The Association between Low-Grade Proteinuria and Adverse Kidney Outcomes in IgA Nephropathy

KEY POINTS: Systematic review/meta-analysis of 23 studies (15,289 patients) quantified prognostic effect of low-grade proteinuria in IgA nephropathy. Low-grade proteinuria (0.5-1.0 g/d) linked to higher kidney risk (hazard ratio, 1.73-2.87) and faster eGFR decline (-1.02 ml/min per year). Long-term suppression below 0.5 g/d should be a key therapeutic goal, supporting current IgA nephropathy clinical guidelines. BACKGROUND: Overt proteinuria (>1.0 g/d) is a well-established risk factor for kidney disease progression in IgA nephropathy. However, recent evidence suggests that even low-grade proteinuria, typically defined as 0.5-1.0 g/d, may be clinically significant. The prognostic effect of low-grade proteinuria has not been systematically evaluated. METHODS: We conducted a systematic review and meta-analysis to evaluate the association between low-grade proteinuria and adverse kidney outcomes in patients with IgA nephropathy. A systematic literature search was performed on PubMed and Web of Science. Eligible studies included those reporting on kidney outcomes such as eGFR decline, kidney failure, or eGFR slope in relation to low-grade proteinuria measured either at baseline or during follow-up ( e.g ., time-averaged proteinuria). Data were synthesized using random-effects meta-analysis. The protocol was registered in the Open Science Framework REGISTRIES ( https://osf.io/5dfqr ). RESULTS: A total of 23 studies ( N =15,289) met the inclusion criteria, of which 15 contributed to at least one meta-analysis. Baseline low-grade proteinuria was significantly associated with an increased risk of adverse kidney outcomes compared with proteinuria below 0.5 g/d (pooled hazard ratio, 1.73; 95% confidence interval [CI], 1.36 to 2.20; nine studies). Similarly, low-grade time-averaged proteinuria was associated with a higher risk of kidney outcomes (pooled hazard ratio, 2.87; 95% CI, 1.48 to 5.56; seven studies) and a significantly steeper annual decline in eGFR (mean difference, -1.02 ml/min per 1.73 m 2 per year; 95% CI, -1.60 to -0.45; four studies). Subgroup analyses and leave-one-out sensitivity analyses were consistent with the overall findings. CONCLUSIONS: Low-grade proteinuria, whether assessed at baseline or over time, is an important predictor of kidney disease progression in patients with IgA nephropathy. These results reinforce recent clinical guidelines recommending proteinuria control under 0.5 g/d. Long-term suppression of proteinuria should be considered a key therapeutic goal in IgA nephropathy.