Impact of proteinuria levels on long-term kidney outcomes in IgA nephropathy: a meta-analysis

Purpose Given the most recent recommendation from KDIGO on proteinuria target levels < 0.5 g/d (preferably < 0.3 g/d) in IgA nephropathy (IgAN), there is an increased need to understand the long-term kidney benefits of achieving these lower proteinuria levels. Two recent systematic literature reviews have been conducted with complementary findings; however, no meta-analysis has quantified the benefit of managing to levels of proteinuria < 0.3 g/d. This study aims to advance the literature by synthesizing the most comprehensive body of evidence and quantifying the association between levels of proteinuria and kidney failure in adults with IgAN, with particular focus on lower proteinuria thresholds (< 0.3 g/d and < 0.5 g/d) relative to higher levels. Methods Evidence from two systematic literature reviews of observational studies (PubMed, Web of Science, and Embase from 2005 to 2025) evaluating associations between proteinuria levels and kidney failure outcomes in IgAN was used as the basis for this multilevel meta-analysis (to address multiple definitions for kidney failure). Heterogeneity across studies was evaluated. Random-effects meta-analyses were conducted to compare kidney failure outcomes for patients with proteinuria < 0.5 g/d (and < 0.3 g/d) to patients who had higher levels. Results Eighteen studies were eligible for inclusion in the meta-analysis, reporting kidney failure outcomes defined by end-stage kidney disease (ESKD), estimated glomerular filtration rate (eGFR)-based outcomes, serum creatinine (SCr)-based outcomes and/or composite kidney outcomes. Across the studies, proteinuria was assessed either at a single timepoint (e.g., at study baseline/biopsy) and/or longitudinally during follow-up (e.g., as time-averaged or remission-based). Using < 0.5 g/d as the reference group, higher proteinuria levels were associated with significantly increased hazards of kidney failure outcomes, with hazard ratios (HRs) of 2.10 (95% CI 1.23–3.59) for 0.5–1.0 g/d and 6.35 (95% CI 2.64–15.26) for ≥ 1.0 g/d. Using < 0.3 g/d as the reference group, a similar association was observed with HRs of 1.99 (95% CI 0.50–7.90) for 0.3–0.5 g/d, 3.86 (95% CI 1.99–7.48) for 0.5–1.0 g/d, and 12.86 (95% CI 4.38–37.80) for ≥ 1.0 g/d. Conclusions Based on a comprehensive evidence base, lower proteinuria levels are associated with substantially more favorable long-term kidney outcomes in IgAN patients, with levels below 0.3 g/d associated with the longest kidney survival. These findings provide supportive evidence of current KDIGO recommendations and substantiate the clinical importance of achieving very low proteinuria levels in contemporary IgAN management.