Hematuria as a biomarker guiding treatment decisions in IgA nephropathy? No

The management of IgA nephropathy (IgAN) is undergoing change at a pace that would have seemed unimaginable only a decade ago. The completion of several Phase 3 trials reporting clinical benefit in terms of proteinuria reduction and preservation of kidney function has led to the approval of several novel therapies specifically for IgAN, with many others likely to be approved in the near future. There is now a pressing need to consider how to best utilize these treatments in the clinical setting for individual patients. One of the most debated (and contentious) questions is whether hematuria can serve as a biomarker to guide treatment decisions. While this may seem biologically plausible and intuitive, it is important to closely examine the available evidence. The most common presenting feature of IgAN is the presence of hematuria, with or without proteinuria. Usually, the hematuria is nonvisible. A subset of patients experiences visible hematuria that often accompanies a mucosal infection (e.g. synpharyngitic hematuria), which is more common in children and younger adults. Longitudinal studies of IgAN have described the finding of recurrent visible hematuria to be associated with better long-term outcomes compared to those with nonvisible hematuria, which may reflect earlier presentation and lead-time bias [1]. The presence of hematuria is promoted by advocates as signifying active glomerular inflammation; however, the data simply do not support this. In a study of 165 patients referred to nephrology with isolated nonvisible hematuria and absence of proteinuria, 87 (52.7%) had no abnormality detected on kidney biopsy, while two of these patients had a potential cause found at cystoscopy [2]. The other misconception is that mesangial IgA deposition can only cause glomerular injury through a hematuria-associated inflammatory process and that IgAN “burns out” and therefore no longer requires disease modifying treatment. Mesangial IgA deposition can drive loss of kidney function through a predominantly fibrosing phenotype associated with podocyte injury, segmental glomerulosclerosis, and tubulointerstitial inflammation and scarring. Those patients with apparently ‘burnt out’ disease who receive a kidney transplant, in the setting of multiple immunosuppressants, can still develop recurrent IgA deposition and glomerular injury. This is indicative of ongoing pathogenic IgA production that is likely driven by mucosal dysregulation, a mechanism supported by multiple genome wide association studies that have implicated pathways involved in IgA production and mucosal immunity. Numerous methods exist to measure hematuria, ranging in complexity from urine dipstick analysis, to microscopy, to automated methods such as flow cytometry. A universally adopted, standardized, and validated measurement for hematuria with thresholds indicative of clinical significance has not been established, making comparisons between observational studies, let alone incorporation into clinical trials and guidelines, difficult. Storage and transportation of urine over extended periods of time may result in red cell lysis, further complicating this issue. Analysis of the urinary sediment is advocated by some for detection of glomerular hematuria; however, this is highly operator-dependent, subjective, and for most does not affect management decisions. Hematuria is not a specific biomarker for glomerular disease activity. Levels of hematuria can be highly variable, fluctuate over short time periods, and are affected by several factors that include intercurrent illness, physical activity, hydration status, menstruation, and the presence of other renal and urological pathologies. Hematuria may resolve spontaneously in IgAN, especially if triggered by infection or vaccination. In a nationwide study of 127 patients in Japan who developed visible hematuria after COVID-19 mRNA vaccination, most were found to have IgAN, and had a low incidence of acute histological lesions such as endocapillary hypercellularity or crescents [3]. Furthermore, the vast majority experienced no sustained worsening in kidney function. Similar to proteinuria, the presence of hematuria does not distinguish between active immune-mediated glomerular disease and chronic structural changes due to prior damage or genetic alterations. A key example is the finding that a proportion of patients with IgAN or their relatives have been found to express mutations in Type IV collagen-encoding genes [4]. These mutations may result in structural weakness and thinning of the glomerular basement, and persistent hematuria that is largely unresponsive to treatment, highlighting another reason why hematuria cannot be relied on as a basis for treatment decisions alone. The 2025 KDIGO clinical practice guidelines in IgAN state that the only validated biomarker that can help guide early treatment decisions is proteinuria. Whether measurement of albuminuria adds precision is also debated. Hematuria is not mentioned in this context. The International IgAN Network risk prediction tool does not include hematuria as a predictive variable. These omissions highlight an absence of prospective clinical trial evidence that identifies hematuria as an independent predictor for prognosis. Insights may also be drawn from other diseases. In a post hoc analysis of the Euro-Lupus Nephritis trial, when hematuria remission (໿urinary RBCs ≤5/hpf) was added to proteinuria reduction of