Time-Weighted Average Proteinuria and Renal Function Decline in IgA Nephropathy: A Retrospective Cohort Study

Ricong Xu,&ast; Tao Cao,&ast; Ying Liao, Yuna Chen, Yi Yu, Jianying Guo, Anni Zhong, Xiaojie Chen, Yi Xu, Qijun Wan Department of Nephrology, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qijun Wan, Department of Nephrology, The Second People’s Hospital of Shenzhen, 3002 Sungang Road, Shenzhen, 518035, People’s Republic of China, Tel +860755 83366388, Email [email protected]: IgA nephropathy (IgAN) is the leading primary glomerulonephritis globally, with many patients advancing to end-stage renal disease. Proteinuria is a key predictor of renal function decline in IgAN, yet the best method for long-term assessment is unclear. This study explores the relationship between time-weighted average proteinuria (TWAP), a novel metric of cumulative proteinuria exposure, and renal function decline in IgAN patients.Methods: This single-center retrospective cohort study encompassed 549 patients with biopsy-confirmed primary IgAN from Shenzhen Second People’s Hospital from 2011 to 2023. TWAP served as the primary exposure variable, calculated using the protein-creatinine ratio values, while changes in estimated glomerular filtration rate (eGFR) constituted the primary outcome. Covariates included age, sex, blood pressure, and mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C) (known as the Oxford Classification MEST-C score system). The associations between TWAP and eGFR trajectories were analyzed using Generalized Additive Mixed Models.Results: In patients with baseline eGFR 15– 60 mL/min/1.73m², higher TWAP levels correlated with accelerated eGFR decline. Compared to TWAP < 0.3 g/g, TWAP 0.3– 0.5 g/g, 0.5– 1 g/g, and ≥ 1 g/g were associated with additional annual eGFR declines of 2.04 (95% CI: − 3.72 to − 0.35), 3.38 (95% CI: − 5.12 to − 1.65), and 4.04 (95% CI: − 6.61 to − 1.47) mL/min/1.73m²/year, respectively. For eGFR ≥ 60 mL/min/1.73m², only TWAP ≥ 1 g/g significantly accelerated eGFR decline 5.70 (95% CI: − 6.84 to − 4.55) mL/min/1.73m²/year.Conclusion: TWAP significantly predicts renal function decline in IgAN, especially in patients with pre-existing renal dysfunction. Maintaining TWAP below 0.3 g/g may significantly slow disease progression, emphasizing the importance of stringent proteinuria control in IgAN management.Keywords: IgA nephropathy, mixed methods, renal function, time-weighted average proteinuria, (TWAP)