The association between low-grade proteinuria and adverse kidney outcomes in IgA nephropathy: A systematic review and meta-analysis

BackgroundOvert proteinuria (>1.0 g/day) is a well-established risk factor for kidney disease progression in IgA nephropathy (IgAN). However, recent evidence suggests that even low-grade proteinuria, typically defined as 0.5-1.0 g/day, may be clinically significant. The prognostic impact of low-grade proteinuria has not been systematically evaluated. MethodsWe conducted a systematic review and meta-analysis to evaluate the association between low-grade proteinuria and adverse kidney outcomes in patients with IgAN. A systematic literature search was performed on PubMed and Web of Science. Eligible studies included those reporting on kidney outcomes such as estimated glomerular filtration rate (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 [TAP]). Data were synthesized using random-effects meta-analysis. No funding was received for this review. The protocol was registered in OSF REGISTRIES [https://osf.io/5dfqr]. ResultsA total of 23 studies involving 15,289 patients met the inclusion criteria. Baseline low-grade proteinuria was significantly associated with an increased risk of adverse kidney outcomes compared to proteinuria below 0.5 g/day (pooled hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.36-2.20). Similarly, low-grade TAP was associated with a higher risk of kidney outcomes (pooled HR 2.87, 95% CI 1.48-5.56) and a significantly steeper annual decline in eGFR (mean difference -1.02 mL/min/1.73 m2/year, 95% CI -1.60 to -0.45). Subgroup analyses based on geographic region and leave-one-out sensitivity analyses were consistent with the overall findings. ConclusionsLow-grade proteinuria, whether assessed at baseline or over time, is an important predictor of kidney disease progression in patients with IgAN. These results reinforce recent clinical guidelines recommending proteinuria control under 0.5 g/day. Long-term suppression of proteinuria should be considered a key therapeutic goal in IgAN.