheng S, Han M, Liu C, Cao G, Zhao L, Qiu S, Dong Y, Zhu Y, Wang F, Zhang D, Li Y, Zhao L, Yang C, Luo X, Chen L, Jiang X, Zhang A, Xu H, for \u0026quot;Internet Plus\u0026quot; Nephrology Alliance of National Center for Children\u0026apos;s C (2019) Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system. Clin Genet 96:402-410.\u003c/li\u003e\n \u003cli\u003eBogdanovic R, Stankovic I, Jojic N, Ognjanovic M, Zlatkovic M, Popovic O, Nikolic V (1997) Recurrent hemolytic uremic syndrome with hypocomplementemia and intestinal lymphangiectasia. Nephron 76:481-484.\u003c/li\u003e\n \u003cli\u003eOzen A, Comrie WA, Ardy RC, Dominguez Conde C, Dalgic B, Beser OF, Morawski AR, Karakoc-Aydiner E, Tutar E, Baris S, Ozcay F, Serwas NK, Zhang Y, Matthews HF, Pittaluga S, Folio LR, Unlusoy Aksu A, McElwee JJ, Krolo A, Kiykim A, Baris Z, Gulsan M, Ogulur I, Snapper SB, Houwen RHJ, Leavis HL, Ertem D, Kain R, Sari S, Erkan T, Su HC, Boztug K, Lenardo MJ (2017) CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 377:52-61.\u003c/li\u003e\n \u003cli\u003eKurolap A, Eshach Adiv O, Hershkovitz T, Tabib A, Karbian N, Paperna T, Mory A, Vachyan A, Slijper N, Steinberg R, Zohar Y, Mevorach D, Baris Feldman H (2019) Eculizumab Is Safe and Effective as a Long-term Treatment for Protein-losing Enteropathy Due to CD55 Deficiency. J Pediatr Gastroenterol Nutr 68:325-333.\u003c/li\u003e\n \u003cli\u003eMishra N, Mohata M, Narang R, Lakshmy R, Hazarika A, Pandey RM, Das N, Luthra K (2019) Altered Expression of Complement Regulatory Proteins CD35, CD46, CD55, and CD59 on Leukocyte Subsets in Individuals Suffering From Coronary Artery Disease. Front Immunol 10:2072.\u003c/li\u003e\n \u003cli\u003eCao M, Leite BN, Ferreiro T, Calvo M, Fernandez C, Alonso A, Rodriguez A, Salvador P, Seijo R, Pita S, Arjona E, Rodriguez de Cordoba S, Valdes Canedo F (2018) Eculizumab Modifies Outcomes in Adults with Atypical Hemolytic Uremic Syndrome with Acute Kidney Injury. Am J Nephrol 48:225-233.\u003c/li\u003e\n \u003cli\u003ePovey H, Vundru R, Junglee N, Jibani M (2014) Renal recovery with eculizumab in atypical hemolytic uremic syndrome following prolonged dialysis. Clin Nephrol 82:326-331.\u003c/li\u003e\n \u003cli\u003eLiu K, Mittelman A, Sproul EE, Elias EG (1971) Renal toxicity in man treated with mitomycin C. Cancer 28:1314-1320.\u003c/li\u003e\n \u003cli\u003eMazzierli T, Allegretta F, Maffini E, Allinovi M (2022) Drug-induced thrombotic microangiopathy: An updated review of causative drugs, pathophysiology, and management. Front Pharmacol 13:1088031.\u003c/li\u003e\n \u003cli\u003eAl Ustwani O, Lohr J, Dy G, Levea C, Connolly G, Arora P, Iyer R (2014) Eculizumab therapy for gemcitabine induced hemolytic uremic syndrome: case series and concise review. J Gastrointest Oncol 5:E30-33.\u003c/li\u003e\n \u003cli\u003eDaviet F, Rouby F, Poullin P, Moussi-Frances J, Sallee M, Burtey S, Mancini J, Duffaud F, Sabatier R, Pourroy B, Grandvuillemin A, Grange S, Fremeaux-Bacchi V, Coppo P, Micallef J, Jourde-Chiche N (2019) Thrombotic microangiopathy associated with gemcitabine use: Presentation and outcome in a national French retrospective cohort. Br J Clin Pharmacol 85:403-412.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable1\u003c/strong\u003e \u003cstrong\u003eProtein-Losing Enteropathy (PLE) and thrombosis disease\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"930\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.774193548387097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFamily ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.290322580645162%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGenetic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge of onset\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.10752688172043%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eThrombosis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.225806451612904%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment of original disease\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.043010752688172%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eComments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.731182795698924%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.795698924731182%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePMID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.774193548387097%\"\u003e\n \u003cp\u003eF1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.290322580645162%\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep. Glu50Alafs*12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003e6m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.10752688172043%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.225806451612904%\"\u003e\n \u003cp\u003eCorticosteroids, mesalazine, azathioprine, anti-TNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.043010752688172%\" rowspan=\"13\"\u003e\n \u003cp\u003eIn vitro studies, eculizumab suppressed C5a production on patient cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.731182795698924%\"\u003e\n \u003cp\u003ePLE persists, Frequent albumin infusion\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.795698924731182%\" rowspan=\"13\"\u003e\n \u003cp\u003e28657829\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.012875536480687%\"\u003e\n \u003cp\u003eF2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.021459227467812%\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep. Gly37Alafs*24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.017167381974248%\"\u003e\n \u003cp\u003e6y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.447782546494993%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.59656652360515%\"\u003e\n \u003cp\u003eCorticosteroids, mesalazine, azathioprine, anti-TNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.904148783977114%\"\u003e\n \u003cp\u003eUnderwent surgery for intestinal obstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.012875536480687%\"\u003e\n \u003cp\u003eF3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.021459227467812%\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep. Gly37Alafs*24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.017167381974248%\"\u003e\n \u003cp\u003e11m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.447782546494993%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.59656652360515%\"\u003e\n \u003cp\u003eCorticoteroids, mesalazine, azathioprine.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.904148783977114%\"\u003e\n \u003cp\u003eRequires intermittent albumin infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.012875536480687%\" rowspan=\"4\"\u003e\n \u003cp\u003eF4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.021459227467812%\" rowspan=\"4\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep. Cys267Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.017167381974248%\"\u003e\n \u003cp\u003eF4-1: 1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.447782546494993%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.59656652360515%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.904148783977114%\"\u003e\n \u003cp\u003ePLE persists, requires intermittent albumin infusion\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.819209039548022%\"\u003e\n \u003cp\u003eF4-2: 2y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.702448210922785%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.163841807909606%\"\u003e\n \u003cp\u003eNoe\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.314500941619585%\"\u003e\n \u003cp\u003eAsymptomatic with subclinical hypoproteinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.819209039548022%\"\u003e\n \u003cp\u003eF4-3: NA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.702448210922785%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.163841807909606%\"\u003e\n \u003cp\u003eNoe\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.314500941619585%\"\u003e\n \u003cp\u003eAsymptomatic, mild hypogammaglobulinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.819209039548022%\"\u003e\n \u003cp\u003eF4-4: NA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.702448210922785%\" valign=\"top\"\u003e\n \u003cp\u003eThrombosis and Cerebral Vascular Disease. Intra-abdominal and cerebral vasculopathies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.163841807909606%\"\u003e\n \u003cp\u003eSteroids and azathioprine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.314500941619585%\"\u003e\n \u003cp\u003ePersistent PLE\u003c/p\u003e\n \u003cp\u003eIntestinal resection to remove obstruction. Died at 33YOA of thrombosis, cardiac arrhythmia, and respiratory distress syndrome following surgical intestinal resection.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.012875536480687%\" rowspan=\"3\"\u003e\n \u003cp\u003eF5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.021459227467812%\" rowspan=\"3\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep. Gly37Alafs*24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.017167381974248%\"\u003e\n \u003cp\u003eF5-1: 1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.447782546494993%\" valign=\"top\"\u003e\n \u003cp\u003eMultiple thrombi in mesenteric and hepatic veins and right atrium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.59656652360515%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.904148783977114%\"\u003e\n \u003cp\u003eResection of localized lymphangiectasis led to an intermittent recovery of PLE.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRequires intermittent albumin infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.819209039548022%\"\u003e\n \u003cp\u003eF5-2: 10y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.702448210922785%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.163841807909606%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.314500941619585%\"\u003e\n \u003cp\u003eHypoalbuminemia alleviated after surgical resection of lymphangiectatic segments\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.819209039548022%\"\u003e\n \u003cp\u003eF5-3: 15m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.702448210922785%\" valign=\"top\"\u003e\n \u003cp\u003eThrombus in the vena cava superior\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.163841807909606%\"\u003e\n \u003cp\u003eNone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.314500941619585%\"\u003e\n \u003cp\u003ePersistent PLE. Patient passed away due to multiple complications.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.012875536480687%\"\u003e\n \u003cp\u003eF6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.021459227467812%\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ec.287-1G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.017167381974248%\"\u003e\n \u003cp\u003e18m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.447782546494993%\" valign=\"top\"\u003e\n \u003cp\u003eMultiple thrombi in IVC, heart, and pulmonary arteries\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.59656652360515%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.904148783977114%\"\u003e\n \u003cp\u003eSevere PLE, frequent albumin infusion, unstable GI disease and thrombosis. Patient passed away due to thrombotic embolism.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.012875536480687%\"\u003e\n \u003cp\u003eF7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.021459227467812%\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep. Glu50Alafs*12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.017167381974248%\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.447782546494993%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.59656652360515%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.904148783977114%\"\u003e\n \u003cp\u003ePLE persists, requires frequent albumin infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.012875536480687%\"\u003e\n \u003cp\u003eF8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.021459227467812%\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep. Thr123Asnfs*5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.017167381974248%\"\u003e\n \u003cp\u003e5y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.447782546494993%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.59656652360515%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.904148783977114%\"\u003e\n \u003cp\u003ePLE persists requiring monthly albumin infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.774193548387097%\"\u003e\n \u003cp\u003eF9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.290322580645162%\"\u003e\n \u003cp\u003eNegative\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003e63y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.10752688172043%\" valign=\"top\"\u003e\n \u003cp\u003eHUS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.225806451612904%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.043010752688172%\"\u003e\n \u003cp\u003ePLE was considered as a trigger of HUS\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.731182795698924%\"\u003e\n \u003cp\u003ePartial remission of renal function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.795698924731182%\"\u003e\n \u003cp\u003e31364428\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.774193548387097%\"\u003e\n \u003cp\u003eF10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.290322580645162%\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003e23y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.10752688172043%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eHUS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.225806451612904%\"\u003e\n \u003cp\u003eNot mentioned\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.043010752688172%\"\u003e\n \u003cp\u003ePLE accompanied during eight distinct episodes of HUS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.731182795698924%\"\u003e\n \u003cp\u003eNot mentioned\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.795698924731182%\"\u003e\n \u003cp\u003e9274848\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.774193548387097%\"\u003e\n \u003cp\u003eF11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.290322580645162%\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003e17y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.10752688172043%\" valign=\"top\"\u003e\n \u003cp\u003eHUS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.225806451612904%\"\u003e\n \u003cp\u003eNot mentioned\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.043010752688172%\"\u003e\n \u003cp\u003ePLE was considered as a trigger of HUS\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.731182795698924%\"\u003e\n \u003cp\u003eNot mentioned\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.795698924731182%\"\u003e\n \u003cp\u003e17514630\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.774193548387097%\"\u003e\n \u003cp\u003eF12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.290322580645162%\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep.Leu15Serfs\u0026lowast;46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003e1y11m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.10752688172043%\" valign=\"top\"\u003e\n \u003cp\u003eAcrodermatitis\u003c/p\u003e\n \u003cp\u003eSinus vein thrombosis, SVC syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.225806451612904%\"\u003e\n \u003cp\u003eSupportive,\u003c/p\u003e\n \u003cp\u003eEculizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.043010752688172%\" rowspan=\"3\"\u003e\n \u003cp\u003eTreatment regimen was adjusted from the PNH and aHUS protocols.\u003c/p\u003e\n \u003cp\u003eDifference: an intensive maintenance phase, included 2 eculizumab infusions per week for 2 weeks followed by 3 weekly doses; thereafter, patients continue to receive a maintenance infusion every 2 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.731182795698924%\"\u003e\n \u003cp\u003eResolved fast\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.795698924731182%\" rowspan=\"3\"\u003e\n \u003cp\u003e30418410\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.012875536480687%\"\u003e\n \u003cp\u003eF13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.021459227467812%\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep.Leu15Serfs\u0026lowast;46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.017167381974248%\"\u003e\n \u003cp\u003e1y3m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.447782546494993%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.59656652360515%\"\u003e\n \u003cp\u003eSupportive, Eculizumab\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.904148783977114%\"\u003e\n \u003cp\u003eResolved fast, weaned off gastrostomy and parenteral dietary supplementation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.012875536480687%\"\u003e\n \u003cp\u003eF14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.021459227467812%\"\u003e\n \u003cp\u003eCD55\u003c/p\u003e\n \u003cp\u003ep.Leu15Serfs\u0026lowast;46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.017167381974248%\"\u003e\n \u003cp\u003e2.5y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.447782546494993%\" valign=\"top\"\u003e\n \u003cp\u003eSVC syndrome (recurrent), central line thrombosis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.59656652360515%\"\u003e\n \u003cp\u003eSomatostatins and corticosteroids, Eculizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.904148783977114%\"\u003e\n \u003cp\u003eResolved fast, weaned off gastrostomy and parenteral dietary supplementation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\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":"atypical hemolytic uremic syndrome, protein-losing enteropathy, new phenotype, chronic kidney failure, eculizumab, recovery ","lastPublishedDoi":"10.21203/rs.3.rs-4019102/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4019102/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eAtypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathies. Genetic defects in complement alternative pathway have been identified in 60-70% of aHUS individuals. Eculizumab is recommended as first-line therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We collected clinical data of a pediatric aHUS case, who accompanied with protein-losing enteropathy (PLE). Genetic testing was performed. Related literatures of aHUS combined with PLE were reviewed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A 15-year-old Chinese girl was diagnosed with aHUS at 3.7-year- old, and suffered with five episodes, she showed completely resolved with plasma treatment. Severe gastrointestinal symptoms and hypoalbuminemia presented after first episode and protein-losing enteropathy (PLE) was diagnosed. A novel homozygous CD46 variant was identified and FACS showed significantly decreased CD46 expression. She presented a recent relapse with persistent GI symptoms and headache, and progressed to\u003cstrong\u003e \u003c/strong\u003echronic kidney failure, peritoneal dialysis was initiated. Eculizumab was given after 8 months of last recurrence. Surprisingly, PLE was cured, Afterwards, dialysis could be discontinued, eGFR recovered to 44.8ml/min/1.73㎡.\u003c/p\u003e\n\u003cp\u003eReview of literatures indicated PLE with thrombosis was caused by CD55 variants with a mechanism of hyperactivation of complement system. We firstly reported an aHUS case with PLE caused by CD46 variants, both symptoms of PLE and aHUS improved significantly in our case and cases reported with CD55 variants treated with eculizumab, which indicates PLE as a new symptom of aHUS in our case with CD46 variants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Our case expands phenotype of aHUS caused by CD46 mutation, and provide evidence of efficiency of eculizumab after a long chronic kidney failure phase.\u003c/p\u003e","manuscriptTitle":"Protein-losing enteropathy as a new phenotype in atypical hemolytic uremic syndrome caused by CD46 gene mutation and recovery from chronic kidney failure by eculizumab treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-12 16:13:43","doi":"10.21203/rs.3.rs-4019102/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-03-12T07:06:48+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-07T22:10:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-07T19:55:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2024-03-05T22:11:10+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":"254c55e6-60c4-4a8f-9f28-f038c9e238d2","owner":[],"postedDate":"March 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-05T16:08:18+00:00","versionOfRecord":{"articleIdentity":"rs-4019102","link":"https://doi.org/10.1007/s00467-024-06451-0","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2024-08-03 15:56:53","publishedOnDateReadable":"August 3rd, 2024"},"versionCreatedAt":"2024-03-12 16:13:43","video":"","vorDoi":"10.1007/s00467-024-06451-0","vorDoiUrl":"https://doi.org/10.1007/s00467-024-06451-0","workflowStages":[]},"version":"v1","identity":"rs-4019102","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4019102","identity":"rs-4019102","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}