Mesangial IgM Deposition Linked to ESKD in Patients with IgA Nephropathy

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Mesangial immunoglobulin M (IgM) deposition may be a potential risk factor for end-stage kidney disease (ESKD) in patients with advanced IgA nephropathy (IgAN), according to findings from a retrospective long-term cohort study.¹

Results provide insight into the role of IgM deposition in IgAN and underscore the broader implication of IgM in the pathology of glomerular diseases, highlighting a possible common mechanistic thread linking these distinct conditions.¹

The most frequent type of primary glomerulonephritis and a prevalent cause of ESKD, IgAN’s pathogenesis is multifactorial. Paired with its often diverse clinical presentations, IgAN management is challenging and the factors affecting its prognosis are not well understood.^1,2

“While the presence of C3 and IgG deposits has been extensively studied and shown to be associated with prognosis to some extent, the clinical significance of mesangial IgM deposition has been less explored and remains a subject of debate,” wrote Gabriel Stefan, of the department of nephrology at the Carol Davila University of Medicine and Pharmacy in Romania, and colleagues.¹

To investigate the prognostic value of mesangial IgM deposition in IgAN, investigators conducted a retrospective, observational study of adult patients diagnosed with IgAN through kidney biopsy at a single center between 2010 and 2015. Patients < 18 years of age with biopsy specimens having < 8 scorable glomeruli, insufficient clinical data, < 3 months of follow-up, absence of a functional glomerulus in the fragment for IgM immunofluorescence analysis, or secondary IgAN related to liver diseases, viral infections, autoimmune disorders, or concurrent glomerular diseases were excluded from the study.¹

Routine processes of light microscopy, immunofluorescence, and transmission electron microscopy were applied to each patient’s kidney biopsy sample. The diagnosis of IgAN was established through light microscopy and immunofluorescence, characterized by dominant IgA presence in the mesangium, and confirmed by transmission electron microscopy. Patients were classified as mesangial IgM positive based on the presence of granular deposits predominantly located in the mesangial area of the glomerulus.¹

A total of 93 patients were enrolled in the study and followed until ESKD, death, or until the end of the study in January 2021, with a median follow-up of 7 years. Among the cohort, the median age was 41 years, 68% of participants were male, estimated glomerular filtration rate (eGFR) was 48.7 mL/min, and proteinuria was 1.1 g/g. The majority of participants had arterial hypertension (68%) and 7% had type 2 diabetes mellitus.¹

Mesangial IgM-positive deposits were observed in 65 (70%) participants, while 28 (30%) were IgM-negative. Investigators noted both groups were similar in terms of age, sex, prevalence of arterial hypertension, Charlson comorbidity scores, kidney function, pathology findings, and transmission electron microscopy analysis. Treatment with renin–angiotensin system inhibitors, immunosuppression, and death rates were also comparable.¹

In total, 27 (29%) participants reached ESKD. The median kidney survival time for the entire cohort was 86.0 (95% CI, 78.5-93.4) months. Kidney survival at 1, 3, and 5 years were 92%, 85%, and 82%, respectively.¹

Further analysis revealed significantly more IgM-positive participants progressed to ESKD compared to those who were IgM-negative (37% vs 11%; P = .01). Those with mesangial IgM positivity at immunofluorescence also had a shorter mean renal survival time: 90.3 (95% CI, 78.8-101.7) versus 116.1 (95% CI, 103.3-128.8) months.¹

Multivariate analysis revealed lower eGFR (Hazard ratio [HR], 0.94; 95% CI, 0.92-0.97; P <.001), higher Oxford MEST-C score (HR, 1.53; 95% CI, 1.16-2.02; P = .002), and the presence of mesangial IgM deposits (HR, 4.75; 95% CI, 1.25-17.99; P = .02) were independently associated with ESKD.¹

Potential limitations to these findings include the single-center patient sample, small cohort size hindering investigators’ ability to perform detailed subanalyses, and potential biases and shortcomings in data collection due to the retrospective nature of the study.¹

“Our study identifies mesangial IgM deposition as a key risk factor for ESKD in IgAN, particularly in advanced stages of the disease. Given the study’s limitations, further research is essential to deepen our understanding of IgM's role in IgAN,” investigators concluded.¹ “However, the insights gained, supported by extensive follow-up and comprehensive pathology, provide a valuable foundation for future investigations.”

References:

1. ^{Stefan G, Stancu S, Zugravu A, et al. Prognostic role of mesangial IgM deposition in IgA nephropathy: a long-term cohort study. Renal Failure. https://doi.org/10.1080/0886022X.2024.2313179}
2. ^{Habas E, Ali E, Farfar K, et al. IgA nephropathy pathogenesis and therapy: Review & updates. Medicine (Baltimore). 2022;101(48):e31219. doi:10.1097/MD.0000000000031219}