Hematuria as a biomarker guiding treatment decisions in IgA nephropathy? Yes

Hematuria is a central clinical feature of IgA nephropathy (IgAN). Episodes of gross hematuria, often triggered by upper respiratory tract infections, are the first manifestation in a substantial proportion of patients, whereas others show microscopic hematuria accompanied by variable degrees of proteinuria from the outset. The trajectory of hematuria throughout the disease course varies: episodes of visible hematuria are more frequent at the onset, whereas microscopic hematuria persists in most cases. However, its degree may decrease or even disappear, either spontaneously or in response to different therapeutic interventions. Despite its clinical significance, hematuria has not been systematically incorporated into treatment decision-making for IgAN. The recently published KDIGO 2025 Clinical Practice Guideline for the Management of IgAN [1] prioritized proteinuria as the primary marker of disease severity, given the strength of the supporting evidence, and focused on strategies to reduce proteinuria to 0.75–1 g/day not accompanied by hematuria have a better kidney survival than those with similar degrees of proteinuria and persistent hematuria [6,7] challenges the exclusive proteinuria-centric approach that has governed IgAN management for decades. Furthermore, nonspecific factors (weight gain, hypertension, residual proteinuria secondary to glomerulosclerotic lesions) can modify proteinuria levels without reflecting true disease activity. Undoubtedly, the main obstacle to adopting hematuria as a clinical biomarker in IgAN has been the variability in detection methods and the inherent imprecision of many of them. Traditionally, hematuria has been assessed using urine dipstick or standard microscopy of urinary sediment. The latter method allows for a more precise quantification of hematuria, usually expressed as the number of RBC per high power field (RBC × HPF). Although it is considered the most reliable method for evaluating microscopic hematuria, it is time-consuming and requires technical expertise. For this reason, it is being replaced in many centers by automated flow cytometry analyzers, which also allow for hematuria quantification. Some studies have shown good correlation between these different methods of estimating hematuria [3,8], but the contrast between the variability and imprecision surrounding hematuria quantification and the precise measurement of proteinuria/albuminuria is evident. This imprecision has prevented an accurate definition of the threshold in the number of RBC/HPF having a prognostic influence on kidney survival. Nevertheless, the absence of hematuria (negative dipsticks, urinary sediments without RBCs or with intermittent hematuria below 5 RBC × HPF) is an important information for guiding treatment in IgAN, as it is a valuable reflection of absent or low glomerular inflammation. Research aimed to refine hematuria measurement is needed to bridge the gap between clinical practice (in which hematuria assessment should be mandatory) and current guidelines (which do not include it due to a lack of conclusive evidence and standardized quantification methods). Except for some recently designed studies, the presence of hematuria has not been used as an inclusion criteria in randomized controlled trials (RCTs) conducted in IgAN. Nevertheless, several studies have reported resolution of hematuria in a significant proportion patients after treatment with various immunomodulatory/anti-inflammatory drugs: corticosteroids, mycophenolate mofetil, targeted-release budesonide, anti-APRIL/BAFF drugs, or complement inhibitors. Subgroup analyses from recent and ongoing RCTs may provide important information about the value of hematuria as a prognostic biomarker in IgAN, although the reliability of such analyses may be limited by the imprecise assessment of hematuria (frequently based on dipstick testing without longitudinal follow-up). Moreover, the incorporation of the disappearance or reduction of hematuria as a treatment goal, alongside the achievement of proteinuria levels below 0.3–0.5 g/day, is a topic of great importance on which current and future RCTs could provide decisive information. In the context of the ongoing therapeutic revolution in IgAN, we think that the need to carefully evaluate hematuria in every patient will become increasingly important. As we recently proposed [10], in patients with persistent proteinuria despite optimized conservative treatment (including renin–angiotensin blockers), the absence or presence of hematuria could guide the subsequent treatment strategies. In patients without hematuria, drugs that primarily induce proteinuria reduction through hemodynamic mechanisms (sodium–glucose co-transporter 2 inhibitors, sparsentan or other endothelin antagonists, mineralocorticoid antagonists) would be the preferred first option. Conversely, in patients with persistent hematuria, particularly when accompanied by active inflammatory lesions in kidney biopsy and/or a declining kidney function, drugs with a proven anti-inflammatory/immunomodulatory effect should be considered. In conclusion, growing evidence supports hematuria as a key marker of glomerular inflammation and a predictor of kidney outcomes in IgAN. Routine assessment of hematuria should therefore be integrated into the clinical monitoring of all patients with IgAN. Although the current evidence remains primarily observational, integrating hematuria with proteinuria and kidney function trajectory could improve therapeutic decision-making and the definition of treatment goals. However, large-scale studies are needed to better define the long-term interaction between proteinuria and hematuria, and to refine and standardize methods for detecting and quantifying hematuria. None declared.