Recent clinical studies suggest that these biomarkers are essential for diagnosing FD and evaluating treatment outcomes. However, it remains unclear whether plasma lyso-GL3 levels are intricately associated with clinical manifestations in each organ, particularly in late-onset FD in male and FD in female. Additionally, depending on the degree of disease progression, plasma lyso-GL3 may not be a reliable biomarker of disease progression [2]. Despite its limitations, plasma lyso-GL3 is widely used and has demonstrated greater efficacy than GL3 for disease monitoring in FD. In contrast to plasma lyso-GL3, urine lyso-GL3 is not recommended for clinical use, despite being less invasive [3]. From the perspective of a nephrologist, precise diagnosis and monitoring of FN are crucial for the proper management of FN. What biomarkers are available for FN diagnosis? What biomarkers indicate disease progression and serve as potential therapeutic targets for FN management? Complementary kidney-specific biomarkers are essential for accurately monitoring organ damage, particularly FD-related tissue damage. Consequently, several investigators have identified reliable markers that reflect the pathophysiology and progression of kidney damage in FD. Currently, no clinical indicators other than the estimated glomerular filtration rate and albuminuria can effectively monitor kidney damage caused by FD or reflect treatment response, even though the kidneys are the primary target organ in FD. Albuminuria is a kidney-specific biomarker independent of the underlying disease. Although albuminuria and proteinuria are early biomarkers of kidney injury, whether enzyme replacement therapy (ERT) influences albuminuria or whether albuminuria is a reliable marker of ERT response in FN remains unclear, as the effect of concurrent CKD therapies, such as angiotensin receptor blockade, cannot be easily excluded [4]. Furthermore, FN in certain patients is not accompanied by albuminuria [5]. Therefore, an early biomarker for FN is required.

Urine microscopy is another noninvasive diagnostic tool for FN assessment. Characteristically, Maltese cross particles or mulberry cells observed in urine microscopy suggest FD and are correlated with albuminuria in FN [6]. Podocytes are the primary target cells within the kidneys, and podocytopathy, characterized by GL3 deposition, occurs before overt clinical CKD. Therefore, podocyturia could serve as an early diagnostic marker with high prognostic value. However, routine measurements are not yet feasible in clinical practice because the methodology has not been standardized and may depend on technical expertise. Furthermore, reliable data on the use of urine microscopy for predicting or monitoring FN progression remain scarce. Considering the critical role of early biomarkers and prognostic indicators in FN, continuous efforts are required to identify and validate potential indicators for early diagnosis and prognosis.

Omics is not a hypothesis-driven approach; rather, it is an exploratory research method that can identify novel disease-associated markers. Using proteomics, Matafora et al. [7] reported that uromodulin (UMOD), prostaglandin-H2 D-isomerase, and prosaposin are FD-related proteins involved in inflammation, immune responses, and glycosphingolipid metabolism. UMOD was more abundant in the urine of patients with FD than in controls and was restored to control levels by ERT. Based on these findings, they proposed that urinary UMOD could serve as an early FN-specific biomarker and an indicator of ERT effectiveness. Metabolic changes occur more rapidly than protein changes, and these characteristics may offer advantages for evaluating and monitoring treatment responses. A recent metabolomics study demonstrated that lyso-GL3 analogs, rather than GL-3/lyso-GL3 alone, may more effectively reflect FD status and response to enzyme replacement therapy. However, no studies have analyzed the significance of urinary lyso-GL3 analogs in FN [8]. Another network-based targeted metabolomics study identified 13 plasma metabolites related to glycerophospholipid metabolism and oxidative stress that correlated with plasma lyso-GL3 levels in patients with FD compared to healthy individuals [9]. Despite several metabolomics studies using different analytical tools, no prospective randomized trials or kidney-specific biomarker studies have been conducted on FN. The figure shows how to assess and monitor kidney injury available to date in FD (Fig. 1).

In this issue of Kidney Research and Clinical Practice, Kim et al. [10] identified 27 key metabolites in the serum and urine of 20-week-old and 40-week-old mice with FD compared to wild-type mice. Eight metabolites were associated with FD in 20-week-old mice, whereas 23 were associated with FD in 40-week-old mice. This study aimed to identify novel biomarkers beyond glycosphingolipids for predicting FN progression. The findings suggest that serum and urine metabolites are largely involved in oxidative stress, nitric oxide biosynthesis, inflammation, and immune regulation. Notably, in 40-week-old mice, the identified metabolites were linked to the kynurenine pathway. Although the correlation between glycosphingolipids and their metabolites remains unclear, this omics study provides foundational data for future experiments and human studies. Despite certain limitations in omics studies, findings to date suggest that metabolite panels, rather than individual metabolites, should be emphasized to identify novel FN biomarkers. FD is a complex disease with multiple phenotypes that do not strongly correlate with genotypes. Therefore, metabolite panels may ultimately facilitate patient stratification and contribute to individualized treatment approaches.