A recent systematic review and meta-analysis has shown that even low-grade proteinuria, defined as 0.5–1.0 g/day, is associated with a significant risk of adverse kidney events in patients with immunoglobulin A (IgA) nephropathy.
During follow-up periods of 46 to 84 months, adverse kidney outcomes occurred in 18 percent of patients with baseline low-grade proteinuria and 12 percent of those with time-averaged low-grade proteinuria.
Study author Dr Takaya Sasaki of the Jikei University School of Medicine in Tokyo, Japan, cautioned that low-grade proteinuria should not be dismissed as reassuring in IgA nephropathy. “Even when proteinuria is below 1 g/day, persistent levels of 0.5 g/day or higher are linked to an increased risk of disease progression.”
IgA nephropathy is the most common primary glomerulonephritis, and up to 50 percent of patients develop kidney failure within 10–20 years. Proteinuria below 1.0 g/day has long been considered a relatively low risk for disease progression in IgA nephropathy. However, current findings challenge that assumption.
23 studies, over 15,000 patients
Sasaki and colleagues analysed 23 published studies involving 15,289 patients from Asia, Europe, and North America, with follow-up periods ranging from 3.1 to >9 years. [Clin J Am Soc Nephrol 2026;21:615-625]
Across nine studies assessing baseline proteinuria, low-grade proteinuria (0.5–1.0 g/day) was associated with a 73 percent higher risk of adverse kidney outcomes than proteinuria below 0.5 g/day (pooled HR 1.73, 95 percent confidence interval [CI], 1.36−2.20). Adverse outcomes were defined as a doubling of serum creatinine, a ≥30–50 percent decline in estimated glomerular filtration rate (eGFR), kidney failure, or kidney replacement therapy.
Similarly, in seven studies assessing time-averaged proteinuria (TAP), low-grade TAP was associated with a nearly threefold risk of adverse kidney outcomes (pooled HR 2.87, 95 percent CI, 1.48−5.56). Across four studies, low-grade TAP was also linked to a significantly faster annual decline in kidney function, with a mean difference in eGFR slope of −1.02 mL/min/1.73 m² per year (95 percent CI, −1.60 to −0.45).
“These findings strengthen the evidence for the 2025 KDIGO guideline treatment target of proteinuria below 0.5 g/day,” said Sasaki.
Additionally, dose-response analyses showed that each increase in baseline proteinuria category was associated with a 1.88-fold higher risk of adverse outcomes, while each increase in TAP category was associated with a 3.06-fold higher risk. These associations remained robust across geographic regions and in sensitivity analyses.
Prognostic significance
The researchers said the findings underscore the importance of reducing proteinuria and maintaining its suppression throughout the disease course. “Therapeutic interventions aimed at sustaining lower proteinuria levels long-term are critical for modifying the disease trajectory,” they added.
In an accompanying editorial, Dr Erin Vaughan of the University of Sydney and Dr Vlado Perkovic of the University of New South Wales, both in Sydney, Australia, said the findings have meaningful prognostic significance. [Clin J Am Soc Nephrol 2026;21:538-540]
“Individuals with low-grade proteinuria have traditionally been considered at low risk of progression in IgA nephropathy, a view that has shaped clinical decision-making and trial design,” Vaughan and Perkovic said. “The present findings add important granularity to the available evidence by demonstrating a graded, continuous association between proteinuria burden and subsequent kidney risk, challenging the assumption that proteinuria goals below conventional thresholds of 1 g/day provide long-term kidney protection.”
Sasaki said an important next step is to determine which treatments, and at what stage of the disease, offer long-term kidney benefits to patients with low-grade proteinuria.