The Correlation Between Podocyte Senescence and the Clinicopathology in Elderly Patients with IgAN

Yan Cai1 ,* Yan Yang1 ,* Yuan Yuan,1,2 Xue Jiang,1,2 Shuman Zhao1,2 1Department of Nephrology, Hangzhou Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Key Laboratory of Precise Prevention and Treatment of Rheumatism Syndrome of Renal Wind Disease, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuman Zhao, Department of Nephrology, Hangzhou Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang Chinese Medical University, No. 453, Tiyuchang Road, Xihu District, Hangzhou City, Zhejiang Province, People’s Republic of China, Tel +86 13260255521, Email [email protected] Xue Jiang, Department of Nephrology, Hangzhou Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang Chinese Medical University, No. 453, Tiyuchang Road, Xihu District, Hangzhou City, Zhejiang Province, People’s Republic of China, Tel +86 15958170363, Email [email protected]: IgAN is a common primary glomerular disease, and age may affect its clinical manifestations and progression. However, age-related differences in elderly IgAN, especially the role of podocyte senescence and the cGAS-STING pathway in elderly IgAN patients, remain incompletely understood.Patients and Methods: This retrospective study analyzed 1012 renal biopsy‑confirmed IgAN patients from January 2014 to January 2024, categorized into elderly (≥ 60 years, n=119) and younger (18– 60 years, n=893)) groups after exclusion. Clinical, laboratory, and pathological data were collected. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate prognostic factors. Expression of the cGAS-STING pathway in renal tissues was detected to explore its association with podocyte injury. SASP in serum was detected by ELISA and qPCR.Results: Compared with the young IgAN group, the elderly IgAN group had higher levels of 24-hour urinary protein, urea and creatinine; lower hemoglobin and albumin; more severe tubular atrophy/interstitial fibrosis (T1/2 lesions, 47.1% vs. 23.9%); lower IgA immunofluorescence intensity; and more severe podocyte fusion. Kaplan-Meier analysis showed poorer renal outcomes in the elderly IgAN group (P< 0.05). Multivariate Cox regression identified podocyte fusion (> 50%) as an independent prognostic factor in the elderly IgAN group (HR=5.72, P=0.011) but not in the young IgAN group.The cGAS-STING pathway is highly expressed in the podocyte of IgAN, especially in the elderly, SASPs in serum, such as IL-6, IL-10, were also highly expressed in the elderly IgAN group, indicating that its activation is related to severe podocyte fusion, elevated proteinuria, and impaired renal function.Conclusion: Elderly IgAN patients exhibit distinct clinicopathological features dominated by chronic lesions and podocyte injury. Severe podocyte fusion (> 50%) is a critical independent prognostic factor for this population. The cGAS-STING pathway may mediate age-related podocyte senescence and injury, representing a potential therapeutic target for elderly IgAN patients.Keywords: immunoglobulin A nephropathy, podocyte senescence, cGAS-STING, elderly patients, clinical studies