Background Overt 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.

Methods We 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].

Results A 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.

Conclusions Low-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.

S.K. has received grant funding from the National Health and Medical Research Council and the Medical Research Future Fund. S.K. has also received consulting fees from Dimerix Pharmaceuticals, Chinook Pharmaceuticals, Novartis Pharmaceuticals, Novo Nordisk, and Amgen. Bayer supplied the trial medication for S.K.'s study. The George Institute for Global Health and its affiliated entities collaborate with various health and pharmaceutical companies in the design, implementation, and analysis of clinical research and trials. Some of these companies may have products related to the clinical area covered by this grant. M.J. oversees research projects funded by Boehringer Ingelheim and the Eli Lilly Alliance. B.L.N. is supported by grants from the National Health and Medical Research Council of Australia, Medical Research Future Fund, Ramaciotti Foundation, and New South Wales Health; he has received fees for advisory boards, scientific presentations, steering committee roles, travel and publication support from AstraZeneca, Alexion, Bayer, Boehringer and Ingelheim, Cornerstone Medical Education, CSL-Behring, CSL-Seqirus, the Limbic, Medscape, Menarini, MJH Life Sciences, Novo Nordisk, Otsuka, Travere, and Vera Therapeutics. All authors declare no conflicts of interest related to the present work.

https://osf.io/5dfqr

No funding was received for this review.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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This is a systematic review and meta-analysis; all data used in the analyses are extracted from previously published studies and are fully presented in the manuscript and supplementary materials.