Iptacopan alleviates serum sickness nephritis after anti- human thymocyte immunoglobulin : One case report and literature review

Iptacopan alleviates serum sickness nephritis after anti- human thymocyte immunoglobulin : One case report and literature review | 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 Case Report Iptacopan alleviates serum sickness nephritis after anti- human thymocyte immunoglobulin : One case report and literature review Ming-lu Xu, Cheng-tao Qin, Yue-min Gong, Ya-wen Zhang, Guang-sheng He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7366407/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Anti-thymocyte globulin (ATG) is used for the treatment for severe aplastic anemia (SAA). Since ATG is a heterologous serum, it can cause serum sickness nephritis. This article reported one case of SAA comorbidited with hypothyroidism, in whom serum sickness nephritis occurred during glucocorticoids tapering rapidly. The renal injury was recovery after being administrating with iptacopan. It was suggested that proximal complement alternative pathway inhibitors had potential application value in ATG-related serum sickness nephritis and provided a new strategy for optimizing individualized therapy. Severe aplastic anemia Serum sickness nephritis Iptacopan Complement Figures Figure 1 Introduction Anti-thymocyte globulin (ATG) serves as a first-line therapeutic agent for severe aplastic anemia (SAA) patients ineligible for allogeneic hematopoietic stem cell transplantation. However, the use of it is complicated by the potential induction of serum sickness and serum sickness nephritis [ 1 – 5 ] , presenting significant clinical challenges. Glucocorticoids are generally used for prevention or treatment of serum sickness in clinical practice. In patients with hypothyroidism, thyroid hormone deficiency exacerbates immune dysregulation and concurrently restricts the use of glucocorticoids [ 6 – 7 ] . Therefore, when administering glucocorticoid to these patients, a rapid glucocorticoid withdrawal strategy is usually used. When combined with ATG therapy, it significantly elevates the risk of ATG-associated serum sickness [ 4 – 5 ] . During ATG treatment for one patient with SAA and concomitant hypothyroidism, serum sickness nephritis happened during rapid glucocorticoid tapering. Intervention with the novel targeted agent iptacopan, a selective factor B inhibitor of the alternative complement pathway, successfully ameliorated the serum sickness nephritis. This case is reported as follows. Case Report A 62-year-old female was admitted with a 3-week history of pallor and fatigue. Laboratory investigations revealed hemoglobin of 79 g/L, absolute reticulocyte count of 0.021 × 10⁹/L, white blood cell count of 3.55 × 10⁹/L, absolute neutrophil count of 0.49 ×10⁹/L, platelet count of 18 × 10⁹/L. Bone marrow examination demonstrated hypoplasia of granulocytic, erythroid, and megakaryocytic lineages with thrombocytopenia. Biopsy showed hypoplasia of all three hematopoietic lineages and increased adipose tissue. Immunophenotyping revealed no aberrant maturation patterns in CD13/CD11b/CD16 or CD15/CD10, and no clonal T-cell population detected. Medical history included hypothyroidism, managed with oral levothyroxine (Euthyrox) 100 µg once daily. Thyroid function tests showed FT3 of 1.89 pmol/L, FT4 of 17.7 pmol/L, TSH of 0.026 mIU/L. The patient was diagnosed with severe aplastic anemia and hypothyroidism. The therapeutic regimen consisted of antithymocyte globulin at a dosage of 3.5mg/kg/d ×5ds administered concurrently with cyclosporine, with the cyclosporine dosage adjusted based on serum drug concentration monitoring. Supplemented with methylprednisolone (0.5 milligrams per kilogram per day) administered as prophylaxis against serum sickness. During ATG infusion, fluid retention developed, resulting in a weight increase from 55 kilograms to 62 kilograms within 5 days. Then glucocorticoids were rapidly tapered, with body weight returning to 55 kilograms within one week. On day 12 post-ATG therapy, the patient developed fever and knee arthralgia, with urinary microalbumin elevated to 188.3 mg/L and occult hematuria graded at 3+, leading to a diagnosis of serum sickness nephritis. The patient was undergoing treatment with oral prednisone 10 milligrams daily, and glucocorticoid dosage escalation was contraindicated. Concurrent laboratory testing revealed significantly decreased serum complement C3 at 0.208 g/L (0.7–1.4 g/L) and C4 at 0.017 g/L (0.1–0.4 g/L), indicating consumptive reduction of complement components. Treatment with iptacopan 200 milligrams twice daily was initiated on day 14 post-ATG therapy. After 12 days of medication, follow-up testing demonstrated elevations in serum complement C3 to 0.453 g/L and C4 to 0.0353 g/L, with urinary microalbumin decreasing to 21.8 mg/L. At the 35-day post-treatment follow-up, repeat testing demonstrated a serum C3 level of 0.87 g/L, C4 of 0.15 g/L, urinary microalbumin of 20.5 mg/L, negative proteinuria, and occult hematuria graded at 1+. Iptacopan therapy was continued at 200 milligrams twice daily. At the 48-day post-ATG therapy follow-up, laboratory assessment revealed a serum complement C3 level of 0.98 g/L, C4 of 0.16 g/L, urinary microalbumin of 6.9 mg/L, negative proteinuria, and occult hematuria with trace positivity. With all parameters fundamentally restored to normal ranges, iptacopan therapy was discontinued. (See Fig. 1 for serial trends in complement components and urinary microalbumin post-ATG initiation.) Discussion and literature review Serum sickness nephritis is a type III hypersensitivity reaction mediated by immune complexes following heterologous serum infusion. Its pathogenesis involves deposition of circulating antigen-antibody complexes in glomeruli, activating the complement system and releasing inflammatory mediators, ultimately manifesting as proteinuria and renal dysfunction [ 2 , 5 ] . In serum sickness nephritis, complement activation is directly triggered by antigen-antibody complexes (IgG/IgM type). These immune complexes initiate the complement cascade through C1q binding, leading to the formation of C3 convertase (C4b2a), which ultimately generates the membrane attack complex (MAC) and anaphylatoxins (C3a/C5a) [ 8 – 12 ] . Animal studies demonstrate that in complement-depleted models (C3-deficient rabbits), glomerular inflammatory severity decreased by 76% following heterologous protein injection compared to wild-type controls, underscoring the critical role of the C3 complement component in nephritis pathogenesis [ 8 ] . In human serum sickness nephritis, complement activation exhibits a biphasic pattern: Early phase (≤ 72 hours after onset): dominated by classical pathway activation, characterized by linear C4d deposition along glomerular capillary walls; Late phase (> 7 days): Features amplification of the alternative pathway, manifested by decreased serum factor B levels and positive C3 nephritic factor [ 8 ] . Glucocorticoids are first-line therapeutic agents for serum sickness nephritis. Through suppression of T-cell activation and mitigation of cytokine release, they effectively inhibit inflammatory responses and immune complex-mediated tissue damage [ 4 , 13 ] . This patient with SAA was ineligible for allogeneic hematopoietic stem cell transplantation. Therefore, ATG in combination with cyclosporine was administered as intensified immunosuppressive therapy [ 1 , 14 – 15 ] . Due to the coexisting diagnosis of hypothyroidism in this patient, significant fluid retention and weight gain occurred during glucocorticoid prophylaxis for ATG-induced serum sickness. Glucocorticoids were therefore rapidly tapered. However, serum sickness nephritis subsequently developed. As it was contraindicated to escalate glucocorticoid dosage, the complement inhibitor iptacopan was administered instead. Complement activation occurs through three distinct pathways: the classical pathway, the mannose-binding lectin pathway, and the alternative pathway. These pathways converge at the central complement component C3, leading to activation of complement receptors and initiation of the terminal lytic pathway [ 11 – 12 ] . The alternative pathway involves activator surface-bound C3b which, with participation of factor B, factor D, and properdin, forms the alternative pathway C3 convertase (C3bBb) and C5 convertase (C3bBb3b). The C3bBb enzyme cleaves additional C3 molecules, thereby generating new C3bBb complexes and establishing a positive feedback amplification loop for alternative pathway activation [ 12 , 16 ] . Iptacopan binds to factor B in the proximal alternative complement pathway, inhibiting its serine protease activity. This action suppresses the cleavage of both C3 and C5, reduces C3 fragmentation, and prevents deposition of C3 breakdown products within the glomerular compartment [ 17 – 19 ] . In C3 glomerulopathy, intrarenal C3 deposition within glomeruli induces inflammation, glomerular injury, and renal fibrosis. Iptacopan achieves therapeutic effects through selective inhibition of alternative pathway overactivation by suppressing the enzymatic activity of the pathway-associated C3 convertase. This intervention leads to reduced C3 cleavage and diminished renal C3 deposition [ 20 – 21 ] . Sustained C3 convertase activity establishes a positive feedback loop through C3b deposition and factor B cleavage. This process continually generates the C5 convertase (C3bBbC3b), which mediates the proteolytic cleavage of C5 into the proinflammatory mediator C5a and the membrane attack complex C5b-9 (MAC) [ 17 – 18 , 22 ] . Iptacopan not only mitigates membrane attack complex-mediated cytolysis (such as erythrocyte destruction) but also inhibits C5a-induced inflammatory responses and subsequent endothelial damage [ 14 – 15 , 23 – 24 ] . Studies have confirmed that overactivation of the alternative pathway plays a pivotal pathological role in thrombotic microangiopathies including atypical hemolytic uremic syndrome and transplantation-associated thrombotic microangiopathy [ 25 – 26 ] . This alternative complement pathway may establish a mutually amplifying "Interferon-Complement Loop" with interferon signaling cascades. Iptacopan's blockade of the complement pathway potentially modulates this circuit indirectly, thereby attenuating endothelial damage [ 18 , 20 , 26 ] . Dario Troise and colleagues recently reported a case of successful iptacopan treatment for recurrent C3 glomerulopathy following renal transplantation [ 20 ] . There are currently no clinical reports documenting the use of factor B complement inhibitors for serum sickness nephritis in domestic or international medical literature. This case provides innovative perspectives for managing immune-mediated kidney injury and more specifically explores novel therapeutic approaches for glucocorticoid-intolerant patients. In this SAA patient with concomitant hypothyroidism, serum sickness nephritis precipitated by rapid glucocorticoid withdrawal following ATG therapy was successfully alleviated through iptacopan administration. Future investigations should further validate the clinical efficacy of iptacopan in serum sickness and serum sickness nephritis while exploring additional individualized therapeutic strategies for specific patient subpopulations to enhance quality of life outcomes. Declarations Funding 1. National Natural Science Foundation of China (82400138) 2. Natural Science Foundation of Jiangsu Province (BK20230734) Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Compliance with ethical standards This study was performed in line with the principles of the Declaration of Helsinki. Written informed consent was obtained from the patient for iptacopan treatment and for data collection and publication. Author Contribution M-L X: Writing– original draft, Data curation, Software,Writing– review & editing, Formal analysis. C-T Q: Writing–review & editing, Writing– original draft, Data curation, Formalanalysis, Methodology, Visualization.Y-M G: Formal Analysis,Visualization, Writing– review & editing, Software. Y-W Z: Project administration, Conceptualization, Writing– review & editing,Methodology. G-S H: Writing– original draft, Project administration, Writing– review & editing, Conceptualization. References Rosenfeld SJ, Kimball J, Vining D, Young NS, et al. Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia [J]. Blood, 1995, 85(11):3058-65. 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Complement in human disease: Approved and up-and-coming therapeutics [J]. Lancet, 2024, 403(10424):392–405. DOI: 10.1016/S0140-6736(23)01524-6. Shanshal M, Ebadian M. Serum Sickness [J]. N Engl J Med, 2023, 389(8):749. DOI:10.1056/NEJMicm2216266. Baltierra D, Harper T, Jones MP, et al. Hematologic Disorders: Bone Marrow Failure [J]. FP Essent. 2015, 433:21-6. Wu LQ, Huang LF, Yang H, Ye BD, Sheng JP, Yu QH, Yang Y, Jia JS, Zhang DH, Lin SY, He GS, Li JY. Comparison of haploidentical-allogeneic hematopoietic stem cell transplantation and intensive immunosuppressive therapy for patients with severe aplastic anemia with an absolute neutrophil count of zero: a retrospective study. Ann Hematol. 2023; 102(8): 2015-2023. DOI: 10.1007/s00277-023-05256-9. Pouw RB, Ricklin D. Tipping the balance: Intricate roles of the complement system in disease and therapy [J]. Semin Immunopathol, 2021, 43(6):757–771. DOI: 10.1007/s00281-021-00892-7. Hillmen P, Horneff R, Yeh M, et al. Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors [J]. Int J Mol Sci, 2024, 25(17): 9477. DOI: 10.3390/ijms25179477. Zewde N, Morikis D. A computational model for the evaluation of complement system regulation under homeostasis, disease, and drug intervention [J]. PLoS One, 2018, 13(6):e0198644. DOI: 10.1371/journal.pone.0198644. Troise D, Allegra C, Cirolla LA, et al. Exploring Potential Complement Modulation Strategies for Ischemia–Reperfusion Injury in Kidney Transplantation [J]. Antioxidants, 2025, 14(1): 66. DOI: 10.3390/antiox14010066. Troise D, Infante B, Mercuri S, et al. Successful Management of C3 Glomerulopathy Recurrence Post-Kidney Transplantation with Iptacopan: A Case Report [J]. Int J Mol Sci, 2025, 26(11):5053. DOI: 10.3390/ijms26115053. Wong E, Nester C, Cavero T, et al. Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy [J]. Kidney Int Rep, 2023, 8(12):2754–2764. DOI: 10.1016/j.ekir.2023.09.017. Stasiłojć M, Stasiłojć G, Kuźniewska A, et al. A Cell-Based Assay to Measure the Activity of the Complement Convertases [J]. Kidney Int Rep, 2024, 9(7):2260-2268. DOI: 10.1016/j.ekir.2024.04.058. Werion A, Rondeau E. Application of C5 inhibitors in glomerular diseases in 2021 [J]. Kidney Res Clin Pract, 2022, 41(4):412-421. DOI: 10.23876/j.krcp.21.248. Stevens KH, Baas LM, Velden TJAM, et al. Modeling complement activation on human glomerular microvascular endothelial cells [J]. Front Immunol, 2023, 14:1206409. DOI: 10.3389/fimmu.2023.1206409. Lee H, Kang E, Kang HG, et al. Consensus regarding diagnosis and management of atypical hemolytic uremic syndrome [J]. Korean J Intern Med, 2020, 35(1):25-40. DOI: 10.3904/kjim.2019.388. Jodele S, Medvedovic M, Luebbering N, et al. Interferon-complement loop in transplant-associated thrombotic microangiopathy [J]. Blood Adv, 2020, 4(6):1166-1177. DOI:10.1182/bloodadvances.2020001515. 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1","display":"","copyAsset":false,"role":"figure","size":60425,"visible":true,"origin":"","legend":"\u003cp\u003eserial trends in complement components and urinary microalbumin post-ATG initiation\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7366407/v1/171b89ae67be36839aa5530a.png"},{"id":96089528,"identity":"213460e6-3e5a-4567-9149-79ea794cf58e","added_by":"auto","created_at":"2025-11-17 13:09:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":367546,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7366407/v1/63b828c3-b0ce-4934-adfa-bbe56a5a7fc2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Iptacopan alleviates serum sickness nephritis after anti- human thymocyte immunoglobulin : One case report and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnti-thymocyte globulin (ATG) serves as a first-line therapeutic agent for severe aplastic anemia (SAA) patients ineligible for allogeneic hematopoietic stem cell transplantation. However, the use of it is complicated by the potential induction of serum sickness and serum sickness nephritis\u003csup\u003e[\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, presenting significant clinical challenges. Glucocorticoids are generally used for prevention or treatment of serum sickness in clinical practice. In patients with hypothyroidism, thyroid hormone deficiency exacerbates immune dysregulation and concurrently restricts the use of glucocorticoids\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Therefore, when administering glucocorticoid to these patients, a rapid glucocorticoid withdrawal strategy is usually used. When combined with ATG therapy, it significantly elevates the risk of ATG-associated serum sickness\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. During ATG treatment for one patient with SAA and concomitant hypothyroidism, serum sickness nephritis happened during rapid glucocorticoid tapering. Intervention with the novel targeted agent iptacopan, a selective factor B inhibitor of the alternative complement pathway, successfully ameliorated the serum sickness nephritis. This case is reported as follows.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 62-year-old female was admitted with a 3-week history of pallor and fatigue. Laboratory investigations revealed hemoglobin of 79 g/L, absolute reticulocyte count of 0.021 × 10⁹/L, white blood cell count of 3.55 × 10⁹/L, absolute neutrophil count of 0.49 ×10⁹/L, platelet count of 18 × 10⁹/L. Bone marrow examination demonstrated hypoplasia of granulocytic, erythroid, and megakaryocytic lineages with thrombocytopenia. Biopsy showed hypoplasia of all three hematopoietic lineages and increased adipose tissue. Immunophenotyping revealed no aberrant maturation patterns in CD13/CD11b/CD16 or CD15/CD10, and no clonal T-cell population detected. Medical history included hypothyroidism, managed with oral levothyroxine (Euthyrox) 100 µg once daily. Thyroid function tests showed FT3 of 1.89 pmol/L, FT4 of 17.7 pmol/L, TSH of 0.026 mIU/L. The patient was diagnosed with severe aplastic anemia and hypothyroidism. The therapeutic regimen consisted of antithymocyte globulin at a dosage of 3.5mg/kg/d ×5ds administered concurrently with cyclosporine, with the cyclosporine dosage adjusted based on serum drug concentration monitoring. Supplemented with methylprednisolone (0.5 milligrams per kilogram per day) administered as prophylaxis against serum sickness. During ATG infusion, fluid retention developed, resulting in a weight increase from 55 kilograms to 62 kilograms within 5 days. Then glucocorticoids were rapidly tapered, with body weight returning to 55 kilograms within one week. On day 12 post-ATG therapy, the patient developed fever and knee arthralgia, with urinary microalbumin elevated to 188.3 mg/L and occult hematuria graded at 3+, leading to a diagnosis of serum sickness nephritis. The patient was undergoing treatment with oral prednisone 10 milligrams daily, and glucocorticoid dosage escalation was contraindicated. Concurrent laboratory testing revealed significantly decreased serum complement C3 at 0.208 g/L (0.7–1.4 g/L) and C4 at 0.017 g/L (0.1–0.4 g/L), indicating consumptive reduction of complement components. Treatment with iptacopan 200 milligrams twice daily was initiated on day 14 post-ATG therapy. After 12 days of medication, follow-up testing demonstrated elevations in serum complement C3 to 0.453 g/L and C4 to 0.0353 g/L, with urinary microalbumin decreasing to 21.8 mg/L.\u003c/p\u003e\u003cp\u003eAt the 35-day post-treatment follow-up, repeat testing demonstrated a serum C3 level of 0.87 g/L, C4 of 0.15 g/L, urinary microalbumin of 20.5 mg/L, negative proteinuria, and occult hematuria graded at 1+. Iptacopan therapy was continued at 200 milligrams twice daily. At the 48-day post-ATG therapy follow-up, laboratory assessment revealed a serum complement C3 level of 0.98 g/L, C4 of 0.16 g/L, urinary microalbumin of 6.9 mg/L, negative proteinuria, and occult hematuria with trace positivity. With all parameters fundamentally restored to normal ranges, iptacopan therapy was discontinued. (See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for serial trends in complement components and urinary microalbumin post-ATG initiation.)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion and literature review","content":"\u003cp\u003eSerum sickness nephritis is a type III hypersensitivity reaction mediated by immune complexes following heterologous serum infusion. Its pathogenesis involves deposition of circulating antigen-antibody complexes in glomeruli, activating the complement system and releasing inflammatory mediators, ultimately manifesting as proteinuria and renal dysfunction \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. In serum sickness nephritis, complement activation is directly triggered by antigen-antibody complexes (IgG/IgM type). These immune complexes initiate the complement cascade through C1q binding, leading to the formation of C3 convertase (C4b2a), which ultimately generates the membrane attack complex (MAC) and anaphylatoxins (C3a/C5a) \u003csup\u003e[\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e–\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Animal studies demonstrate that in complement-depleted models (C3-deficient rabbits), glomerular inflammatory severity decreased by 76% following heterologous protein injection compared to wild-type controls, underscoring the critical role of the C3 complement component in nephritis pathogenesis\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. In human serum sickness nephritis, complement activation exhibits a biphasic pattern: Early phase (≤ 72 hours after onset): dominated by classical pathway activation, characterized by linear C4d deposition along glomerular capillary walls; Late phase (\u0026gt; 7 days): Features amplification of the alternative pathway, manifested by decreased serum factor B levels and positive C3 nephritic factor\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Glucocorticoids are first-line therapeutic agents for serum sickness nephritis. Through suppression of T-cell activation and mitigation of cytokine release, they effectively inhibit inflammatory responses and immune complex-mediated tissue damage\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThis patient with SAA was ineligible for allogeneic hematopoietic stem cell transplantation. Therefore, ATG in combination with cyclosporine was administered as intensified immunosuppressive therapy\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e–\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Due to the coexisting diagnosis of hypothyroidism in this patient, significant fluid retention and weight gain occurred during glucocorticoid prophylaxis for ATG-induced serum sickness. Glucocorticoids were therefore rapidly tapered. However, serum sickness nephritis subsequently developed. As it was contraindicated to escalate glucocorticoid dosage, the complement inhibitor iptacopan was administered instead.\u003c/p\u003e\u003cp\u003eComplement activation occurs through three distinct pathways: the classical pathway, the mannose-binding lectin pathway, and the alternative pathway. These pathways converge at the central complement component C3, leading to activation of complement receptors and initiation of the terminal lytic pathway\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e–\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. The alternative pathway involves activator surface-bound C3b which, with participation of factor B, factor D, and properdin, forms the alternative pathway C3 convertase (C3bBb) and C5 convertase (C3bBb3b). The C3bBb enzyme cleaves additional C3 molecules, thereby generating new C3bBb complexes and establishing a positive feedback amplification loop for alternative pathway activation\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Iptacopan binds to factor B in the proximal alternative complement pathway, inhibiting its serine protease activity. This action suppresses the cleavage of both C3 and C5, reduces C3 fragmentation, and prevents deposition of C3 breakdown products within the glomerular compartment\u003csup\u003e[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. In C3 glomerulopathy, intrarenal C3 deposition within glomeruli induces inflammation, glomerular injury, and renal fibrosis. Iptacopan achieves therapeutic effects through selective inhibition of alternative pathway overactivation by suppressing the enzymatic activity of the pathway-associated C3 convertase. This intervention leads to reduced C3 cleavage and diminished renal C3 deposition \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e–\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSustained C3 convertase activity establishes a positive feedback loop through C3b deposition and factor B cleavage. This process continually generates the C5 convertase (C3bBbC3b), which mediates the proteolytic cleavage of C5 into the proinflammatory mediator C5a and the membrane attack complex C5b-9 (MAC) \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Iptacopan not only mitigates membrane attack complex-mediated cytolysis (such as erythrocyte destruction) but also inhibits C5a-induced inflammatory responses and subsequent endothelial damage\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e–\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e–\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Studies have confirmed that overactivation of the alternative pathway plays a pivotal pathological role in thrombotic microangiopathies including atypical hemolytic uremic syndrome and transplantation-associated thrombotic microangiopathy\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e–\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. This alternative complement pathway may establish a mutually amplifying \"Interferon-Complement Loop\" with interferon signaling cascades. Iptacopan's blockade of the complement pathway potentially modulates this circuit indirectly, thereby attenuating endothelial damage\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDario Troise and colleagues recently reported a case of successful iptacopan treatment for recurrent C3 glomerulopathy following renal transplantation\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. There are currently no clinical reports documenting the use of factor B complement inhibitors for serum sickness nephritis in domestic or international medical literature. This case provides innovative perspectives for managing immune-mediated kidney injury and more specifically explores novel therapeutic approaches for glucocorticoid-intolerant patients.\u003c/p\u003e\u003cp\u003eIn this SAA patient with concomitant hypothyroidism, serum sickness nephritis precipitated by rapid glucocorticoid withdrawal following ATG therapy was successfully alleviated through iptacopan administration. Future investigations should further validate the clinical efficacy of iptacopan in serum sickness and serum sickness nephritis while exploring additional individualized therapeutic strategies for specific patient subpopulations to enhance quality of life outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. National Natural Science Foundation of China (82400138)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. Natural Science Foundation of Jiangsu Province (BK20230734)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with ethical standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Written informed consent was obtained from the patient for iptacopan treatment and for data collection and publication.\u0026nbsp;\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM-L X: Writing\u0026ndash; original draft, Data curation, Software,Writing\u0026ndash; review \u0026amp; editing, Formal analysis. C-T Q: Writing\u0026ndash;review \u0026amp; editing, Writing\u0026ndash; original draft, Data curation, Formalanalysis, Methodology, Visualization.Y-M G: Formal Analysis,Visualization, Writing\u0026ndash; review \u0026amp; editing, Software. Y-W Z: Project administration, Conceptualization, Writing\u0026ndash; review \u0026amp; editing,Methodology. G-S H: Writing\u0026ndash; original draft, Project administration, Writing\u0026ndash; review \u0026amp; editing, Conceptualization.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRosenfeld SJ, Kimball J, Vining D, Young NS, et al. Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia [J]. Blood, 1995, 85(11):3058-65.\u003c/li\u003e\n\u003cli\u003eLi R, Wang N, Chai X, Yang L, Liu K, He H, Lin S, Yang Y, Jia J, Zhang D, Gong Y, Shi J, He G, Li J. Prolonged use of eltrombopag in patients with severe aplastic anemia in the real world. 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DOI: 10.1016/j.ekir.2024.04.058.\u003c/li\u003e\n\u003cli\u003eWerion A, Rondeau E. Application of C5 inhibitors in glomerular diseases in 2021 [J]. Kidney Res Clin Pract, 2022, 41(4):412-421. DOI: 10.23876/j.krcp.21.248.\u003c/li\u003e\n\u003cli\u003eStevens KH, Baas LM, Velden TJAM, et al. Modeling complement activation on human glomerular microvascular endothelial cells [J]. Front Immunol, 2023, 14:1206409. DOI: 10.3389/fimmu.2023.1206409.\u003c/li\u003e\n\u003cli\u003eLee H, Kang E, Kang HG, et al. Consensus regarding diagnosis and management of atypical hemolytic uremic syndrome [J]. Korean J Intern Med, 2020, 35(1):25-40. DOI: 10.3904/kjim.2019.388.\u003c/li\u003e\n\u003cli\u003eJodele S, Medvedovic M, Luebbering N, et al. Interferon-complement loop in transplant-associated thrombotic microangiopathy [J]. Blood Adv, 2020, 4(6):1166-1177. DOI:10.1182/bloodadvances.2020001515.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Severe aplastic anemia, Serum sickness nephritis, Iptacopan, Complement","lastPublishedDoi":"10.21203/rs.3.rs-7366407/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7366407/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAnti-thymocyte globulin (ATG) is used for the treatment for severe aplastic anemia (SAA). Since ATG is a heterologous serum, it can cause serum sickness nephritis. This article reported one case of SAA comorbidited with hypothyroidism, in whom serum sickness nephritis occurred during glucocorticoids tapering rapidly. The renal injury was recovery after being administrating with iptacopan. It was suggested that proximal complement alternative pathway inhibitors had potential application value in ATG-related serum sickness nephritis and provided a new strategy for optimizing individualized therapy.\u003c/p\u003e","manuscriptTitle":"Iptacopan alleviates serum sickness nephritis after anti- human thymocyte immunoglobulin : One case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-05 11:37:32","doi":"10.21203/rs.3.rs-7366407/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b00c765e-4016-4c54-9dfa-770370d1a465","owner":[],"postedDate":"October 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T13:08:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-05 11:37:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7366407","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7366407","identity":"rs-7366407","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}