Introduction
IgM-positive plasma cell tubulointerstitial nephritis (IgMPC-TIN) is a rare immune-mediated kidney disease first described in 2017,1 characterized by dense IgM-producing plasma cell infiltration, distal renal tubular acidosis, Fanconi syndrome, and frequent coexistence with Sjögren’s syndrome and primary biliary cholangitis.
Several Japanese studies have demonstrated short-term clinical responses to glucocorticoids,2, 3, 4, 5, 6, 7 typically accompanied by reduction in serum IgM levels, improvement in tubular injury markers, and partial recovery of renal function. However, nearly all published cases describe follow-up periods of only several months to a few years, leaving the long-term renal trajectory, including the durability of treatment response, relapse patterns, and the influence of metabolic or structural complications, largely unknown. Furthermore, international awareness of this entity remains limited, and there is no consensus regarding phase-specific therapeutic strategies.
Here, we report the longest observational series of biopsy-proven IgMPC-TIN, involving 5 patients followed-up with for 3 to 17 years. By analyzing sequential monthly change in estimated glomerular filtration rate (eGFR, ΔeGFR) trajectories using an expanding-window regression approach, we aimed to characterize both the early and chronic phases of renal function and to clarify the extent to which glucocorticoids and ursodeoxycholic acid (UDCA) may contribute to disease stabilization. This study provides new insights into the potential therapeutic windows for this rare disorder.
Results
Five women (mean age: 50 years) with biopsy-proven IgMPC-TIN were followed-up with for 3 to 17 years (mean: 112 months). At the time of diagnosis, the mean serum IgM concentration was 833 ± 257 mg/dl and the mean eGFR was 43.9 ± 13.3 ml/min per 1.73 m2. Three patients had primary biliary cholangitis, 1 had suspected asymptomatic primary biliary cholangitis, and 1 had cholestatic liver injury. All patients received UDCA; 3 (cases 1, 3, and 5) received prednisolone (30 mg/d), and 2 received immunosuppressants (cyclosporine in case 1 and mycophenolate mofetil in case 5). Treatment selection reflected clinical judgment at the time of diagnosis, largely based on systemic involvement and presumed inflammatory activity, which may have introduced treatment selection bias. Baseline interstitial fibrosis ranged from 20% to 70% across patients (Supplementary Table S1). Four patients developed nephrolithiasis during follow-up, 3 of whom showed a gradual increase in stone burden. One patient (case 3) developed hydronephrosis caused by ureteral stones, coinciding with renal deterioration. The detailed clinical data are summarized in the Supplementary Case Description and Table S1.
In Figure 1, we illustrate the sequential ΔeGFR trajectories for each patient across the entire observation period, providing a dynamic view of how the eGFR slope evolved as follow-up progressed. Glucocorticoid-treated patients showed marked early improvement: +6.5 (case 1 at 1 month), +3.7 (case 3 at 1 month), and +2.1 (case 5 during months 3–7), followed by gradual stabilization. In contrast, case 2 in patients treated solely with UDCA exhibited an initial decline in ΔeGFR of −6.2 at 1 month. However, she recovered and showed, similar to case 4, consistent ΔeGFR in the later follow-up period. Detailed longitudinal laboratory and clinical data corresponding to these trajectories are provided in Supplementary Figures S1 to S5.
Figure 1.
Sequential changes in the monthly slope of eGFR (ΔeGFR) in 5 patients with IgMPC-TIN. Sequential ΔeGFR values (ml/min per 1.73 m2/mo) were calculated using expanding-window regression for each patient during the full individual follow-up period. Panels (a) to (e) correspond to cases 1 to 5, with total follow-up durations of (a) 201, (b)151, (c) 64, (d) 108, and (e) 37 months, respectively. ΔeGFR values represent the slope of the change in eGFR derived from serial measurements over increasing time intervals. eGFR, estimated glomerular filtration rate; ΔeGFR, monthly change in eGFR.
For all analyses, the early phase was defined a priori as 0 to 7 months after diagnosis and the chronic phase as the period thereafter, as detailed in the Supplementary Methods. Regression analyses (Figure 2) confirmed the following biphasic pattern, except for case 3 suffering from hydronephrosis: a glucocorticoid-responsive early phase (0–7 months), with ΔeGFR/mo of +0.5 (case 1) and +2.1 (case 5), followed by a chronic phase (> 7 months) in which annual ΔeGFR declined or approached 0 (−1.4 and +0.7 ml/min per 1.73 m2/yr). In nonglucocorticoid patients, ΔeGFR/mo remained near 0 (−0.5 to +0.5) in the early phase, and ΔeGFR/yr gradually declined in the chronic phase (−0.8 to −0.4).
Figure 2.
Regression analyses of eGFR during the early and chronic clinical phases in 5 patients with IgMPC-TIN. Regression lines were calculated separately for the early phase (0–7 months) and chronic phases (> 7 months). Panels (a) and (b) show glucocorticoid-treated patients (case 1, •; case 3, ◆; case 5, ⬡), illustrating early phase slopes in panel a and chronic-phase slopes in panel (b). Panels (c) and (d) show patients treated without glucocorticoids (case 2, ▲; case 4, □), with early phase slopes in (c) and chronic-phase slopes in (d). The total follow-up duration ranged from 37 to 201 months for the 5 patients. eGFR, estimated glomerular filtration rate.
Overall, these findings indicate that IgMPC-TIN comprises 2 pathophysiologic phases: an inflammatory phase responsive to glucocorticoids and a chronic maintenance phase predominantly shaped by metabolic and structural factors, including nephrolithiasis and obstructive events. Early antiinflammatory therapy appears to be central to short-term improvements, whereas long-term stability depends on metabolic control, stone prevention, and ongoing monitoring.
Discussion
This study provides the longest longitudinal evaluation of IgMPC-TIN reported to date; and demonstrates a consistent biphasic renal trajectory: an early inflammatory phase that is glucocorticoid-responsive, followed by a chronic maintenance phase in which renal function stabilizes or gradually declines. Although limited by the small cohort size, the reproducible pattern across patients supports the concept that IgMPC-TIN follows a phase-dependent therapeutic profile and behaves as a chronic autoimmune tubulointerstitial disease with a definable therapeutic window.
In glucocorticoid-treated patients, renal function improves during the early phase, paralleling reductions in serum IgM and urinary tubular markers,2, 3, 4, 5, 6, 7, 8 indicating suppression of acute inflammation. However, this benefit diminished over time, and the ΔeGFR slope approached 0 within several years. Once inflammatory activity subsides, transitioning to or combining steroid-sparing immunosuppressants such as calcineurin inhibitors or mycophenolate may help sustain disease control while limiting long-term steroid toxicity. B-cell–directed therapy (e.g., rituximab) remains theoretical, with minimal evidence of efficacy in IgMPC-TIN. From a chronic kidney disease perspective, sodium-glucose cotransporter-2 inhibitors may offer renoprotectionS1,S2; though their role in IgMPC-TIN remains uncertain.
Two patients treated with UDCA alone remained stable for over a decade without relapse or hydronephrosis. Although this likely reflects milder baseline disease, UDCA’s cytoprotective and antiinflammatory effects, including the mitigation of endoplasmic reticulum stress, may contribute to stability during the chronic phase.S3–S5 Taken together, these findings support a phase-adapted strategy in which treatment intensity is aligned with inflammatory activity and overall disease severity.
Long-term renal outcomes are strongly influenced by metabolic and structural complications. Most patients developed progressive nephrolithiasis, whereas 1 patient experienced hydronephrosis because of obstructive stones, coinciding with renal deterioration. Distal renal tubular acidosis likely promotes lithogenesis,9 underscoring the importance of metabolic correction, urinary alkalinization, adequate hydration, and regular imaging. Coexisting Sjögren’s syndrome or primary biliary cholangitis may further accelerate renal damage and warrants ongoing systemic assessment.7
Baseline interstitial fibrosis ranged from 20% to 70% across patients. Although milder fibrosis appeared to be associated with greater renal reserve at presentation, the small cohort size precluded determining a consistent influence on longitudinal ΔeGFR trajectories. These observations suggest that preexisting fibrosis may contribute to chronic-phase variability, but its effect could not be definitively established in this series.
Despite the limitations of a small single-center cohort and nonstandardized treatment, the long observation period and use of sequential ΔeGFR analyses provide unique insights into the dynamic interplay between inflammation, metabolic stress, and structural remodeling in patients with IgMPC-TIN. Given the rarity of this disease, assembling larger biopsy-proven cohorts is challenging. Future multicenter collaborations are essential to validate phase-specific trajectories and refine treatment strategies for both early inflammatory and chronic maintenance phases. Our findings may serve as a foundation for future studies.
In conclusion, IgMPC-TIN follows a biphasic course in which glucocorticoids drive early improvement, whereas UDCA and metabolic management support long-term stability. Tailored immunosuppressive and metabolic strategies may help preserve renal function across disease phases.
Disclosure
All the authors declared no competing interests.
Acknowledgments
Ms. Midori Tamagawa, Ms. Yumiko Ota, and Ms. Hiromi Takahashi provided technical assistance.
Funding
This work was supported by JSPS KAKENHI Grant Numbers JP17K09692, JP20K08630, and JP23K07695 from the Japan Society for the Promotion of Science; a research grant (2019), a grant for life cycle medicine (2020), and a Dean's discretionary grant (2024) from the Faculty of Medical Sciences, University of Fukui; and grants from the Daiwa Securities Health Foundation (2019), the Novartis Foundation (Japan) for the Promotion of Science (2020), and the Japanese Association of Dialysis Physicians (2023–2024). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding institutions.
Data Availability Statement
The data underlying this article will be shared upon reasonable request to the corresponding author.
Author Contributions
Conceptualization, formal analysis, visualization, and writing of original draft were by NT. Methodology was by NT, HY, and HN. Investigation was by HY, HK, CY, MY, NI, KM, SN, KN, SF, YN, and MK. Data curation was by HY, HK, CY, and KK. Validation was by NI and KM. Resources was by CY, MY, and HN. Writing – review and editing was by all the authors (led by TT and MI). Supervision was by TT (lead) and MI. Project administration was by NT. Funding acquisition was by NT.
Declaration of Generative AI and AI-assisted technologies in the writing process:
During the preparation of this manuscript, the authors used DeepL (https://www.deepl.com), Paperpal (version Extensive 2.0), and ChatGPT (https://chatgpt.com/) to assist with language editing and to improve readability. Following the use of these tools, the authors reviewed, edited, and verified all the content and took full responsibility for the integrity and accuracy of the manuscript.
Footnotes
Supplementary Methods.
Supplementary References.
Supplementary Case Description.
Figure S1. Serial clinical data for case 1.
Figure S2. Serial clinical data for case 2.
Figure S3. Serial clinical data for case 3.
Figure S4. Serial clinical data for case 4.
Figure S5. Serial clinical data for case 5.
Table S1. Clinical, laboratory, and pathological findings at diagnosis and final follow-up in 5 patients with IgMPC-TIN.
Supplementary Material
Supplementary Methods. Supplementary References. Supplementary Case Description. Figure S1. Serial clinical data for case 1. Figure S2. Serial clinical data for case 2. Figure S3. Serial clinical data for case 3. Figure S4. Serial clinical data for case 4. Figure S5. Serial clinical data for case 5. Table S1. Clinical, laboratory, and pathological findings at diagnosis and final follow-up in 5 patients with IgMPC-TIN.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Methods. Supplementary References. Supplementary Case Description. Figure S1. Serial clinical data for case 1. Figure S2. Serial clinical data for case 2. Figure S3. Serial clinical data for case 3. Figure S4. Serial clinical data for case 4. Figure S5. Serial clinical data for case 5. Table S1. Clinical, laboratory, and pathological findings at diagnosis and final follow-up in 5 patients with IgMPC-TIN.
Data Availability Statement
The data underlying this article will be shared upon reasonable request to the corresponding author.