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A systematic review and meta-analysis of 23 studies found that people with IgA nephropathy and proteinuria of 0.5–1.0 g/day had higher rates of adverse kidney outcomes than those below 0.5 g/day. The observational findings support the stricter proteinuria target in updated KDIGO guidance, but do not establish that treatment to reach that target improves outcomes.
A systematic review and meta-analysis has linked proteinuria of 0.5–1.0 g/day with a higher risk of worsening kidney outcomes in people with IgA nephropathy, challenging the view that levels below 1 g/day are necessarily reassuring. The findings support the tighter proteinuria target in the 2025 KDIGO guidelines, but the underlying studies were observational and do not show that lowering proteinuria to a particular level directly prevents kidney decline.
Published in the Clinical Journal of the American Society of Nephrology, the analysis combined 23 studies and 15,289 patients from Asia, Europe and North America. Follow-up ranged from 3.1 years to more than nine years, and the studies included research published through July 2025. The investigators assessed both proteinuria at baseline and time-averaged proteinuria during follow-up.
In nine studies assessing baseline levels, patients with proteinuria of 0.5–1.0 g/day had a higher risk of adverse kidney outcomes than those with levels below 0.5 g/day: pooled hazard ratio 1.73 (95% CI 1.36–2.20). In seven studies assessing time-averaged proteinuria, the corresponding pooled hazard ratio was 2.87 (95% CI 1.48–5.56). These outcomes included measures such as a doubling of serum creatinine, a decline in estimated glomerular filtration rate (eGFR), kidney failure or kidney replacement therapy.
Across four studies, low-grade time-averaged proteinuria was also associated with a faster annual decline in eGFR, averaging 1.02 mL/min/1.73 m² more loss per year than the comparison group. The researchers reported that the associations remained robust across geographic regions and sensitivity analyses. They also reported higher risk with each incremental proteinuria category, though those dose-response results describe associations, not proof of cause and effect.
Why the 0.5 g/day Threshold Matters
The findings add evidence relevant to how clinicians assess risk in IgA nephropathy, a kidney disease in which protein in the urine is used as a marker of disease activity and prognosis. If proteinuria between 0.5 and 1.0 g/day is associated with poorer outcomes, treating every level below 1 g/day as low risk could overlook some patients who may need closer evaluation.
The analysis also aligns with the 2025 KDIGO guideline update, which lowered its proteinuria target from below 1.0 g/day to below 0.5 g/day. However, a risk association does not establish that treatment aimed at crossing that threshold will improve a patient’s long-term kidney health. Decisions about monitoring or treatment remain matters for patients and qualified clinicians, based on individual circumstances and the available evidence.
The results may also affect research planning. The source report says many recent clinical trials have enrolled patients with proteinuria above 1.0 g/day. People with levels of 0.5–1.0 g/day may consequently be underrepresented in trials of newer disease-modifying therapies, leaving less direct evidence about treatment for this group.
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How Guidelines and Evidence Align
IgA nephropathy is described in the report as the most common primary glomerulonephritis globally. The report says up to 50% of patients ultimately progress to kidney failure within 10 to 20 years; that figure is a broad estimate and does not predict the course for any individual patient.
Before the 2025 KDIGO update, proteinuria below 1.0 g/day had often been regarded as relatively low risk. The updated target reflects growing attention to lower levels, but the study authors noted that prior recommendations relied largely on individual observational studies and narrative reviews. Their meta-analysis specifically examined kidney risks associated with low-grade proteinuria.
In an accompanying editorial, Erin Vaughan of the University of Sydney and Vlado Perkovic of the University of New South Wales said the findings add detail to the relationship between proteinuria burden and later kidney risk. They pointed to reported adverse outcomes over follow-up periods of 46 to 84 months: 18% among patients with low-grade baseline proteinuria and 12% among those with low-grade time-averaged proteinuria. These figures refer to different study groupings and should not be read as a direct comparison between them.
“Low-grade proteinuria should not be dismissed as reassuring in IgA nephropathy.”
— Takaya Sasaki, MD, PhD, Jikei University School of Medicine, speaking to MedPage Today
Treatment Benefit Still Unproven
The meta-analysis pooled observational studies, so it cannot establish that proteinuria itself caused the outcomes or that lowering it below 0.5 g/day will prevent kidney decline. The report does not identify which treatments, if any, produce long-term benefit specifically for people whose proteinuria is between 0.5 and 1.0 g/day, or when such treatment should begin.
The source report also says trials have largely enrolled patients with proteinuria above 1.0 g/day. That leaves uncertainty about how well results from those trials apply to people with lower levels and whether approved therapies benefit them. The supplied report does not provide details about individual study limitations or a single pooled absolute risk estimate across all patients.
Trials Must Include Lower-Risk Groups
The study authors and accompanying editorialists called for interventional trials that enroll patients with low-grade proteinuria. Such research would need to test whether specific therapies, started at different stages of disease, can safely maintain lower proteinuria and improve kidney outcomes over time.
Until those results are available, the meta-analysis offers evidence about prognosis rather than a treatment prescription. The next key development will be trial evidence that directly tests benefits for patients in the 0.5–1.0 g/day range, a group the source report says has often been excluded from recent studies.
Key Questions
What does low-grade proteinuria mean in this study?
It means proteinuria of 0.5 to 1.0 grams per day. The analysis compared that range with proteinuria below 0.5 g/day in people with IgA nephropathy.
What kidney risks did the meta-analysis report?
For baseline proteinuria, the pooled hazard ratio for adverse kidney outcomes was 1.73 for the 0.5–1.0 g/day group compared with levels below 0.5 g/day. For time-averaged proteinuria, it was 2.87. These are associations from observational studies, not proof that proteinuria caused the outcomes.
Does this study prove that treatment below 0.5 g/day prevents kidney damage?
No. The researchers said the evidence was observational and does not directly establish that treating to below 0.5 g/day improves kidney outcomes. Trials are needed to answer that question.
How does this relate to the KDIGO guidelines?
The findings align with the 2025 KDIGO update, which lowered the proteinuria target from below 1.0 g/day to below 0.5 g/day. The meta-analysis provides supporting risk evidence but does not test the effect of following the target.
What research is needed next?
Researchers called for treatment trials that include people with proteinuria of 0.5–1.0 g/day and test which therapies, and what timing, can improve long-term kidney outcomes.
Source: medpagetoday.com
