Light chain proximal tubulopathy in a 59-year-old woman with Sjögren’s syndrome: a case report and review of the literature

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. Notably, her autoimmune condition preceded the development of MGRS by nearly a decade. While this temporal association raises the possibility that chronic immune stimulation in SS could contribute to clonal plasma cell proliferation and subsequent LCPT, such a link remains speculative and cannot be established from a single case. This case highlights the importance of considering MGRS in SS patients with worsening renal tubular dysfunction.

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 [3]. Although renal involvement in Sjögren’s syndrome (SS) most commonly manifests as distal renal tubular acidosis, proximal tubular dysfunction can also occur. In particular, Fanconi syndrome—a generalized disorder of proximal tubular reabsorption—has been reported in a small subset of pSS patients; in a cohort of 130 pSS patients with renal involvement, Ren et al., identified only four cases (3.1%) of Fanconi syndrome, underscoring its rarity compared to distal tubular defects [11]. Herein, we report a patient with a long-standing diagnosis of Sjögren’s syndrome who subsequently developed κ-light chain–restricted light chain proximal tubulopathy (LCPT), illustrating the clinical, pathological, and therapeutic aspects of this rare condition. We believe that this case, with its clear temporal sequence, further strengthens the proposed link and expands the recognized spectrum of MGRS.

We report a patient with a long-standing diagnosis of Sjögren’s syndrome who subsequently developed κ-light chain–restricted LCPT. This case illustrates the clinical, pathological, and therapeutic aspects of LCPT in the setting of an underlying autoimmune condition and, given its clear temporal sequence, further strengthens the proposed link between Sjögren’s syndrome and MGRS-related tubulopathies, thereby expanding the recognized spectrum of both disorders.

Case report

A 59-year-old female patient was referred for evaluation of a 6-year history of elevated serum creatinine (fluctuating between 1.02 and 1.24 mg/dL) and proteinuria (urine dipstick ranging from 1 + to 2+). 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.

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). In addition to the above, a comprehensive immunological workup was performed. Anti-dsDNA antibody was 24.52 IU/mL (reference range: 0–200 IU/mL). Complement levels were within normal limits: C3 1.33 g/L (normal: 0.9–1.8 g/L) and C4 0.28 g/L (normal: 0.1–0.4 g/L). Cryoglobulins were negative on qualitative testing. ANA was positive at 1:80 with a homogeneous pattern. Notably, anti-SSA and Ro-52 antibodies were positive with semi-quantitative titers of 2 + and 3+, respectively, while anti-SSB was negative. 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+).

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.

The patient had no history of systemic lupus erythematosus, rheumatoid arthritis, or other connective tissue diseases, confirming a diagnosis of primary Sjögren’s syndrome. She reported intermittent arthralgia but no synovitis or visceral involvement (e.g., interstitial lung disease or liver dysfunction). For sicca symptoms, she had been using artificial tears intermittently.

Urinary protein electrophoresis and quantitative aminoaciduria were not performed due to technical limitations at our institution. Nevertheless, the proteinuria is strongly indicative of a tubular origin. This is supported by the presence of full-blown Fanconi syndrome, characterized by renal glycosuria (urine glucose 4 + despite normoglycemia), hypophosphatemia (0.85 mmol/L), hypokalemia (2.79 mmol/L), and a normal anion gap metabolic acidosis confirmed by arterial blood gas analysis: pH 7.336, HCO₃⁻ 18.1 mmol/L, PaCO₂ 34.8 mmHg, and PaO₂ 101.2 mmHg. Notably, the urinary pH was 7.5, which is inappropriately alkaline given the systemic acidosis—further evidence of proximal tubular dysfunction and impaired bicarbonate reabsorption. The fractional excretion of phosphate (FePi) was markedly elevated at 32.4%, confirming significant renal phosphate wasting. Additionally, the patient exhibited inappropriate renal potassium loss, with a 24-hour urinary potassium excretion of 44.2 mmol/day (reference range in hypokalemia: <20–25 mmol/day) and a transtubular potassium gradient (TTKG) of 7.34. Notably, the degree of proteinuria (1878 mg/24 h) was moderate and disproportionate to the only mild glomerular changes observed on renal biopsy, further supporting a tubular rather than glomerular source.

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, and intracytoplasmic accumulation of coarse granular crystalline material. 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).

Fig. 1.

Microscopic findings of the kidney biopsies. (A) HE staining of kidney biopsies, tubular epithelial swelling with intracytoplasmic coarse granular deposits. Detached epithelial cells are present within tubular lumens (Scale bar, 50 μm). (B) High-power view of HE staining showing irregular rod-shaped and amorphous eosinophilic crystalline-like material within proximal tubular epithelial cells (arrows) (Scale bar, 20 μm). (C to F) Periodic acid-Schiff (PAS) and Masson trichrome stains: Negative for red staining. (Scale bar, 50 μm). (G to H) Jones silver stain showing intracytoplasmic silver-negative spaces (arrows) in proximal tubular epithelial cells—characteristic of light chain proximal tubulopathy. Glomeruli show no evidence of spikes or immune-complex deposition (Scale bar, 50 μm)

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).

Fig. 2.

Representative immunofluorescent figure(Scale bar, 50 μm). (A) Immunofluorescence revealed segmental granular IgA deposition in the mesangium. (B) Immunofluorescence for IgG showing weak granular mesangial staining. (C) The κ light chain is positive in the proximal tubular cytoplasm. (D) Immunofluorescence for λ light chain showing negative staining

Electron microscopy confirmed mesangial widening without electron-dense deposits. Glomerular basement membranes measured 280–430 nm 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 monoclonal restriction, showing specific immunogold labeling for κ-light chains localized to these crystalline deposits, with no labeling for λ-light chains. (as shown in Fig. 4).

Fig. 3.

Transmission electron micrographs (Scale bar, 2 μm). (A) No electron-dense deposits are observed in the mesangium or along the glomerular basement membrane. Foot processes are focally fused in about 30–40% of the glomerular tuft. Cytoplasm contains few microvilli and vacuoles, with occasional lysosomes. (B to D) Proximal tubular epithelial cells show intracytoplasmic crystalline-like deposits with rhomboid, rod-shaped, and irregular forms(arrows)

Fig. 4.

Immuno-electron microscopy demonstrates κ crystals in the tubular cytoplasm. (A) Immuno-electron microscopy showing κ light chain–restricted crystalline deposits within the cytoplasm of proximal tubular epithelial cells. Gold particles (arrows) are densely localized within lysosomes of proximal tubular epithelial cells, confirming κ-restricted light chain storage. (B) While no labeling is observed for λ light chain (Scale bar, 500 nm)

Diagnosis

The patient was diagnosed with Sjögren’s syndrome complicated by κ-light chain monoclonal gammopathy of renal significance, manifesting as light chain proximal tubulopathy with full-blown Fanconi syndrome (proximal tubular dysfunction with metabolic acidosis, hypophosphatemia, hypokalemia, renal glycosuria, and low-molecular-weight proteinuria).

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 1101 mg/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) occurring in a patient with a nine-year history of Sjögren’s syndrome (SS). This co-occurrence raises the important question of whether these two conditions are coincidental or reflect a potential pathophysiological link, wherein chronic B-cell dysregulation in SS may predispose to monoclonal gammopathies.

LCPT is a rare renal manifestation of monoclonal gammopathy of renal significance (MGRS) [6], caused by excessive production and tubular reabsorption of nephrotoxic monoclonal light chains—most commonly κ isotype, VκI subtype [5]. These light chains resist lysosomal degradation, leading to intracellular crystallization within proximal tubular epithelial cells, resulting in cellular dysfunction and often presenting as Fanconi syndrome [9].

Renal involvement in primary Sjögren’s syndrome typically manifests as tubulointerstitial nephritis (TIN), frequently associated with distal renal tubular acidosis (dRTA) [4]. However, SS is also characterized by profound and persistent B-cell hyperactivity, which is well established as a risk factor for lymphoproliferative disorders—including polyclonal hypergammaglobulinemia, monoclonal gammopathy, and non-Hodgkin B-cell lymphoma. In fact, Brito-Zerón et al., demonstrated in a large cohort that monoclonal gammopathy occurs in 5–10% of primary SS patients and serves as a key biomarker of severe disease and lymphoma risk, reflecting underlying B-cell clonal dysregulation rather than being a direct consequence of autoimmunity [2]. Notably, the association between SS and lymphoma is strongly supported by epidemiological and mechanistic evidence, with lymphoma widely regarded as a complication of long-standing autoimmune stimulation [1]. In contrast, the relationship between SS and MGRS remains less definitively causal, though clinically plausible.

As early as the 1980s, Moutsopoulos et al., detected free monoclonal light chains in 67% of SS patients [8]. Chronic B-cell hyperactivity, a hallmark of SS, drives polyclonal autoantibody production and inflammatory tissue damage [8]. 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 [12]. 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 [14]. 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. 5).

Fig. 5.

Pathogenic mechanism between SS and MGRS-mediated renal injury. In patients with Sjögren’s syndrome, chronic immune activation in salivary and lacrimal glands is associated with B-cell dysregulation, including overexpression of BAFF/Blys and increased production of IL-6 and IFN-γ. This microenvironment may support the formation of germinal center–like structures and, in rare instances, clonal B-cell expansion. While autoantibodies such as anti-SSA/Ro, anti-SSB/La, and rheumatoid factor are commonly produced, monoclonal immunoglobulins or free light chains can occasionally co-occur, potentially leading to monoclonal gammopathy of renal significance (MGRS) in susceptible individuals. Abbreviations: BAFF/Blys, B-cell activating factor / Bel-1; IL-6, interleukin-6; IFN-γ, interferon-gamma; RF, rheumatoid factor; Anti-SSA/Ro and Anti-SSB/La, autoantibodies against Sjögren’s syndrome-related antigens; MIDD, membranoproliferative glomerulonephritis with dense deposits disease; Ig, immunoglobulin; FLC, free light chain; eGFR, estimated glomerular filtration rate; PGNMID C3, pauci-immune C3 glomerulonephritis; LCPT, light chain proximal tubulopathy; MGRS, monoclonal gammopathy of renal significance

In our case, SS preceded renal disease by several years, providing a temporal framework consistent with—but not proof of—a pathogenic sequence. We hypothesize that the chronic inflammatory milieu of SS may have facilitated the emergence of an IgA-κ plasma cell clone (identified in the bone marrow), which subsequently produced nephrotoxic light chains leading to LCPT (Fig. 5). Thus, while SS may have provided a “first hit” through sustained B-cell activation, the direct mechanistic link to MGRS remains incompletely define.

Clinically, this case highlights a critical diagnostic dilemma. Although both SS and LCPT can cause renal tubular dysfunction, Fanconi syndrome—a hallmark of proximal tubule injury—is exceedingly rare in SS (< 3%) [15] but highly characteristic of LCPT. Therefore, the emergence of Fanconi syndrome in a patient with known SS should prompt urgent evaluation for an underlying monoclonal gammopathy. Renal biopsy is essential, as only histopathological identification of monoclonal light chain–restricted coarse granular crystalline materia can reliably distinguish LCPT from SS-related TIN and guide appropriate therapy.

Regarding management, LCPT without overt myeloma may follow an indolent course, and the role of aggressive chemotherapy remains uncertain. While Nawata et al. [10] reported stable or improved kidney function in patients with crystalline LCPT following stem cell transplantation, their cohort included cases with concomitant hematologic malignancy, limiting generalizability to isolated MGRS. Conversely, Ma et al. [7] observed no significant renal improvement in six patients with Fanconi syndrome treated with chemotherapy over 4–26 months. Notably, not all renal lesions in patients with SS and monoclonal gammopathy represent classic MGRS; some, such as monotypic tubulointerstitial nephritis, may retain responsiveness to corticosteroids or other immunosuppressive agents, suggesting a dominant inflammatory rather than immune-complex–mediated or direct light chain–toxic mechanism [13]. Thus, the optimal timing and benefit of clone-directed therapy in MGRS occurring in the context of SS require further investigation.

Conclusion

In summary, we describe an 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.

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.

Funding

This study was supported by the Zhejiang Provincial Natural Science Foundation of China under Grant No. LQN26H270002. This sudy was also funded by the Research Project of Zhejiang Chinese Medical University (2022JKZKTS36), National Natural Science Foundation of China (82304989), “Pioneer” and “Leading Goose” R&D Program of Zhejiang (2023C03075).

Data availability

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.

Declarations

Ethical approval

This study protocol was reviewed and approved by the First Affiliated Hospital of Zhejiang Chinese Medical University, approval number 2025-KLS-429-01.

Consent to publication

Written informed consent was obtained from participants for publication of the details of their medical case and any accompanying images.

Competing interests

The authors declare no competing interests.