Light Chain Proximal Tubulopathy in a 59-Year-Old Woman with Sjögren’s Syndrome: A Case Report and Review of the Literature

Light Chain Proximal Tubulopathy in a 59-Year-Old Woman with Sjögren’s Syndrome: A Case Report and Review of the Literature | 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 Light Chain Proximal Tubulopathy in a 59-Year-Old Woman with Sjögren’s Syndrome: A Case Report and Review of the Literature Jiayin Tao, Yan Liu, Zhejun Chen, Hongbo Chen, Lingzhi He, Juan Jin, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8077745/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Feb, 2026 Read the published version in BMC Nephrology → Version 1 posted 15 You are reading this latest preprint version Abstract Light chain proximal tubulopathy (LCPT) is a rare form of monoclonal gammopathy of renal significance (MGRS), characterized by the deposition of monoclonal light chains in proximal renal tubules. We present a case of a 59-year-old female with a 9-year established history of Sjögren’s syndrome (SS) who presented with progressive renal dysfunction. A comprehensive workup revealed a monoclonal IgA-kappa paraproteinemia and a renal biopsy confirmed LCPT. Her diagnosis of SS was re-confirmed with positive anti-SSA/Ro-52 antibodies and focal lymphocytic sialadenitis. The patient exhibited metabolic acidosis, hypophosphatemia, and hypokalemia, consistent with Fanconi syndrome. The long-standing nature of her autoimmune disease prior to the development of MGRS lends support to our unifying hypothesis: chronic antigenic stimulation from SS may drive clonal plasma cell expansion, leading to monoclonal gammopathy and subsequent renal light chain deposition. This case highlights the importance of considering MGRS in SS patients with worsening renal tubular dysfunction. Light chain proximal tubulopathy Monoclonal gammopathy of renal significance Fanconi syndrome Chronic kidney disease Case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Monoclonal gammopathy of renal significance (MGRS) encompasses a spectrum of renal disorders caused by monoclonal immunoglobulin deposition without hematologic malignancy. Light chain proximal tubulopathy (LCPT) is a rare subtype, resulting from the reabsorption and crystallization of monoclonal light chains in proximal tubules, leading to tubular dysfunction and Fanconi syndrome [1]. We report a case of Sjögren’s syndrome (SS) in a patient with κ-light chain-restricted LCPT, illustrating the clinical, pathological, and therapeutic aspects of this condition. Herein, We report a case of a patient with a long-standing diagnosis of Sjögren’s syndrome who subsequently developed κ-light chain-restricted LCPT, illustrating the clinical, pathological, and therapeutic aspects of this condition. We believe that this case, with its clear temporal sequence, further strengthens the proposed link and expands the recognized spectrum of MGRS. Case Report/Case Presentation A 59-year-old female patient was referred for evaluation of a 6-year history of elevated serum creatinine and proteinuria. The patient had been diagnosed with Sjögren’s syndrome nine years prior, based on her hallmark symptoms of severe dry mouth and eye soreness, although detailed laboratory and pathological records from that initial diagnosis were unavailable. She reported that her foamy urine began approximately 6 years ago. Past medical history included hyperlipidemia and recurrent urinary tract infections. During the current admission, her diagnosis of SS was re-confirmed: serological tests were strongly positive for ANA, anti-SSA, and Ro-52 antibodies, and a new labial gland biopsy revealed focal lymphocytic sialadenitis with a focus score of > 1. Immunohistochemical staining on the infiltrating plasma cells in the salivary gland showed a polyclonal pattern. Her renal workup showed a serum creatinine of 1.27 mg/dL and a 24-h urine protein of 1878.3 mg/day. She had normochromic normocytic anemia (hemoglobin 10.8 g/dL). Serum protein electrophoresis and immunofixation studies revealed a monoclonal IgA-kappa paraprotein. Serum free kappa and lambda light chain levels were 506.22 and 33.98 mg/L, respectively, with an abnormal kappa/lambda ratio of 14.9. A bone marrow biopsy suggested increased plasma cells (3.45%) with κ-light chain restriction (CD38+, CD138+, CD56+). Further laboratory findings confirmed Fanconi syndrome, with profound renal glycosuria (urine glucose 4+), hypokalemia (2.79 mmol/L), metabolic acidosis (HCO3 − 18.1 mmol/L), and hypophosphatemia (0.76 mmol/L). Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. Renal biopsy: Light microscopic examination revealed two cortical and one medullary renal tissue strip containing 19 glomeruli, with 2 showing global sclerosis. The remaining glomeruli exhibited segmental mild mesangial widening with hypercellularity and matrix expansion, patent capillary loops, and focal capsular thickening. Proximal tubules demonstrated focal brush border loss, epithelial cell swelling containing eosinophilic round-to-rod-shaped crystalline inclusions, and sloughed epithelial cells in lumina. Arteries showed segmental elastic lamina duplication. The interstitium displayed focal mononuclear infiltration with cortical fibrosis (focal) and medullary fibrosis (+). Congo red stains were negative for amyloid (as shown in Fig. 1 ). Immunofluorescence studies of two glomeruli (0 sclerotic) revealed segmental granular mesangial deposits of IgA ± and IgM±, while IgG, C3, C4c, C1q, fibrin, and both κ/λ light chains were negative. Tubular epithelial cells showed strong cytoplasmic κ-light chain positivity with λ-light chain negativity. PLA2R staining was negative (as shown in Fig. 2 ). Electron microscopy confirmed mesangial widening without electron-dense deposits. Glomerular basement membranes measured 280-430nm with subendothelial widening and new basement membrane formation. Podocytes showed 30–40% foot process effacement with cytoplasmic vacuolization and phagolysosomes. Proximal tubular cells contained rhomboid, rod-shaped, and irregular crystalline structures with brush border loss (as shown in Fig. 3 ). Furthermore, immunoelectron microscopy confirmed the monoclonal nature of these inclusions, demonstrating specific immunogold labeling for κ-light chains on the crystalline structures, whereas labeling for λ-light chains was negative (as shown in Fig. 4 ). Diagnosis: The patient was diagnosed with LCPT secondary to κ-light chain MGRS, complicated with Sjögren’s syndrome and Fanconi syndrome (proximal tubular dysfunction with metabolic acidosis, hypophosphatemia, and hypokalemia). Management: Treatment included potassium supplementation, angiotensin receptor blocker (losartan 50 mg/day) and renal monitoring. After excluding contraindications, daratumumab combination of bortezomib, cyclophosphamide, and dexamethasone (D-VCD) was initiated. After 4 cycles of D-VCD, serum free kappa light chain significantly decreased to 36 mg/dL with simultaneous decrease in 24-h urine protein to 1101mg/day and serum creatinine level to 1.23 mg/dl. Currently, she is still under follow-up. Following completion of D-VCD chemotherapy, treatment was switched to bortezomib monotherapy. The patient continues to be followed up on therapy. Discussion We report a rare case of light chain proximal tubulopathy (LCPT) developing in a patient with a nine-year history of Sjögren’s syndrome (SS). This case raises the critical question of whether this co-occurrence is a mere coincidence or represents a pathogenetic continuum, where chronic autoimmunity triggers clonal plasma cell proliferation. LCPT is a rare manifestation of monoclonal gammopathy of renal significance (MGRS) [2], resulting from the excessive production and subsequent tubular reabsorption of nephrotoxic monoclonal light chains (typically κ isotype, VκI subtype) [3].These pathologic light chains are resistant to lysosomal degradation, leading to their crystallization within proximal tubular epithelial cells. This process disrupts cellular function, causing acute tubular injury and frequently manifesting as Fanconi syndrome [4]. The renal involvement in primary Sjögren's syndrome (pSS) most commonly presents as tubulointerstitial nephritis (TIN), often leading to distal renal tubular acidosis (dRTA) [5]. More relevant to our case is the well-established link between SS and profound B-cell hyperactivity. This state of chronic immune stimulation is known to increase the risk of lymphoproliferative disorders, ranging from polyclonal hypergammaglobulinemia to monoclonal gammopathies and even B-cell lymphoma. In the 1980s, Moutsopoulos et al. found free circulating monoclonal chains in 14/21 (67%) SS patients [6]. Chronic B-cell hyperactivity, a hallmark of SS, drives polyclonal autoantibody production and inflammatory tissue damage [6]. This sustained activation may foster genomic instability, creating a permissive microenvironment for monoclonal B - cell expansion - a prerequisite for MGRS. Critically, nephrotoxic monoclonal immunoglobulins produced in MGRS (e.g., LCPT) directly injure renal tubules via endocytosis, lysosomal dysfunction, and mitochondrial impairment [7]. Conversely, SS-related tubulointerstitial nephritis (TIN), characterized by lymphocytic infiltration and autoantibody-mediated injury, may increase renal susceptibility to monoclonal protein deposition. Shared mechanisms include dysregulated T - B cell interactions (particularly follicular helper T cell involvement), aberrant cytokine networks (e.g., BAFF/APRIL overexpression promoting B - cell survival), and complement activation [8]. While SS primarily involves autoimmune - driven inflammation and MGRS centers on direct monoclonal protein toxicity, their convergence suggests that SS-associated lymphoproliferation may serve as a precursor state for MGRS in susceptible individuals, necessitating vigilant renal monitoring in SS patients with paraproteinemia (Fig. 4 ). In our patient, the diagnosis of SS preceded the onset of significant renal disease by several years. This clear temporal sequence provides strong support for the hypothesis that long-standing, autoimmune-driven inflammation served as a trigger for clonal evolution. We propose that the chronic antigenic stimulation inherent to SS created a permissive environment for the expansion of the IgA-kappa plasma cell clone identified in the bone marrow, which in turn produced the nephrotoxic light chains causing LCPT (as shown in Fig. 5 ). This model positions SS-associated lymphoproliferation as a potential precursor state for MGRS in susceptible individuals. Despite this compelling temporal link, it is crucial to carefully interpret the pathological findings. The renal biopsy revealed a mild interstitial mononuclear infiltrate, a feature that could be attributed to either SS-associated TIN or a reactive process secondary to LCPT-induced tubular damage. Importantly, immunohistochemical analysis of the plasma cells within both the kidney and the salivary gland revealed a polyclonal pattern (i.e., no light chain restriction). This suggests that the nephrotoxic clone originated systemically, likely within the bone marrow, rather than evolving locally at the sites of autoimmune inflammation. Therefore, while SS likely provided the "first hit" by fostering a pro-proliferative milieu, the direct causal pathway remains complex and not definitively proven by the tissue pathology. From a clinical perspective, this case underscores a crucial diagnostic challenge. While both SS and LCPT can cause renal tubular acidosis, their typical presentations differ. Fanconi syndrome—a generalized proximal tubular dysfunction—is a hallmark of LCPT but is exceedingly rare in SS, with a prevalence below 3% [9]. Therefore, the development of Fanconi syndrome in a patient with SS should be a red flag, prompting an immediate workup for a superimposed monoclonal gammopathy. A renal biopsy is indispensable in this scenario, as the histopathological identification of crystalline inclusions with monoclonal light chain restriction is the only way to differentiate LCPT from SS-related TIN, guiding appropriate clone-directed therapy. In the absence of other myeloma complications, LCPT may exhibit an indolent clinical course. Therefore, the therapeutic benefit of aggressive chemotherapy in LCPT remains uncertain. Stokes et al. [10] reported patients with crystalline LCPT treated with stem cell transplant had stable or improved kidney function, suggesting therapeutic efficacy of aggressive intervention in selected cases. Notably, however, their analysis did not specifically evaluate the impact of chemotherapy in the subgroup lacking concomitant hematologic malignancies. Conversely, Ma et al. [11] reported no significant improvement in renal function among 6 patients with Fanconi syndrome treated with chemotherapy during 4–26 months of follow - up. Therefore, the optimal timing for chemotherapy initiation and the magnitude of its potential therapeutic benefit require substantiation through further clinical studies. Conclusion In summary, we describe an extremely rare case of a patient with SS who developed LCPT. In patients with SS that present with exacerbating renal tubular acidosis and development of Fanconi syndrome without significant tubulointerstitial inflammation, LCPT should be included in the differential diagnosis, and renal biopsy should be performed. Declarations Statement of Ethics Study approval statement : This study protocol was reviewed and approved by the First Affiliated Hospital of Zhejiang Chinese Medical University, approval number 20 25 -KLS-429-01. Consent to publish statement : Written informed consent was obtained from participants for publication of the details of their medical case and any accompanying images. Conflict of Interest Statement The authors have no conflicts of interest to declare. Funding Sources This study was supported by the National Natural Science Foundation of China(82304989), This study were also funded by a grant (2023ZR094) from Zhejiang Provincial Administration of Traditional Chinese Medicine and grants(2023RC195, 2025KY973) from Zhejiang Provincial Health Commission. Author Contributions Jiayin Tao: Investigation, Data Curation, Writing – Original Draft. Yan Liu: Investigation, Formal Analysis. Zhejun Chen: Investigation, Resources, Data Curation. Hongbo Chen: Investigation, Resource. Lingzhi He: Investigation, Resources. Juan Jin: Conceptualization, Supervision, Writing – Review & Editing, Project Administration. Liqing Ye: Conceptualization, Supervision, Writing – Review & Editing, Project Administration. Data Availability Statement The data that support the findings of this case report are available from the corresponding author upon reasonable request. The data are not publicly available due to their containing information that could compromise the privacy of the research participant. References Fogo AB, Lusco MA, Najafian B, Alpers CE (2016). AJKD Atlas of Renal Pathology: Light Chain Proximal Tubulopathy. American journal of kidney diseases : the official journal of the National Kidney Foundation, 67(2), e9–e10. https://doi.org/10.1053/j.ajkd.2015.12.006 Leung N, Bridoux F, Batuman V, Chaidos A, Cockwell P, D'Agati VD, et al. (2019). The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nature reviews. Nephrology, 15(1), 45–59. https://doi.org/10.1038/s41581-018-0077-4 Hogan JJ, Alexander MP, Leung N. Dysproteinemia and the kidney: core curriculum 2019. Am J Kidney Dis, 2019, 74(6): 822-836. https://doi.org/10.1053/j.ajkd.2019.04.029 Nasr SH, Sirac C, Leung N, Bridoux, F. (2024). Monoclonal immunoglobulin crystalline nephropathies. Kidney international, 106(2), 201-213. https://doi.org/10.1016/j.kint.2024.02.027 François, H., Mariette, X. (2016). Renal involvement in primary Sjögren syndrome. Nature reviews. Nephrology, 12(2), 82-93. https://doi.org/10.1038/nrneph.2015.174 Moutsopoulos HM, Steinberg AD, Fauci AS, Lane HC, Papadopoulos NM. High incidence of free monoclonal lambda light chains in the sera of patients with Sjogren’s syndrome. J Immunol 1983;130:2663e5. Saglam A, Balaban S, Yıldırım T, Erdem Y, Uner A, Büyükaşık Y. Monoclonal gammopathy of renal significance presenting as monotypic plasma cell interstitial nephritis in two patients with Sjögren's syndrome. Virchows Arch. 2018 May;472(5):865-869. doi: 10.1007/s00428-017-2270-4. Stokes MB, Valeri AM, Herlitz L, Khan AM, Siegel DS, Markowitz GS, Agati VD. (2016). Light Chain Proximal Tubulopathy: Clinical and Pathologic Characteristics in the Modern Treatment Era. Journal of the American Society of Nephrology : JASN, 27(5), 1555–1565. https://doi.org/10.1681/ASN.2015020185 Wang B, Chen S, Li Y, Xuan J, Liu Y,Shi G. (2021). Targeted Therapy for Primary Sjögren's Syndrome: Where are We Now? BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy, 35(6), 593-610. https://doi.org/10.1007/s40259-021-00505-7 Nawata A, Iwamura R, Shiba E, Inaba Y, Kubo C, Kusano M, et al. (2022). Light chain proximal tubulopathy after improvement of tubulointerstitial nephritis in Sjögren's syndrome. Pathology international, 72(10), 525-527. https://doi.org/10.1111/pin.13263 Ma CX, Lacy MQ, Rompala JF, et al. Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myelom. Blood, 2004, 104(1): 40-42. https://doi.org/10.1182/blood-2003-10-3400 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Feb, 2026 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 29 Dec, 2025 Reviews received at journal 23 Dec, 2025 Reviews received at journal 15 Dec, 2025 Reviews received at journal 11 Dec, 2025 Reviews received at journal 07 Dec, 2025 Reviewers agreed at journal 02 Dec, 2025 Reviewers agreed at journal 02 Dec, 2025 Reviewers agreed at journal 01 Dec, 2025 Reviewers agreed at journal 01 Dec, 2025 Reviewers agreed at journal 30 Nov, 2025 Reviewers invited by journal 30 Nov, 2025 Editor assigned by journal 28 Nov, 2025 Editor invited by journal 20 Nov, 2025 Submission checks completed at journal 20 Nov, 2025 First submitted to journal 20 Nov, 2025 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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16:23:22","extension":"html","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":44022,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8077745/v1/d40467e48cfc51130f3df384.html"},{"id":97370117,"identity":"06b3c4ae-1db2-42ed-84a9-1f6387dedb84","added_by":"auto","created_at":"2025-12-03 16:26:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":25968736,"visible":true,"origin":"","legend":"\u003cp\u003eMicroscopic findings of the kidney biopsies. HE, PAS, Masson staining. (Scale bar, 50µm)\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-8077745/v1/ffcebcf0599d983bcab420b8.png"},{"id":97299237,"identity":"c6618e57-cf75-4407-a8f0-62bcfceeb993","added_by":"auto","created_at":"2025-12-03 00:49:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4929440,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative immunofluorescent figure. The κ light chain is positive in the proximal tubular cytoplasm (Scale bar, 50µm)\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-8077745/v1/8d990056d316a441c7e85b35.png"},{"id":97299243,"identity":"4e4452a8-9215-4c84-a99a-09535686c6d9","added_by":"auto","created_at":"2025-12-03 00:49:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":9106249,"visible":true,"origin":"","legend":"\u003cp\u003eTransmission electron micrographs demonstrates numerous rhomboid or needle‐like crystals in the tubular cytoplasm (Scale bar, 2µm).\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-8077745/v1/3b8aa58df768c1c4dd7d8ea1.png"},{"id":97299241,"identity":"ace8334b-0996-4c32-a007-c15ac26babef","added_by":"auto","created_at":"2025-12-03 00:49:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":16125847,"visible":true,"origin":"","legend":"\u003cp\u003eImmuno-electron microscopy demonstrates κ crystals in the tubular cytoplasm(A, κ light chain staining; B, λ light chain staining) (Scale bar, 500nm).\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-8077745/v1/3b9188c9d6e7662e2215a5cb.png"},{"id":97370292,"identity":"e1f20e13-aedb-4620-8f5a-9aaf85c4d294","added_by":"auto","created_at":"2025-12-03 16:27:06","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1517406,"visible":true,"origin":"","legend":"\u003cp\u003ePathogenic mechanism between SS and MGRS-mediated renal injury.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-8077745/v1/b901a6029a46e3112afd9909.png"},{"id":103766403,"identity":"71f5ba91-4c09-4ae1-8844-db4eab3fe927","added_by":"auto","created_at":"2026-03-02 16:14:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":56046111,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8077745/v1/a8920987-7e33-42df-88c3-59c5ed0c468d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Light Chain Proximal Tubulopathy in a 59-Year-Old Woman with Sjögren’s Syndrome: A Case Report and Review of the Literature","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMonoclonal gammopathy of renal significance (MGRS) encompasses a spectrum of renal disorders caused by monoclonal immunoglobulin deposition without hematologic malignancy. Light chain proximal tubulopathy (LCPT) is a rare subtype, resulting from the reabsorption and crystallization of monoclonal light chains in proximal tubules, leading to tubular dysfunction and Fanconi syndrome [1]. We report a case of Sj\u0026ouml;gren\u0026rsquo;s syndrome (SS) in a patient with κ-light chain-restricted LCPT, illustrating the clinical, pathological, and therapeutic aspects of this condition. Herein, We report a case of a patient with a long-standing diagnosis of Sj\u0026ouml;gren\u0026rsquo;s syndrome who subsequently developed κ-light chain-restricted LCPT, illustrating the clinical, pathological, and therapeutic aspects of this condition. We believe that this case, with its clear temporal sequence, further strengthens the proposed link and expands the recognized spectrum of MGRS.\u003c/p\u003e"},{"header":"Case Report/Case Presentation","content":"\u003cp\u003eA 59-year-old female patient was referred for evaluation of a 6-year history of elevated serum creatinine and proteinuria. The patient had been diagnosed with Sj\u0026ouml;gren\u0026rsquo;s syndrome nine years prior, based on her hallmark symptoms of severe dry mouth and eye soreness, although detailed laboratory and pathological records from that initial diagnosis were unavailable. She reported that her foamy urine began approximately 6 years ago. Past medical history included hyperlipidemia and recurrent urinary tract infections.\u003c/p\u003e\u003cp\u003eDuring the current admission, her diagnosis of SS was re-confirmed: serological tests were strongly positive for ANA, anti-SSA, and Ro-52 antibodies, and a new labial gland biopsy revealed focal lymphocytic sialadenitis with a focus score of \u0026gt;\u0026thinsp;1. Immunohistochemical staining on the infiltrating plasma cells in the salivary gland showed a polyclonal pattern.\u003c/p\u003e\u003cp\u003eHer renal workup showed a serum creatinine of 1.27 mg/dL and a 24-h urine protein of 1878.3 mg/day. She had normochromic normocytic anemia (hemoglobin 10.8 g/dL). Serum protein electrophoresis and immunofixation studies revealed a monoclonal IgA-kappa paraprotein. Serum free kappa and lambda light chain levels were 506.22 and 33.98 mg/L, respectively, with an abnormal kappa/lambda ratio of 14.9. A bone marrow biopsy suggested increased plasma cells (3.45%) with κ-light chain restriction (CD38+, CD138+, CD56+).\u003c/p\u003e\u003cp\u003eFurther laboratory findings confirmed Fanconi syndrome, with profound renal glycosuria (urine glucose 4+), hypokalemia (2.79 mmol/L), metabolic acidosis (HCO3\u0026thinsp;\u0026minus;\u0026thinsp;18.1 mmol/L), and hypophosphatemia (0.76 mmol/L).\u003c/p\u003e\u003cp\u003e Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eRenal biopsy:\u003c/h2\u003e\u003cp\u003eLight microscopic examination revealed two cortical and one medullary renal tissue strip containing 19 glomeruli, with 2 showing global sclerosis. The remaining glomeruli exhibited segmental mild mesangial widening with hypercellularity and matrix expansion, patent capillary loops, and focal capsular thickening. Proximal tubules demonstrated focal brush border loss, epithelial cell swelling containing eosinophilic round-to-rod-shaped crystalline inclusions, and sloughed epithelial cells in lumina. Arteries showed segmental elastic lamina duplication. The interstitium displayed focal mononuclear infiltration with cortical fibrosis (focal) and medullary fibrosis (+). Congo red stains were negative for amyloid (as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eImmunofluorescence studies of two glomeruli (0 sclerotic) revealed segmental granular mesangial deposits of IgA\u0026thinsp;\u0026plusmn;\u0026thinsp;and IgM\u0026plusmn;, while IgG, C3, C4c, C1q, fibrin, and both κ/λ light chains were negative. Tubular epithelial cells showed strong cytoplasmic κ-light chain positivity with λ-light chain negativity. PLA2R staining was negative (as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eElectron microscopy confirmed mesangial widening without electron-dense deposits. Glomerular basement membranes measured 280-430nm with subendothelial widening and new basement membrane formation. Podocytes showed 30\u0026ndash;40% foot process effacement with cytoplasmic vacuolization and phagolysosomes. Proximal tubular cells contained rhomboid, rod-shaped, and irregular crystalline structures with brush border loss (as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Furthermore, immunoelectron microscopy confirmed the monoclonal nature of these inclusions, demonstrating specific immunogold labeling for κ-light chains on the crystalline structures, whereas labeling for λ-light chains was negative (as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDiagnosis:\u003c/h3\u003e\n\u003cp\u003eThe patient was diagnosed with LCPT secondary to κ-light chain MGRS, complicated with Sj\u0026ouml;gren\u0026rsquo;s syndrome and Fanconi syndrome (proximal tubular dysfunction with metabolic acidosis, hypophosphatemia, and hypokalemia).\u003c/p\u003e\n\u003ch3\u003eManagement:\u003c/h3\u003e\n\u003cp\u003eTreatment included potassium supplementation, angiotensin receptor blocker (losartan 50 mg/day) and renal monitoring. After excluding contraindications, daratumumab combination of bortezomib, cyclophosphamide, and dexamethasone (D-VCD) was initiated.\u003c/p\u003e\u003cp\u003eAfter 4 cycles of D-VCD, serum free kappa light chain significantly decreased to 36 mg/dL with simultaneous decrease in 24-h urine protein to 1101mg/day and serum creatinine level to 1.23 mg/dl. Currently, she is still under follow-up. Following completion of D-VCD chemotherapy, treatment was switched to bortezomib monotherapy. The patient continues to be followed up on therapy.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe report a rare case of light chain proximal tubulopathy (LCPT) developing in a patient with a nine-year history of Sj\u0026ouml;gren\u0026rsquo;s syndrome (SS). This case raises the critical question of whether this co-occurrence is a mere coincidence or represents a pathogenetic continuum, where chronic autoimmunity triggers clonal plasma cell proliferation.\u003c/p\u003e\u003cp\u003eLCPT is a rare manifestation of monoclonal gammopathy of renal significance (MGRS) [2], resulting from the excessive production and subsequent tubular reabsorption of nephrotoxic monoclonal light chains (typically κ isotype, VκI subtype) [3].These pathologic light chains are resistant to lysosomal degradation, leading to their crystallization within proximal tubular epithelial cells. This process disrupts cellular function, causing acute tubular injury and frequently manifesting as Fanconi syndrome [4].\u003c/p\u003e\u003cp\u003eThe renal involvement in primary Sj\u0026ouml;gren's syndrome (pSS) most commonly presents as tubulointerstitial nephritis (TIN), often leading to distal renal tubular acidosis (dRTA) [5]. More relevant to our case is the well-established link between SS and profound B-cell hyperactivity. This state of chronic immune stimulation is known to increase the risk of lymphoproliferative disorders, ranging from polyclonal hypergammaglobulinemia to monoclonal gammopathies and even B-cell lymphoma. In the 1980s, Moutsopoulos et al. found free circulating monoclonal chains in 14/21 (67%) SS patients [6]. Chronic B-cell hyperactivity, a hallmark of SS, drives polyclonal autoantibody production and inflammatory tissue damage [6]. This sustained activation may foster genomic instability, creating a permissive microenvironment for monoclonal B - cell expansion - a prerequisite for MGRS. Critically, nephrotoxic monoclonal immunoglobulins produced in MGRS (e.g., LCPT) directly injure renal tubules via endocytosis, lysosomal dysfunction, and mitochondrial impairment [7]. Conversely, SS-related tubulointerstitial nephritis (TIN), characterized by lymphocytic infiltration and autoantibody-mediated injury, may increase renal susceptibility to monoclonal protein deposition. Shared mechanisms include dysregulated T - B cell interactions (particularly follicular helper T cell involvement), aberrant cytokine networks (e.g., BAFF/APRIL overexpression promoting B - cell survival), and complement activation [8]. While SS primarily involves autoimmune - driven inflammation and MGRS centers on direct monoclonal protein toxicity, their convergence suggests that SS-associated lymphoproliferation may serve as a precursor state for MGRS in susceptible individuals, necessitating vigilant renal monitoring in SS patients with paraproteinemia (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn our patient, the diagnosis of SS preceded the onset of significant renal disease by several years. This clear temporal sequence provides strong support for the hypothesis that long-standing, autoimmune-driven inflammation served as a trigger for clonal evolution. We propose that the chronic antigenic stimulation inherent to SS created a permissive environment for the expansion of the IgA-kappa plasma cell clone identified in the bone marrow, which in turn produced the nephrotoxic light chains causing LCPT (as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). This model positions SS-associated lymphoproliferation as a potential precursor state for MGRS in susceptible individuals.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eDespite this compelling temporal link, it is crucial to carefully interpret the pathological findings. The renal biopsy revealed a mild interstitial mononuclear infiltrate, a feature that could be attributed to either SS-associated TIN or a reactive process secondary to LCPT-induced tubular damage. Importantly, immunohistochemical analysis of the plasma cells within both the kidney and the salivary gland revealed a polyclonal pattern (i.e., no light chain restriction). This suggests that the nephrotoxic clone originated systemically, likely within the bone marrow, rather than evolving locally at the sites of autoimmune inflammation. Therefore, while SS likely provided the \"first hit\" by fostering a pro-proliferative milieu, the direct causal pathway remains complex and not definitively proven by the tissue pathology.\u003c/p\u003e\u003cp\u003eFrom a clinical perspective, this case underscores a crucial diagnostic challenge. While both SS and LCPT can cause renal tubular acidosis, their typical presentations differ. Fanconi syndrome\u0026mdash;a generalized proximal tubular dysfunction\u0026mdash;is a hallmark of LCPT but is exceedingly rare in SS, with a prevalence below 3% [9]. Therefore, the development of Fanconi syndrome in a patient with SS should be a red flag, prompting an immediate workup for a superimposed monoclonal gammopathy. A renal biopsy is indispensable in this scenario, as the histopathological identification of crystalline inclusions with monoclonal light chain restriction is the only way to differentiate LCPT from SS-related TIN, guiding appropriate clone-directed therapy.\u003c/p\u003e\u003cp\u003eIn the absence of other myeloma complications, LCPT may exhibit an indolent clinical course. Therefore, the therapeutic benefit of aggressive chemotherapy in LCPT remains uncertain. Stokes et al. [10] reported patients with crystalline LCPT treated with stem cell transplant had stable or improved kidney function, suggesting therapeutic efficacy of aggressive intervention in selected cases. Notably, however, their analysis did not specifically evaluate the impact of chemotherapy in the subgroup lacking concomitant hematologic malignancies. Conversely, Ma et al. [11] reported no significant improvement in renal function among 6 patients with Fanconi syndrome treated with chemotherapy during 4\u0026ndash;26 months of follow - up. Therefore, the optimal timing for chemotherapy initiation and the magnitude of its potential therapeutic benefit require substantiation through further clinical studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we describe an extremely rare case of a patient with SS who developed LCPT. In patients with SS that present with exacerbating renal tubular acidosis and development of Fanconi syndrome without significant tubulointerstitial inflammation, LCPT should be included in the differential diagnosis, and renal biopsy should be performed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eStatement of Ethics\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStudy approval statement\u003c/u\u003e: \u003cem\u003eThis study protocol was reviewed and approved by the First Affiliated Hospital of Zhejiang Chinese Medical University, approval number\u0026nbsp;\u003c/em\u003e\u003cem\u003e20\u003c/em\u003e\u003cem\u003e25\u003c/em\u003e\u003cem\u003e-KLS-429-01.\u003c/em\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent to publish statement\u003c/u\u003e: Written informed consent was obtained from participants for publication of the details of their medical case and any accompanying images.\u003c/p\u003e\n\u003cp\u003eConflict of Interest Statement\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003eFunding Sources\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China(82304989), This study were also funded by a grant (2023ZR094) from Zhejiang Provincial Administration of Traditional Chinese Medicine and grants(2023RC195, 2025KY973) from Zhejiang Provincial Health Commission.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eJiayin Tao: Investigation, Data Curation, Writing \u0026ndash; Original Draft. Yan Liu: Investigation, Formal Analysis. Zhejun Chen: Investigation, Resources, Data Curation. Hongbo Chen: Investigation, Resource. Lingzhi He: Investigation, Resources. Juan Jin: Conceptualization, Supervision, Writing \u0026ndash; Review \u0026amp; Editing, Project Administration. Liqing Ye: Conceptualization, Supervision, Writing \u0026ndash; Review \u0026amp; Editing, Project Administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this case report are available from the corresponding author upon reasonable request. The data are not publicly available due to their containing information that could compromise the privacy of the research participant.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFogo AB, Lusco MA, Najafian B, Alpers CE (2016). AJKD Atlas of Renal Pathology: Light Chain Proximal Tubulopathy. American journal of kidney diseases : the official journal of the National Kidney Foundation, 67(2), e9\u0026ndash;e10. https://doi.org/10.1053/j.ajkd.2015.12.006\u003c/li\u003e\n\u003cli\u003eLeung N, Bridoux F, Batuman V, Chaidos A, Cockwell P, D\u0026apos;Agati VD, et al. (2019). The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nature reviews. Nephrology, 15(1), 45\u0026ndash;59. https://doi.org/10.1038/s41581-018-0077-4\u003c/li\u003e\n\u003cli\u003eHogan JJ, Alexander MP, Leung N. Dysproteinemia and the kidney: core curriculum 2019. Am J Kidney Dis, 2019, 74(6): 822-836. https://doi.org/10.1053/j.ajkd.2019.04.029\u003c/li\u003e\n\u003cli\u003eNasr SH, Sirac C, Leung N, Bridoux, F. (2024). Monoclonal immunoglobulin crystalline nephropathies. Kidney international, 106(2), 201-213. https://doi.org/10.1016/j.kint.2024.02.027\u003c/li\u003e\n\u003cli\u003eFran\u0026ccedil;ois, H., Mariette, X. (2016). Renal involvement in primary Sj\u0026ouml;gren syndrome. Nature reviews. Nephrology, 12(2), 82-93. https://doi.org/10.1038/nrneph.2015.174\u003c/li\u003e\n\u003cli\u003eMoutsopoulos HM, Steinberg AD, Fauci AS, Lane HC, Papadopoulos NM. High incidence of free monoclonal lambda light chains in the sera of patients with Sjogren\u0026rsquo;s syndrome. J Immunol 1983;130:2663e5.\u003c/li\u003e\n\u003cli\u003eSaglam A, Balaban S, Yıldırım T, Erdem Y, Uner A, B\u0026uuml;y\u0026uuml;kaşık Y. Monoclonal gammopathy of renal significance presenting as monotypic plasma cell interstitial nephritis in two patients with Sj\u0026ouml;gren\u0026apos;s syndrome. Virchows Arch. 2018 May;472(5):865-869. doi: 10.1007/s00428-017-2270-4.\u003c/li\u003e\n\u003cli\u003eStokes MB, Valeri AM, Herlitz L, Khan AM, Siegel DS, Markowitz GS, Agati VD. (2016). Light Chain Proximal Tubulopathy: Clinical and Pathologic Characteristics in the Modern Treatment Era. Journal of the American Society of Nephrology : JASN, 27(5), 1555\u0026ndash;1565. https://doi.org/10.1681/ASN.2015020185\u003c/li\u003e\n\u003cli\u003eWang B, Chen S, Li Y, Xuan J, Liu Y,Shi G. (2021). Targeted Therapy for Primary Sj\u0026ouml;gren\u0026apos;s Syndrome: Where are We Now? BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy, 35(6), 593-610. https://doi.org/10.1007/s40259-021-00505-7\u003c/li\u003e\n\u003cli\u003eNawata A, Iwamura R, Shiba E, Inaba Y, Kubo C, Kusano M, et al. (2022). Light chain proximal tubulopathy after improvement of tubulointerstitial nephritis in Sj\u0026ouml;gren\u0026apos;s syndrome. Pathology international, 72(10), 525-527. https://doi.org/10.1111/pin.13263\u003c/li\u003e\n\u003cli\u003eMa CX, Lacy MQ, Rompala JF, et al. Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myelom. Blood, 2004, 104(1): 40-42. https://doi.org/10.1182/blood-2003-10-3400\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Light chain proximal tubulopathy, Monoclonal gammopathy of renal significance, Fanconi syndrome, Chronic kidney disease, Case report","lastPublishedDoi":"10.21203/rs.3.rs-8077745/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8077745/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLight chain proximal tubulopathy (LCPT) is a rare form of monoclonal gammopathy of renal significance (MGRS), characterized by the deposition of monoclonal light chains in proximal renal tubules. We present a case of a 59-year-old female with a 9-year established history of Sj\u0026ouml;gren\u0026rsquo;s syndrome (SS) who presented with progressive renal dysfunction. A comprehensive workup revealed a monoclonal IgA-kappa paraproteinemia and a renal biopsy confirmed LCPT. Her diagnosis of SS was re-confirmed with positive anti-SSA/Ro-52 antibodies and focal lymphocytic sialadenitis. The patient exhibited metabolic acidosis, hypophosphatemia, and hypokalemia, consistent with Fanconi syndrome. The long-standing nature of her autoimmune disease prior to the development of MGRS lends support to our unifying hypothesis: chronic antigenic stimulation from SS may drive clonal plasma cell expansion, leading to monoclonal gammopathy and subsequent renal light chain deposition. This case highlights the importance of considering MGRS in SS patients with worsening renal tubular dysfunction.\u003c/p\u003e","manuscriptTitle":"Light Chain Proximal Tubulopathy in a 59-Year-Old Woman with Sjögren’s Syndrome: A Case Report and Review of the Literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-03 00:49:50","doi":"10.21203/rs.3.rs-8077745/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-29T18:07:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-23T15:00:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-15T15:40:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-11T18:05:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-07T10:29:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"192472878028887729282581212918479924595","date":"2025-12-03T04:32:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230745971791356058819195172668895176822","date":"2025-12-02T19:21:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"125707863614093112072377734513016940189","date":"2025-12-01T19:18:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"314030827018077533180822023012513949493","date":"2025-12-01T18:54:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"226056615779676326087778349432780407011","date":"2025-12-01T01:53:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-01T01:06:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-29T03:31:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-20T21:54:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-20T16:25:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-11-20T16:22:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"55cff065-9bcb-4f61-9b59-1ca3666bf8a8","owner":[],"postedDate":"December 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:10:36+00:00","versionOfRecord":{"articleIdentity":"rs-8077745","link":"https://doi.org/10.1186/s12882-026-04845-w","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2026-02-26 15:59:09","publishedOnDateReadable":"February 26th, 2026"},"versionCreatedAt":"2025-12-03 00:49:50","video":"","vorDoi":"10.1186/s12882-026-04845-w","vorDoiUrl":"https://doi.org/10.1186/s12882-026-04845-w","workflowStages":[]},"version":"v1","identity":"rs-8077745","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8077745","identity":"rs-8077745","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}