Abstract
Background
Progressive nephropathy (Fabry nephropathy), as observed in both the early-onset and later-onset types of Fabry disease and in as many as 50% of males and 20% of females, represents a major driver of overall disease burden in this population. Nonetheless, recognizing and diagnosing Fabry nephropathy remains clinically demanding for nephrologists given its pivotal role in altering disease progression and improving patients’ quality of life. Therapeutics presents additional complexity as evidence-based criteria for treatment and prognostic algorithms remain limited.
Summary
Against this background, this expert opinion aims to address the current knowledge on conceptual, clinical, and therapeutic aspects of Fabry nephropathy from a nephrologist’s perspective and to provide a guidance document for the best practice in the management and monitoring of the disease.
Key Messages
The participating experts considered the indispensable role of heightened disease awareness among nephrologists, the maintenance of a high diagnostic index in symptomatic individuals, and the importance of systematic screening of at-risk populations to enable prompt identification of Fabry nephropathy. This is particularly important in the current availability of enzymatic and genetic screening tests and the specific disease-modifying treatments capable of decelerating kidney function deterioration when initiated at an early disease stage. Implementation of a multidisciplinary approach with an experienced team of clinicians, and continued monitoring and assessment of clinical status are considered critical to optimal patient care, as well as the timely initiation of ERT in conjunction with appropriately selected adjunctive treatments within a care plan individualized to the patient’s clinical signs and symptoms.
Keywords: Awareness, Biomarkers, Diagnosis, Expert opinion, Fabry disease, Fabry nephropathy, Monitoring, Nephrologist’s perspective, Screening, Treatment
Introduction
Fabry disease (FD) is a progressive X-linked lysosomal storage disorder caused by decreased activity of the lysosomal enzyme α-galactosidase A (α-Gal A) due to mutations in the GLA gene [1–3]. The subsequent accumulation of glycosphingolipids, specifically globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), within and outside lysosomes across various cell types including renal, endothelial cells, cardiac and neuronal cells, results in characteristic damage to the kidney, heart, and cerebrovascular system [2, 4, 5].
FD phenotypes involve the classical early-onset type (little or no residual α-Gal A activity with general manifestations starting from childhood) and the later-onset type (relatively higher residual α-Gal A activity with later-age manifestations limited to renal or cardiac involvement) [2, 3, 6, 7]. Due to random X-chromosome inactivation, the female phenotype is variable, ranging from asymptomatic to as severe as that of the male phenotype [6–8].
Progressive nephropathy (Fabry nephropathy) presents one of the cardinal manifestations of FD, occurring across both the early-onset form (associated with a reduction in life expectancy of approximately 25 years in men and 10 years in women) and the later-onset form (which may remain clinically silent until the fifth or sixth decade of life), and substantially adds to the total burden of disease [2, 5, 6, 8–13]. The condition is defined by ongoing lysosomal Gb3 deposition within podocytes and across endothelial, epithelial, and tubular cell populations, resulting in proteinuria and declining glomerular filtration rate (GFR) that ultimately progress toward renal failure and end-stage renal disease (ESRD) in at least 50% of patients by the age of 53 [2, 5, 6, 10, 13, 14]. Histopathological evaluation of renal biopsies consistently reveals progressive Gb3 accumulation even in individuals with no clinical signs of renal involvement [15–17]. Early detection of kidney damage is critical as the treatment, which provides improved renal outcomes and prolonged survival, yields its greatest benefits at the early stages of kidney damage [6, 14, 17–19].
Establishing a new diagnosis requires sustained clinical vigilance, making nephrologists’ awareness of Fabry nephropathy indispensable, an imperative that has grown with wider access to enzymatic and genetic testing platforms and targeted disease-modifying therapies [7, 14, 17]. Despite this, diagnosis is frequently delayed because proteinuria and chronic kidney disease (CKD), the hallmark presentations of Fabry nephropathy, overlap considerably with features of numerous other renal disorders [7, 14, 17, 20]. Accordingly, placing Fabry nephropathy on the differential diagnosis, a step of critical importance for modifying disease course and improving patients’ quality of life (QoL), can be a considerable challenge in nephrology practice [7, 17, 20–22]. The therapeutic decision-making process is also considered challenging given the lack of evidence-based criteria on therapeutic and prognostic algorithms [7, 22].
In Türkiye, the burden of inherited metabolic disorders is disproportionately elevated, a pattern largely attributable to the comparatively high prevalence of consanguineous marriages in the population [23]. The data from the largest screening study (using enzymatic analysis and cascade family testing of index patients) conducted in Türkiye identified FD in 0.17% of patients on dialysis and in 0.32% of male dialysis recipients [24]. This further emphasizes the need for an improved awareness of nephrologists about Fabry nephropathy, as a readily diagnosable and potentially treatable disease.
While several international guidelines and consensus statements have addressed FD management, notably the KDIGO Controversies Conference [25] and the European expert consensus [26], substantial new evidence has emerged since these publications that warrant an updated nephrology-focused perspective. These include expanded screening data demonstrating an FD prevalence of up to 2.3% when screening criteria are broadened beyond unexplained CKD [21], novel insights into immune cell infiltration and complement activation as drivers of renal damage beyond glycolipid storage [27, 28], the discovery of α-synuclein-mediated podocyte injury as an ERT-resistant mechanism [29], and the regulatory approval of pegunigalsidase alfa as a third enzyme replacement option [30]. Furthermore, emerging evidence on the renoprotective potential of SGLT2 inhibitors [31] and oral substrate reduction therapy (SRT) [32] in Fabry nephropathy has expanded the adjunctive treatment landscape beyond conventional renin-angiotensin-aldosterone system blockade. These developments create the need for a practical, nephrology-oriented update that addresses clinical decision points not fully covered in prior guidance, including indications for measured GFR, re-biopsy criteria, and integration of multiple monitoring parameters to assess renal stability.
This manuscript is designed as a practical guide based on expert opinion rather than a narrative review. It synthesizes available evidence together with the clinical experience of an expert nephrology panel to provide pragmatic recommendations for the management of Fabry nephropathy. The primary aim is to provide a nephrologist-oriented, practical framework for the recognition, diagnosis, treatment, and monitoring of Fabry nephropathy based on current evidence and expert clinical experience. The secondary aims are to highlight areas where expert opinion fills gaps in formal evidence, particularly regarding screening strategies in high-risk kidney populations, individualized treatment decisions, and renal biopsy indications, and to incorporate recent therapeutic and pathophysiologic advances relevant to nephrology practice.
Methods
A targeted literature search was conducted in PubMed/MEDLINE and Scopus databases from inception through December 2025 using the following search terms: “Fabry disease” OR “Fabry nephropathy” OR “Anderson-Fabry” combined with “kidney,” “renal,” “nephropathy,” “screening,” “diagnosis,” “biomarker,” “enzyme replacement therapy,” “treatment,” and “monitoring.” Additional references were identified through manual review of bibliographies of retrieved articles, recent consensus statements, and clinical guidelines. No formal systematic review protocol was applied as this manuscript is designed as a practical guide based on expert opinion.
The expert panel, comprising nephrology specialists with long-term clinical and research experience in Fabry nephropathy, convened in a series of structured meetings to review and discuss the retrieved evidence. Each panel member was assigned specific topic areas based on their expertise. Draft sections were circulated among all panel members for critical review, and areas of disagreement or uncertainty were discussed iteratively until consensus was reached. Where published evidence was insufficient, recommendations were based on collective clinical experience, and such instances are indicated in the text. The final manuscript was reviewed and approved by all authors.
Fabry Nephropathy: Conceptual Framework and Diagnostic Approaches
Progressive Renal Involvement
Fabry nephropathy involves the consecutive phases of (a) the tissue accumulation of Gb3 and lyso-Gb3, (b) the cellular injury, (c) the organ damage with initiation of fibrosis, and (d) the progressive loss of kidney function [25, 33, 34]. Gb3 deposition has been documented across a broad spectrum of renal cell types with evidence of accumulation detectable as early as fetal development, while albuminuria/proteinuria (as initial signs of renal impairment) may occur as early as 10 years of age and a decline in estimated GFR (eGFR) may emerge during adolescence in classic patients [2, 25, 35, 36]. Progressive CKD with albuminuria and overt proteinuria emerging during the second decade is followed by the development of chronic renal insufficiency in the 3rd to 5th decades and ultimately the ESRD in the 4th to 5th decades of life [15, 16, 25, 34, 37]. The rate of progression of CKD is similar to that of diabetic nephropathy, while the decline in eGFR is directly correlated to the degree of proteinuria and is more pronounced in treatment-naïve patients with an initial eGFR of <60 mL/min/1.73 m2 [10, 33].
The pathway from the initial damage caused by the abnormal deposit of Gb3 and lyso-Gb3A to the eventual tissue fibrosis and chronic kidney injury is mediated by cascade of events including histological damage, release of inflammatory mediators, microvascular damage, heightened oxidative stress, apoptotic cell death, and ischemic injury [2, 14, 18, 34, 35, 38–40]. Nonetheless, the renal involvement is multifactorial with a complex genotype-phenotype correlation, and the exact pathophysiological mechanisms underlying the progression to CKD and ESRD remain unknown [5, 9, 14, 39, 41].
Screening in High-Risk Populations
Inherited renal disease is the fifth most common cause of ESRD, emphasizing the value of a comprehensive family history of renal and extra-renal phenotypes in a new patient presenting to renal clinics with hypertension, proteinuria, or CKD [42]. Screening for FD in high-risk populations (i.e., ESRD) is a fundamental clinical tool for the detection of index cases and family members, thereby facilitating genetic counseling and enabling early disease-specific intervention [43, 44]. In a recent systematic review and meta-analysis of 55 screening studies in 84,062 CKD patients, the overall prevalence of FD in dialysis and kidney transplantation patients was 0.10% and 0.28%, respectively [44].
Screening for patients with an unknown etiology of CKD is also recommended by many guidelines. In this regard, the TURKFAB study on screening of 313 stage 1–5 CKD patients (aged 18–70 years, 167 were males) with unknown etiology and without renal replacement therapy (RRT) from six different regions and ten centers of Türkiye revealed the diagnosis of FD in 3 (all males) of 313 CKD patients, corresponding to FD prevalence of 0.95% overall and 1.80% among males [45]. Also, in a large cohort study from Türkiye on FD screening in 5,657 renal transplant recipients and dialysis patients, 17 patients were found to have a pathogenic mutation of FD, and the prevalence of FD in patients receiving RRT was 0.3% [46].
Notably, recent evidence suggests that restricting screening to patients with unexplained CKD may underestimate the true prevalence of FD in nephrology populations. Battaglia et al. [47] screened 385 non-dialysis CKD outpatients at Italian nephrology centers using an expanded approach that included patients with known CKD etiologies (e.g., hypertension, diabetes) in addition to those with unexplained CKD. The prevalence of genetically confirmed FD was 2.3%, rising to 5.4% when cascade family screening was performed, substantially higher than previously reported in studies limited to unexplained CKD. This finding underscores that FD may coexist with other common nephropathies and be overlooked when screening is restricted to patients without an apparent diagnosis.
Hence, it is recommended to perform screening for FD (based on α-Gal A activity assay and confirmatory DNA analysis) in male (<50 years of age) and female (regardless of age) patients who present with unexplained CKD and features potentially attributable to FD [5, 48]. In addition, emerging data support consideration of expanded screening approaches that include CKD patients with established diagnoses but atypical features, disproportionate proteinuria, or concurrent extra-renal manifestations suggestive of FD [47].
Clinical Suspicion and Diagnosis of Fabry Nephropathy
Given the nonspecific nature of renal manifestations and the frequent co-occurrence of other kidney disorders, clinical suspicion of the nephrologist remains the most crucial element in the inclusion of Fabry nephropathy in the differential diagnosis in patients presenting with altered renal function and/or abnormal findings on urinalysis (mainly albuminuria) [20, 46]. In fact, due to the availability of feasible tests for enzyme activity, lysoGb3 accumulation, and eventually the presence of GLA pathogenic variants, the main limitation to early diagnosis is considered the lack of clinical suspicion of the disease [20, 49].
Figure 1 illustrates a proposed stepwise diagnostic algorithm for Fabry nephropathy, outlining a practical approach for nephrologists, from identification of high-risk patients through screening, diagnostic confirmation, baseline assessment, and consideration of kidney biopsy. Nephrologists should consider Fabry nephropathy in patients with CKD of unclear etiology, particularly in those presenting with even mild proteinuria, an accelerated decline in kidney function compared with the normal adult population (eGFR loss >−1 mL/min/1.73 m2/year), or a family history of nephropathy and kidney failure, especially along the maternal branch [20, 25, 38, 41, 50–52] (Table 1; Fig. 1).
Fig. 1.
Stepwise diagnostic algorithm for Fabry nephropathy. The flowchart outlines a practical approach for nephrologists, from identification of high-risk patients through screening, diagnostic confirmation, baseline assessment, and consideration of kidney biopsy. A critical sex-based distinction is emphasized at step 2: in males, α-galactosidase A (α-Gal A) enzyme activity measurement (DBSs or leukocytes) is a reliable initial screening tool, whereas in females, direct GLA gene sequencing should be the primary diagnostic test due to the limited sensitivity of enzyme assays resulting from random X-chromosome inactivation [53, 54]. Indications for kidney biopsy with electron microscopy are specified, including variants of uncertain significance, female patients with uncertain renal involvement, suspected dual pathology, and borderline clinical presentations with therapeutic implications. The standardized ISGFN scoring system is recommended for histopathological assessment [55]. Cascade family screening of index cases is strongly recommended given its high diagnostic yield [47]. Extrarenal signs suggestive of FD are listed in the footnote. EM, electron microscopy; ISGFN, International Study Group of Fabry Nephropathy.
Table 1.
| Clinical manifestations |
|---|
| High index of clinical suspicion in a patient presenting to nephrology clinic |
|
| Extrarenal signs and symptoms |
|
| Laboratory investigation – renal involvement |
|
|
|
|
|
| Confirming the diagnosis of FD |
|
| Recording the baseline values for monitoring parameters |
| Calculation of eGFR slope |
| Urinary albumin and protein levels |
| Lyso-Gb3 levels |
| Family screening |
| Immediate and extended family members of index case |
CKD, chronic kidney disease; Lyso-Gb3, globotriaosylsphingosine; eGFR, estimated glomerular filtration rate; ECG, electrocardiogram.
Beyond renal parameters, systematic evaluation of extrarenal features is essential, including subjective symptoms such as acroparesthesia, burning or heat pain in the extremities, anhidrosis, and exercise, heat, or cold intolerance and the systemic organ involvement in terms of cardiac disease (ECG abnormalities: short PR interval, left ventricular hypertrophy [LVH], and arrhythmia), history of early cerebrovascular disease, skin lesions (i.e., angiokeratomas), cornea verticillata, and peripheral neuropathy [7, 20, 51, 57] (Table 1). Renal glomerular features share similarities with diabetic nephropathy, with hyperfiltration (GFR >135 mL/min/1.73 m2) in the early stages, followed by albuminuria, proteinuria, and progressive decrease in GFR [14, 58, 59]. Tubular manifestations are less frequent and may include distal renal tubular acidosis and isosthenuria [14, 58, 60]. Endothelial cells, especially podocytes, play an important role in the pathogenesis of Fabry nephropathy by contributing to irreversible ischemic injury to the renal microcirculation through luminal obstruction, ultimately precipitating interstitial fibrosis and glomerulosclerosis [14, 61].
Accordingly, the laboratory investigation of renal involvement is based on eGFR, urinalysis (albuminuria, proteinuria), urine microscopy (Maltese cross, urinary mulberry cells, and podocyturia), ultrasound findings (renal cysts, mainly parapelvic ones, with a reported prevalence of 28.9% in FD vs. 1.1% in controls [62]), and kidney biopsy [14, 20, 38, 41] (Table 1; Fig. 1). The definitive diagnosis is made by the enzymatic analyses of dried blood spots (DBSs) and confirmatory genetic mutation analysis [38, 60]. DBS assay allows population screening and an initial diagnosis in males, while in heterozygous females with highly variable α-Gal A activity genetic mutation analysis is essential for a diagnosis [38, 63] (Table 1; Fig. 1). After the diagnosis, it is important to record the baseline values for monitoring parameters such as the calculation of eGFR, the measurement of urinary albumin and protein levels, and the lyso-Gb3 levels [2, 7, 31, 49, 56] (Table 1; Fig. 1). Family screening among immediate and extended relatives of the index case is critically important as several relatives (on average, five per index case) may be diagnosed at a younger age, before irreversible complications develop, and therefore stand to benefit most from early initiation of therapy [5, 12, 64] (Table 1; Fig. 1).
| Key messages I – screening and diagnosis |
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|
Immunologic Aspects of Fabry Nephropathy
As described in the section on progressive renal involvement, the cascade from glycosphingolipid accumulation to inflammation and tissue fibrosis in Fabry nephropathy involves multiple mediators. The immunologic aspects of this cascade deserve particular attention with the possibility of alternative damaging mechanisms including immune cells as the major player. Previously, Pereira et al. [65] analyzed invariant NKT cells and their subsets among patients with FD and also reported that age-dependent alterations in invariant NKT cells of Fabry knock-out mice were partially prevented by ERT [66].
In an analysis of the subpopulations of immune infiltrating cells in renal biopsies from Fabry patients on ERT by Turkmen et al. [67], there were reductions inCD8, CD16, T cells, and NK cells but an increase in CD20 B cells and CD38 plasma cells, emphasizing the active participation of interstitial immune infiltrating cells in the inflammation and the subsequent renal damage.
These findings are further supported by recent studies implicating the complement system in Fabry nephropathy. Laffer et al. [27] demonstrated activation of complement pathways in renal tissue of Fabry patients, suggesting that complement-mediated injury may amplify podocyte damage and glomerular inflammation beyond direct Gb3 toxicity. Similarly, Bondar et al. [28] reported evidence of complement deposition in Fabry kidney biopsies, with correlations to the degree of histological damage. Additionally, Braun et al. [29] identified α-synuclein accumulation in FD using a novel mechanistic approach, providing a potential link between lysosomal dysfunction and neuroinflammatory pathways that may also have renal implications.
From a clinical perspective, these immune-mediated mechanisms may partially explain several key challenges in Fabry nephropathy management. First, the heterogeneity of renal involvement – even among patients with the same GLA variant – may reflect individual differences in immune response magnitude. Second, persistent proteinuria or progressive renal dysfunction despite optimized ERT and antiproteinuric therapy may indicate ongoing immune-mediated injury that is not addressable by enzyme replacement alone. Third, the observation of increased CD20 B cells and CD38 plasma cells in Turkmen et al. [67] raises the possibility that humoral immune responses, including anti-drug antibody formation, may be linked to intrarenal immune activation. Notably, immune complex-mediated membranoproliferative glomerulonephritis has been reported in a patient receiving pegunigalsidase alfa in the BALANCE trial [30], underscoring the clinical relevance of immune surveillance in treated patients.
Recognition of these immune pathways has practical implications for patient management. Clinicians should consider immune-mediated mechanisms in the differential diagnosis when Fabry patients exhibit progressive nephropathy despite adequate disease-specific therapy. Integrating immunologic assessments – including anti-drug antibody monitoring, complement markers, and careful interpretation of kidney biopsy inflammatory infiltrates – with standard biomarkers and clinical outcomes may contribute to a more individualized management approach. Furthermore, the elucidation of these secondary immune pathways provides a rationale for investigating adjunctive anti-inflammatory or immunomodulatory strategies in Fabry nephropathy, an area where formal clinical evidence is currently lacking (expert opinion).
| Key messages II – immunologic mechanisms |
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Biomarkers for Monitoring Fabry Nephropathy: Assessment of Renal Involvement and Disease Progression/Burden
Fabry nephropathy exhibits substantial phenotypic and clinical variability, even among family members carrying the same pathogenic GLA variant, underscoring the importance of regular and consistent assessment of kidney function in disease management [10, 31, 41, 68]. Biomarkers serve a dual role: the assessment of renal involvement in the initial diagnosis of Fabry nephropathy and guiding the timing of treatment initiation, while also enabling ongoing surveillance of disease activity, progression, and therapeutic response [5, 38, 41, 59, 69]. Accordingly, the markers of kidney injury, including albuminuria/proteinuria, serum creatinine, GFR, and cystatin C, are typically assessed alongside urine microscopy, renal biopsy findings, and plasma lyso-Gb3 measurement for the initial diagnosis, the assessment of renal involvement, and the monitoring of treatment in Fabry nephropathy [5, 38, 41].
Albuminuria/Proteinuria
Clinically, albuminuria and proteinuria are the most routinely applied indicators of Fabry nephropathy [41, 69]. However, because renal biopsy often reveals significant histological changes (such as Gb3 accumulation and cellular or vascular injury) before pathological albuminuria appears, it is not a sensitive marker for detecting early kidney damage or identifying incipient nephropathy [14, 15, 18, 38, 41, 70, 71].
Nonetheless, the proteinuria (a stimulatory factor for interstitial inflammation and fibrosis) stands among the most informative parameters for tracking nephropathy progression in both treated and untreated patients and those with higher proteinuria exhibit a much steeper decline in renal function over time [33, 34, 41, 72, 73]. Proteinuria is considered an independent risk factor for renal functional decline and poor response to ERT and therefore should be monitored closely and treated appropriately [38, 50].
GFR (Measured GFR, Creatinine-Based eGFR, or Cystatin C-Based eGFR)
As a marker of advancing kidney damage, GFR ranks among the most clinically informative determinants of prognosis in patients with Fabry nephropathy [69]. The pace of GFR deterioration among untreated individuals differs considerably, while baseline proteinuria, reduced baseline GFR, and male sex are associated with more rapid disease progression and a faster decline in GFR [10, 14]. The trajectory of kidney function varies according to baseline eGFR, which was reported to be −3.0/min/1.73 m2/year in men and −0.9 mL/min/1.73 m2/year in women in case of a baseline eGFR of >60 mL/min/1.73 m2 and to be −6.8 mL/min/1.73 m2/year in men and −2.1 mL/min/1.73 m2/year in women in case of a baseline eGFR of <60 mL/min/1.73 m2 [10].
The GFR decline is often slower and less predictable in patients with late-onset variants or in female patients, while glomerular hyperfiltration is also a likely feature in young Fabry patients as an early indicator of incipient nephropathy that may mask underlying functional renal impairment [14, 36, 59, 74, 75]. Although measured GFR (e.g., iohexol clearance) surpasses eGFR equations relying on serum creatinine and/or cystatin C in terms of accuracy for renal function assessment in Fabry patients, it is a time-consuming and complex procedure requiring marker injection followed by multiple blood samples [69, 76]. Also, cystatin C is considered less subject to bias and more sensitive than serum creatinine in detecting small reductions in GFR and is considered a muscle-mass-independent marker for early-stage Fabry nephropathy guiding timely initiation of disease-specific treatment [38, 41, 69, 77]. However, it is a more expensive tool not available in all centers [41, 64, 72]. In this regard, providing a more practical assessment of GFR, the eGFR formulas based on serum creatinine are more commonly used in clinical practice [41, 69]. In FD, measured GFR may be particularly warranted in specific clinical scenarios where eGFR-based assessments may be unreliable or insufficient for clinical decision-making [78, 79]. These include patients with extremes of body size or altered body composition, in whom creatinine-based eGFR equations may be inaccurate; cases with discordant results between creatinine-based and cystatin C-based eGFR estimates; and borderline clinical situations in which treatment initiation, modification, or prognostic assessment has important therapeutic implications [78]. Additionally, glomerular hyperfiltration may occur as an early manifestation of Fabry nephropathy in young patients, potentially masking underlying renal injury [14, 36, 74, 75]. Hence, measured GFR may help identify this phenomenon more reliably than eGFR, particularly when normal or elevated eGFR values are discordant with histopathological findings or biomarker evidence of early nephropathy [80]. When measured GFR is not feasible, pragmatic alternatives include repeated longitudinal assessment using the same eGFR equation, incorporation of cystatin C-based estimates, and careful evaluation of proteinuria trends alongside eGFR trajectory to guide clinical decision-making.
Urine Microscopy (Podocyturia)
Urine microscopy enables identification of three hallmark abnormalities in FD: Maltese cross particles, urinary mulberry cells, and podocyturia, each of which can be valuable in diagnosing and assessing disease progression [5, 14, 38, 41]. Detection of mulberry cells, distal tubular epithelial cells laden with Gb3 deposits exhibiting the characteristic “Maltese cross” birefringence pattern under polarized light (also termed oval fat bodies), during urinalysis has been proposed to be a simple and low-cost, noninvasive approach to identifying Fabry nephropathy in the setting of absent proteinuria [55, 81, 82]. In addition, their excretion is correlated with the urinary albumin concentration, suggesting usefulness for assessing disease burden [82].
As terminally differentiated cells with negligible regenerative capacity in adult kidneys, podocytes accumulate Gb3 more extensively than other renal cell types, resulting in podocyte foot process effacement and podocyte loss to urine [16, 41, 61, 83, 84]. The urinary loss of podocytes compromises glomerular filtration selectivity and causes albuminuria/proteinuria, leading to glomerulosclerosis and fibrosis [18, 85]. Since the podocyte foot process effacement is considered the earliest sign of renal damage, podocyturia provides robust evidence of podocyte damage, correlating with continuous glomerular injury and the clinical severity of Fabry nephropathy [14, 41, 61].
Significant podocyturia has been observed in patients with normoalbuminuria or normoproteinuria compared to healthy controls, alongside substantial Gb3 accumulation in podocytes on renal biopsy in young Fabry patients with normal albuminuria and GFR [5, 14, 61, 86]. These findings emphasize the potential of podocyturia as an earlier biomarker of clinically silent kidney damage and the relevance of renal biopsy for the early diagnosis of nephropathy [5, 14, 61, 86]. Nevertheless, it is not routinely used in clinical practice due to the absence of standardized methodology and the limited availability of specialized equipment (such as phase-contrast microscopy) and adequately trained personnel in most clinical settings [41, 69].
Renal Biopsy
Early nephropathy may be clinically silent, with histopathological evidence, such as marked Gb3 accumulation predominantly in podocytes and endothelial cells, detectable on kidney biopsy even before the onset of albuminuria [5, 14–17]. Therefore, kidney biopsy histopathological findings are considered an early indicator of renal damage with diagnostic as well as prognostic roles in Fabry nephropathy, in addition to their help for choosing the optimal therapeutic strategy and follow-up in high-risk patients [7, 38, 41, 58, 87, 88]. Clinical scenarios warranting renal biopsy in patients with known or suspected Fabry nephropathy comprise the following [2, 14, 38, 41, 52, 89]:
All individuals with CKD (to evaluate the extent of glomerulosclerosis and interstitial damage as indicators of chronicity with strong prognostic value)
Patients with 30- to 300-mg/g albumin-to-creatinine ratio (ACR) and normal kidney function and those with a sudden, unexplained decline in renal function (to determine whether there are Gb3 deposits and quantify them)
Patients with genetic variants of unknown significance (VUSs) and atypical presentations (to assist diagnosis)
Patients with the possibility of concurrent nephropathy (e.g., diabetic glomerulopathy or other immune-mediated glomerular disorders) and an uncertain diagnosis of FD (to rule out other nephropathies or overlapping diseases)
In male patients with the classic phenotype presenting with renal involvement, a kidney biopsy can provide important prognostic information based on the severity of established glomerular sclerosis [90]. Renal biopsy is much more important in females with even the slightest evidence of Fabry nephropathy as the presence of histological signs of chronicity together with the significant renal Gb3 deposits is an indication for initiating ERT [14, 38].
Electronic microscopy remains the definitive modality for unambiguously confirming or excluding Fabry nephropathy, which demonstrates Gb3 deposits inside lysosomes of different cell types and can take forms known as “myelin figure,” “onion skin,” or “zebra bodies” [2, 7, 14, 61, 83]. The main histologic differential diagnoses are iatrogenic renal lipidosis due to toxicity by α-GAL enzyme inhibitors (chloroquine, hydroxychloroquine, amiodarone) and other renal lipidoses with foamy podocytes (i.e., GM1 gangliosidosis, Hurler syndrome, I-cell disease, Farber disease Niemann-Pick disease, and infantile nephrosialidosis) [14, 61, 83, 91, 92]. Although kidney biopsy is not routinely repeated in Fabry nephropathy, re-biopsy may be clinically informative in selected situations to guide therapeutic decision-making [26, 59]. These include an unexpected or accelerated decline in eGFR not explained by hemodynamic factors, persistent or progressive albuminuria despite optimized disease-specific and adjunctive antiproteinuric therapy, and suspicion of a superimposed or alternative renal pathology such as diabetic nephropathy, IgA nephropathy, or immune-mediated glomerulonephritis [59]. Re-biopsy may also be considered in cases where distinguishing chronic irreversible damage (glomerulosclerosis, interstitial fibrosis) from potentially active and treatable lesions may influence decisions regarding treatment continuation, modification, or switching [55]. An additional emerging indication is the evaluation of suspected immune complex-mediated nephropathy in the context of anti-drug antibodies, which has been reported as a rare but clinically significant complication of enzyme replacement therapy [30]. In such scenarios, the use of the standardized ISGFN scoring system enables meaningful comparison between initial and repeat biopsy findings [55]. However, the decision to perform re-biopsy must be individualized, weighing the expected impact on management against procedural risks and patient burden, particularly in patients with advanced CKD or significant comorbidities.
Plasma Lyso-Gb3
Although initially considered as surrogate of the renal biopsy, plasma and/or urinary Gb3 levels have failed to adequately correlate with the tissue pathological modifications as well as with the degree of renal involvement and disease severity, especially in late-onset forms and in heterozygous females [76, 93–95]. In contrast, plasma lyso-Gb3, identified via innovative proteomic techniques (matrix-assisted laser desorption/ionization mass spectrometry), showed a higher diagnostic and discriminative (classical vs. atypical distinction) performance [93, 96]. Plasma lyso-Gb3, and more recently serum and DBS lyso-Gb3, has been established as a diagnostic biomarker with a diagnostic sensitivity and specificity close to 100% for males or for the classic phenotype along with a contributory role in the stratification of phenotypes associated with FD [9, 69, 94, 97–99]. The urinary lyso-Gb3 levels, which correlate with proteinuria and albuminuria but not with GFR, are not considered a reliable biomarker of renal involvement [38, 94, 99, 100]. Further investigation is needed to clarify whether lyso-Gb3 correlates with surrogate disease markers (i.e., left ventricular mass index, LVH, eGFR) or clinical events (i.e., stroke) or indices of disease severity [69].
Novel Biomarkers of Nephropathy
With the development of new “-omics” technologies, recent studies have reported alternative approaches for identifying novel biomarkers with potential diagnostic and prognostic value in Fabry nephropathy [41, 71]. Markers of glomerular (such as transferrin and type IV collagen) and tubular (including α1-microglobulin, N-acetyl-β-glucosaminidase, and alanine aminopeptidase) injury are considered promising for detecting renal damage at the normoalbuminuric stage, in contrast to conventional late-stage biomarkers such as albuminuria and reduced GFR [41, 71].
Urinary excretion of podocyte-associated proteins (e.g., podocalyxin, podocin, nephrin, and synaptopodin) can also be measured as indicators of podocyte injury [101]. These markers have been suggested to be particularly useful in untreated male patients with the classic phenotype, given their strong correlation with urinary lyso-Gb3 levels [101]. In addition, in early-stage disease, treatment has been associated with decreased urinary levels of proteins such as prosaposin, GM2 activator protein, uromodulin, and prostaglandin H2 d-isomerase [102, 103]. In a targeted proteomic analysis of Fabry patients, urine profiling identified nephrin, podocalyxin, fibroblast growth factor 23, cubilin, and alpha-1-microglobulin/bikunin precursor (AMBP) as potential biomarkers of renal injury [104].
In addition, periostin has been suggested to be a valuable marker of Fabry nephropathy and proteinuria, as a molecule with an important role in the management of the fibrotic process [39]. In patients with FD, periostin exhibited an inverse association with age at first symptom onset and GFR, while demonstrating positive correlations with proteinuria and lyso-Gb3; it was identified as the sole independent determinant of proteinuria [39]. Hence, the possibility of periostin to participate in secondary pathways (i.e., TGF-β-mediated) that induce worsening of kidney function after the initial kidney injury by Gb3 deposition is considered to be a plausible explanation for the failure of ERTs to prevent progression to ESRD in some patients [39].
Nonetheless, further large, longitudinal observational studies are needed to evaluate the clinical utility of these novel biomarkers as well as their correlations with nephropathy progression, currently used biomarkers, and response to ERT [41]. Multifactorial models integrating clinical, biochemical, and genetic factors are considered more likely to provide more robust evidence on the development and progression of nephropathy and to be successfully translated into clinical practice [41, 105].
| Key messages III – biomarkers and renal assessment |
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| Key messages IV – kidney biopsy |
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Therapeutic Aspects of Fabry Nephropathy
Currently, ERT with recombinant human α-Gal A and oral pharmacological chaperone therapy are the approved disease-specific treatment options for FD. In addition, several emerging approaches, including SRT and gene therapy, are in advanced clinical development, and early-phase results have been reported for mRNA-based strategies [106, 107]. ERT, the first disease-specific therapy approved for FD, remains the preferred treatment for most patients as it has been shown to improve QoL and slow the progression of declining kidney function [7, 71, 107].
Licensed ERT treatments include agalsidase alfa (Replagal®; Takeda, licensed in Europe but not in the USA), agalsidase beta (Fabrazyme®; Sanofi-Genzyme, licensed in both the USA and Europe), and pegunigalsidase alfa (Elfabrio®; Chiesi/Protalix), a PEGylated form of α-Gal A approved by the FDA (May 2023) and EMA (May 2023) for adults diagnosed with FD [30]. All three preparations are administered intravenously, with agalsidase alfa at 0.2 mg/kg and agalsidase beta at 1.0 mg/kg every other week and pegunigalsidase alfa at 1 mg/kg every other week [30, 106, 108, 109]. Oral pharmacological chaperone therapy with migalastat (Galafold®, Amicus), approved in the EU (2016) and USA (2018), stabilizes endogenous α-Gal A in patients with amenable GLA variants to increase enzyme activity [7, 107, 110].
Indications for ERT and Therapeutic Goals Specific to Nephropathy
For male classic patients (either symptomatic or asymptomatic), ERT should be considered and is appropriate at any age of presentation [14]. In symptomatic females, the presence of signs or symptoms indicating major organ involvement, along with evidence of renal impairment, justifies the initiation of therapy [14]. In asymptomatic females, laboratory, histological, or imaging findings suggestive of renal injury should be evaluated, including reduced GFR (<90 mL/min/1.73 m2), persistent ACR >30 mg/g, podocyte foot process effacement or glomerulosclerosis on renal biopsy, and moderate to severe Gb3 inclusions [14]. In males and females with late-onset pathogenic variants or VUS, treatment should be considered in the presence of laboratory, histological, or imaging evidence of renal injury, even in the absence of typical clinical symptoms [14] (Table 2).
Table 2.
| Patient subgroups | Indications that warrant the start of therapy |
|---|---|
| Male classic patients (symptomatic or asymptomatic) | Therapy should be considered and is appropriate at any age of presentation |
| Symptomatic females | The signs or symptoms suggesting major organ involvement and evidence of renal impairment |
| Asymptomatic females | Laboratory/histological evidence of renal injury
|
| Males and females with late-onset mutation or VUS | Laboratory/histological evidence of renal injury, even in the absence of typical symptoms |
| Patients with already established renal impairment (eGFR<60 mL/min/1.73 m2 or proteinuria >1g/day) | Non-renal symptoms that require treatment |
| Baseline renal involvement (eGFR) | Therapeutic goals |
|---|---|
| No or mild kidney involvement, eGFR at normal levels (90–120 mL/min/1.73 m2), or hyperfiltration (eGFR >90 mL/min/1.73 m2) | Maintaining eGFR in an age-appropriate normal range |
| Avoiding eGFR loss | |
| Mild-to-moderate kidney function impairment, mild eGFR decreases (eGFR 60–90 mL/min/1.73 m2) | Preventing progression of eGFR loss and stabilizing eGFR level |
| Moderate-to-severe kidney function impairment, mild-to-moderate eGFR decreases (eGFR 45–59 mL/min/1.73 m2), or moderate-to-severe eGFR decreases (eGFR 30–44 mL/min/1.73 m2) | Preventing progression of eGFR loss to delay/avoid ESRD |
| Severe eGFR decreases (eGFR 15–29 mL/min/1.73 m2) | Decreasing the slope of eGFR, and delaying the progression to ESRD |
| ESRD | Providing optimal RRT by dialysis or kidney transplantation |
| Maintaining ERT for cardiac and cerebrovascular protection | |
| Kidney transplantation rather than dialysis |
| Renal function under therapy | Criteria |
|---|---|
| Stabilization of function | A GFR slope loss ≤1–3 mL/min/1.73 m2/year |
| Progression of renal disease | |
| Overall | An annual decrease in GFR >3 mL/min/1.73 m2 |
| Rapid renal progression | Rate of progression is >5 mL/min/1.73 m2 |
| Response to treatment | |
| Overall | Annual slope loss reduced to <3 mL/min/1.73 m2/year |
| Rapid renal progression | Annual slope loss reduced to <5 mL/min/1.73 m2/year, or more than 50% decrease in progression |
eGFR, estimated glomerular filtration rate; ACR, albumin-to-creatinine ratio; VUS, variant of unknown significance; ERT, enzyme replacement therapy; ESRD, end-stage renal disease.
In general, ERT aims to halt or partially reverse the pathological changes associated with FD and slow multisystem functional decline, particularly in older patients [14]. In the context of nephropathy, treatment goals – depending on the individual clinical condition – include preventing or stabilizing albuminuria, slowing the progression of significant proteinuria, preserving renal function, and delaying progression to ESRD [14, 38, 108].
However, ERT does not uniformly influence the progression of glomerulosclerosis or proteinuria across all patients and may fail to prevent ongoing renal injury, particularly in those with proteinuria exceeding 1 g/day [39, 90]. Moreover, given the clinical heterogeneity of FD, disease-specific therapies vary in effectiveness depending on disease severity, timing of treatment initiation, ADA status in males, and patient adherence, highlighting the need for individualized therapeutic targets [69, 112, 113].
Considering the therapeutic goals with respect to the GFR level, which serves as an accessible noninvasive surrogate marker of Fabry nephropathy severity, the overall therapeutic goal for management of eGFR (at any stage of disease) is to stabilize or reduce the slope loss of eGFR and avoid or delay progression of CKD to ESRD and the need for RRT [12, 14, 50, 108, 111] (Table 2). The renal function under therapy is categorized as the stabilization of function (GFR slope loss ≤1–3 mL/min/1.73 m2/year), progression of nephropathy (annual decrease in GFR >3 mL/min/1.73 m2; rapid progression: >5 mL/min/1.73 m2), and response to treatment (annual slope loss to <3 mL/min/1.73 m2; slowing the process to <5 mL/min/1.73 m2/year, or ≥50% decrease in progression in patients with rapid progression) [50, 108, 111] (Table 2).
Long-Term Efficacy of ERT on Renal Outcomes
Long-Term Efficacy of Agalsidase Alfa
Pooled data from three randomized, placebo-controlled trials evaluating ERT in adult males with FD (n = 108) showed that eGFR remained stable for at least 4.5 years of treatment with agalsidase alfa. Multivariate analysis further demonstrated that baseline eGFR and baseline proteinuria level (≤1 g/day vs. ≥1 g/day) were significant predictors of the rate of eGFR decline [114].
Data from the observational Fabry Outcome Survey (FOS) registry reported the mean annual decline in eGFR (mL/min/1.73 m2) after 5 years of ERT. In the overall population, the decline was −3.17 in men and −0.89 in women. Subgroup analyses showed declines of −2.83 in men and −0.87 in women for stage I CKD, −2.17 and −0.85 for stage II CKD, and −3.00 and −1.01 for stage III CKD at baseline, respectively [115].
Ten-year outcomes of agalsidase alfa ERT in a renal cohort of 152 patients showed that mean eGFR at baseline and at year 10 were 80.4 and 79.1 mL/min/1.73 m2 in females and 95.0 and 77.5 mL/min/1.73 m2 in males, respectively [116]. In females, eGFR remained relatively stable over time. In males, however, those with baseline eGFR <60 mL/min/1.73 m2 experienced a faster annual decline in kidney function compared with those with baseline eGFR ≥60 mL/min/1.73 m2 (−2.79 vs. −1.99 mL/min/1.73 m2 per year) [116].
Long-Term Efficacy of Agalsidase Beta
In an open-label phase III extension study of agalsidase beta (n = 58) with a 54-month follow-up, median eGFR remained stable within the normal range (∼120 mL/min/1.73 m2) throughout treatment, accompanied by a mean eGFR slope of −0.4 mL/min/1.73 m2 and complete clearance of Gb3 from renal cells [90]. The rate of eGFR decline was higher in patients with baseline proteinuria >1 g/day compared with those with <1 g/day (mean eGFR slope −7.4 vs. −1.0 mL/min/1.73 m2), as well as in those with >50% glomerulosclerosis compared with <50% (−8.955 vs. −1.404 mL/min/1.73 m2) [90].
Data from the Fabry Registry in male patients treated with agalsidase beta for ≥2 years showed that renal disease progression was strongly associated with higher urinary protein levels, with a 4.5-fold increased risk of progression in patients with a UP/Cr ratio >1 g/g compared with those <0.3 g/g. In addition, a longer delay between symptom onset and initiation of ERT was linked to worse outcomes, with a 2.9-fold higher risk of progression in patients starting treatment more than 24 years after symptom onset compared with those treated earlier [58].
In an observational study of 40 patients with advanced FD followed for a median of 6 years under agalsidase beta therapy, the mean annual decline in eGFR was −2.3 mL/min/year. eGFR remained stable over time in patients without baseline proteinuria (<0.15 g/day), remaining unchanged from 88 to 88 mL/min/1.73 m2 (n = 14), whereas 4 of 5 patients with proteinuria >2 g/24 h progressed to ESRD [117].
In a 10-year outcome study in 52 classic FD patients treated with agalsidase beta (1 mg/kg EOW), the majority of patients survived without major clinical events, and mean plasma Gb3 levels normalized within approximately 6 months of treatment initiation, while the mean slope of the eGFR was lower (−1.89 vs. −6.82 mL/min/1.73 m2) in patients with low renal involvement (UP/Cr ratio <0.5 g/g or <50% sclerotic glomeruli at baseline, n = 32) versus those with high renal involvement (UP/Cr ratio >0.5 g/g or >50% sclerotic glomeruli at baseline, n = 20) [118]. An analysis of the Fabry Registry in adult patients with FD treated with agalsidase beta (1 mg/kg every other week) for up to 5 years showed a reduced incidence rate of severe clinical events (including renal failure, cardiac events, stroke, and death) after the first 6 months of ERT, particularly among those at highest risk, such as older patients and males [19].
The results from an individual patient data meta-analysis indicated better preservation of renal function in agalsidase beta-treated patients with the classic phenotype (median 2.64 mL/min/1.73 m2/year slower decline in eGFR) when compared to untreated patients, indicating the effectiveness of agalsidase beta on the decline of eGFR in patients with more severe classic phenotype [119]. In addition, the significant association of baseline proteinuria, as a marker of disease progression, with the treatment response indicated the likelihood of more favorable treatment outcomes if agalsidase beta is initiated before significant disease progression [119].
Agalsidase Alfa versus Agalsidase Beta
Currently, there is no conclusive evidence demonstrating the superiority of either therapy in the treatment of FD [5, 109, 120, 121]. Two published trials have directly evaluated both preparations head-to-head, including a small RCT, which showed no clinically relevant differences between two agents at 0.2 mg/kg/EOW doses, except for a dose-dependent decline of plasma lysoGb3 in a follow-up study [121, 122], and the Canadian Fabry Disease Initiative (CFDI), which showed no difference between agalsidase alfa or beta at licensed doses in terms of the event rate after a mean of 50 months of follow-up [123].
In a multicenter retrospective cohort study, there was no significant difference in the slope of the eGFR between agalsidase alfa and beta treatment in patients with a baseline eGFR ≥60 mL or ≤60 mL [124]. Similarly, comparable rates were observed for renal events (CKD stage G5, eGFR <15 mL/min, renal transplantation, or dialysis), cerebral events (implantation of a cardioverter-defibrillator or pacemaker), and all-cause mortality [124]. However, a 10-year follow-up of CFDI male patients showed that kidney events, defined as nephrotic-range proteinuria, doubling of serum creatinine, or kidney failure, were four times less likely in those treated with agalsidase beta (1.0 mg/kg EOW) compared with agalsidase alfa (0.2 mg/kg EOW) [125].
Indeed, the primary distinction between agalsidase alfa and agalsidase beta lies in dosing, with agalsidase beta administered at a fivefold higher dose [5]. This is notable given the reported dose-dependent effect of agalsidase treatment on the clearance of Gb3 in podocytes in young patients after 5 years of ERT [6, 126].
Clearance of Gb3 deposits in renal tissue appears to be more pronounced with agalsidase beta than with agalsidase alfa, and effective removal of Gb3 from podocytes has been observed only in patients treated with agalsidase beta [6]. Differences in the extent of glycolipid reduction reported in pivotal trials further support a dose-response relationship: agalsidase alfa at 0.2 mg/kg every 2 weeks reduced kidney capillary endothelial deposits by 60% and serum Gb3 by 54% over 24 weeks, whereas agalsidase beta at 1.0 mg/kg every 2 weeks achieved reductions of 84% in endothelial deposits and over 90% in serum Gb3 within 20 weeks [127–129]. Findings from the FIELD trial indicate that podocytes are more resistant to Gb3 clearance than endothelial cells, suggesting that lower doses of agalsidase beta may effectively clear capillary endothelial deposits but result in variable and less predictable clearance in podocytes [130].
Following a global supply shortage, a subset of patients was transitioned from a standard regimen of agalsidase beta to agalsidase alfa; this cohort subsequently experienced more rapid eGFR deterioration and increased disease severity. Notably, these trends reversed upon resuming agalsidase beta, with dose-related improvements observed in both renal function stability and lyso-Gb3 reduction [14, 128, 131]. Although various studies monitored the consequences of switching or reducing agalsidase beta doses during the drug shortage, clinical event rates remained unchanged, a result potentially explained by the short-term nature of the follow-up and the small number of participants involved [109, 131–133].
Furthermore, research indicates a heightened risk of developing neutralizing ADAs in male patients receiving agalsidase beta compared to those on agalsidase alfa. These antibodies typically diminish the efficacy of ERT by interfering with cellular internalization, altering enzymatic catalysis, and exacerbating the loss of renal function [6, 124]. Interestingly, the clinical impact of ADAs appears to differ by agent: while antibodies in patients treated with agalsidase alfa correlate with a slower reduction in lyso-Gb3, the response to agalsidase beta remains largely resilient to ADA formation. This stability is likely due to the fivefold higher dosage of agalsidase beta, which may saturate and overcome the inhibitory effects of the antibodies [97, 122]. This is further supported by evidence showing that transitioning antibody-positive males from low-dose agalsidase alfa (0.2 mg/kg) to high-dose agalsidase beta (1.0 mg/kg) biweekly results in a significant decline in lyso-Gb3 levels [128, 134, 135].
In a study comparing clinical outcomes and biochemical response in a large cohort of 387 FD patients (192 women) treated with either agalsidase alfa (n = 248) or agalsidase beta at the authorized dose (mean age at start of ERT: 46 ± 15 years), propensity score matched analysis revealed a similar event rate for both enzymes [109]. However, agalsidase beta was associated with a more robust decrease in plasma lysoGb3 (specifically in men with classical FD), persisting in the presence of antibodies, and a better reduction in left ventricular mass index while eGFR slopes were similar between groups [109].
Pegunigalsidase Alfa: Clinical Evidence for Renal Outcomes
Pegunigalsidase alfa is a PEGylated, plant cell-derived recombinant α-Gal A designed to provide enhanced pharmacokinetics, reduced immunogenicity, and prolonged plasma half-life compared with conventional ERT formulations [136]. In the phase 3 BALANCE trial, a head-to-head comparison with agalsidase beta in 78 ERT-experienced patients, pegunigalsidase alfa met the primary non-inferiority endpoint for eGFR slope (−2.51 vs. −2.16 mL/min/1.73 m2/year) [30]. In the BRIDGE trial, 22 patients switched from agalsidase alfa demonstrated a significant improvement in eGFR slope from −5.90 to −1.19 mL/min/1.73 m2/year, with a concomitant 31% reduction in plasma lyso-Gb3 [137]. Six-year follow-up data showed a sustained eGFR slope of −1.6 mL/min/1.73 m2/year with an 83% reduction in lyso-Gb3 [136]. More recently, a monthly dosing regimen (2 mg/kg every 4 weeks) evaluated in the BRIGHT trial demonstrated a median eGFR change of −1.9 mL/min at 52 weeks, receiving a positive CHMP opinion in January 2026 [138]. One case of immune complex-mediated membranoproliferative glomerulonephritis was reported in the BALANCE trial, warranting vigilance for this rare but clinically significant renal adverse event [30].
Substrate Reduction Therapy
SRT aims to decrease glycosphingolipid synthesis by inhibiting glucosylceramide synthase, thereby reducing the substrate burden upstream of the enzymatic deficiency. Lucerastat (Idorsia), an oral iminosugar-based glucosylceramide synthase inhibitor, was evaluated in the phase 3 MODIFY trial (n = 118) [32]. Although the primary endpoint of neuropathic pain reduction was not met, exploratory renal analyses demonstrated a favorable eGFR difference of +5.4 mL/min/1.73 m2/year in the subgroup with baseline eGFR <90 mL/min (lucerastat +3.8 vs. placebo −1.6). In the open-label extension, the eGFR slope improved from −3.50 to −1.48 mL/min/1.73 m2/year, and protocol kidney biopsies in 6 male patients after 56 months showed low-to-absent Gb3 deposits [32]. Based on these renal findings, a phase 3 registration program focused on renal endpoints has been agreed upon with the FDA (February 2026). Venglustat (Sanofi), another oral glucosylceramide synthase inhibitor, did not meet its primary pain endpoint in the phase 3 PERIDOT trial (February 2026), and its renal effects remain under evaluation in the ongoing CARAT trial.
Gene Therapy
Gene therapy approaches aim to provide sustained endogenous α-Gal A production through a single administration. The most advanced renal data come from isaralgagene civaparvovec (ST-920, Sangamo/4D), an AAV-based gene therapy evaluated in the phase 1/2 STAAR trial (n = 32) [139]. Notably, treated patients demonstrated positive eGFR slopes of +1.965 mL/min/1.73 m2/year at 52 weeks and +1.747 at 104 weeks, in contrast to the expected decline under conventional ERT. The FDA has agreed to an Accelerated Approval pathway using the 52-week eGFR slope as a surrogate endpoint, and a rolling BLA submission was initiated in late 2025. Other gene therapy programs include 4D-310 (4D Molecular Therapeutics), a cardiac-targeted AAV vector that demonstrated supraphysiologic α-Gal A levels but was associated with atypical hemolytic uremic syndrome in 3 of 6 patients, leading to a temporary clinical hold [140], and AMT-191 (uniQure), an AAV5-based therapy that achieved high enzyme expression but encountered hepatotoxicity signals requiring a dosing pause in January 2026 (NCT06270316). These safety events underscore that while gene therapy holds considerable promise, careful long-term monitoring of both efficacy and adverse effects will be essential before widespread clinical adoption.
mRNA-Based Therapy
mRNA-based approaches using lipid nanoparticle-encapsulated mRNA encoding α-Gal A have shown encouraging preclinical results, including sustained enzyme activity and Gb3 clearance in mouse models [141, 142]. However, no mRNA-based therapy for FD has yet entered clinical trials, and the translational path from preclinical to clinical application remains to be established.
Adjunctive Therapy for Fabry nephropathy
A cornerstone approach in CKD management, equally relevant to Fabry nephropathy, is the minimization of urinary protein excretion to the lowest possible levels as stabilizing proteinuria is vital for the preservation of renal function [6, 143]. Because ERT often fails to exert a consistent antiproteinuric impact in clinical trials, the co-administration of renin-angiotensin-aldosterone system blockers, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, is considered indispensable for managing proteinuria in these patients [5, 6, 144]. Furthermore, modern therapeutic agents with proven renoprotective benefits in diabetic CKD, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, finerenone (a non-steroidal mineralocorticoid receptor antagonist), and sacubitril/valsartan, represent promising adjunctive options for the treatment of Fabry nephropathy [6, 145–147].
Although RAS blockers and SGLT2 inhibitors ameliorate the glomerular hyperfiltration and albuminuria, known as the key drivers of CKD progression, initial decline in eGFR is expected with these treatments, which does not represent progression of nephropathy and is associated with long-term kidney protection [26, 148, 149]. Emerging Fabry-specific data support the renoprotective potential of SGLT2 inhibitors in this population. In a retrospective Australian cohort of 11 Fabry patients treated with SGLT2 inhibitors, the median urinary albumin-to-creatinine ratio decreased from 76 to 39 mg/mmol (approximately 49% reduction, p = 0.05) [31]. In a Korean comparative study of 10 Fabry patients versus 18 CKD controls, SGLT2 inhibitor use was associated with an improvement in eGFR slope from −4.38 to +1.25 mL/min/1.73 m2/year (p < 0.05), notably without the initial eGFR dip typically observed in non-Fabry CKD [150]. A prospective randomized trial of dapagliflozin in Fabry patients with CKD stages 1–3 and albuminuria (DEFY study) is currently ongoing, with its primary endpoint of ≥20% albuminuria reduction anticipated to provide more definitive evidence [145]. The additional cardioprotective actions of RAS inhibitors as well as their inhibitory effects on the inflammatory and fibrotic process provide a further rationale for their use in patients with CKD [14, 38, 39].
Adjunctive management includes the use of analgesics, statins, dietary sodium restriction, anticoagulants and antiarrhythmic agents, vitamin D supplementation when indicated, and lifestyle modifications such as avoiding extreme temperatures and smoking cessation. For patients with ESRD, RRT in the form of dialysis or, preferably, kidney transplantation is available [2, 25, 56, 76]. Patients with ESRD undergoing dialysis and transplant recipients may still derive benefit from ERT for extra-renal manifestations (i.e., neurological and cardiac disease) and improvement in QoL [5, 151].
| Key messages V – treatment |
|---|
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Monitoring Treatment Response and Organ Involvement in Fabry Nephropathy
Factors Associated with Response to ERT
Urinary protein excretion exceeding 1 g/day, a GFR below 60 mL/min/1.73 m2, or the presence of glomerulosclerosis demonstrated by kidney biopsy are important indicators of inadequate response to ERT [25, 90]. The age at which ERT is initiated, sex-related differences, disease phenotype (classical versus later-onset), and the use of adjunctive therapies such as ACE inhibitors or angiotensin receptor blockers are key determinants of ERT’s impact on renal outcomes [6]. Overall, early treatment initiation is strongly recommended as ERT is less effective in advanced disease in preventing major adverse clinical events affecting the renal, cardiac, or nervous systems [38, 58, 152, 153]. Differences between treated and untreated patients typically become evident after at least 4 years of therapy, indicating a reduced risk of complications with longer treatment duration [38, 117].
In FD, the primary pathogenic mechanism, Gb3 accumulation initiating renal injury, and the secondary fibrosis-propagating processes (including TGF-β pathway activation downstream of lyso-Gb3 deposition) are fundamentally distinct [15, 18, 39]. Therefore, ERT per se may not be able to stop kidney injury in all patients, while initiating ERT after the onset of tissue fibrosis does not regress the fibrosis or completely prevent organ dysfunction [38, 39, 90]. Identifying and targeting the secondary mechanisms that perpetuate renal injury may enable new treatment options with better outcomes for Fabry nephropathy [39].
Multidisciplinary Approach for Management and Continued Monitoring of Disease
Achieving optimal outcomes in Fabry nephropathy patients requires (a) a multidisciplinary team-based approach by an experienced team of clinicians across different specialties (nephrology, cardiology, neurology, genetics, psychology, pathology), (b) timely initiation of ERT, combined with appropriately selected adjunctive therapies and tailored within an individualized care plan based on the patient’s clinical signs and symptoms, and (c) improving QoL [4, 7, 26, 76, 108]. Continued monitoring and assessment of clinical status are essential to optimal patient care [26, 108]. Regular monitoring for signs of organ involvement in asymptomatic late-onset patients, as well as assessment of treatment response in those receiving therapy, through a multidisciplinary team approach, is also essential to continuously reassess and refine individualized therapeutic goals [7, 76, 108]. Therefore, all FD patients require an initial assessment of affected organs alongside a thorough routine monitoring to assess disease burden, therapeutic response, and disease progression [26, 76, 154].
Monitoring Parameters for Treatment Response and Organ Involvement
Plasma and/or DBS Lyso-Gb3, Albuminuria/Proteinuria, Serum Creatinine, and eGFR
For the best follow-up of patients, the treatment monitoring parameters should include the assessment of glycolipid burden via plasma and/or DBS lyso-Gb3 (at onset of treatment and every 6–12 months thereafter), the assessment of the need for antiproteinuric therapy and risk stratification via albuminuria (preferred, more sensitive) and/or proteinuria (at treatment onset and at least annually thereafter, more frequently if moderate or high risk), and the assessment of renal functional status via serum creatinine and eGFR (at onset of treatment and at least annually thereafter, more frequently if moderate or high risk) [9, 69, 76] (Table 3). Given the reduction in lyso-Gb3 levels in response to ERT, particularly within the first 3 months of treatment in all patients with the classic phenotype and in male patients, lyso-Gb3 may be a useful biomarker for monitoring treatment response in these groups [9, 69]. Accordingly, assessment of glycolipid burden via lyso-Gb3 measurement at baseline (prior to treatment initiation) and at 6–12-month intervals thereafter is recommended to track longitudinal changes [26, 69, 130]. However, it should be noted that the relationship between treatment-induced reductions in lyso-Gb3 and a decreased incidence of clinical events remains uncertain as improvements in clinical outcomes may take at least 6 months to become apparent in FD patients [19, 69, 155].
Table 3.
| | Parameters and monitoring frequency |
|---|---|
| Treatment response | |
| Plasma and/or DBS lyso-Gb3 | Pre-treatment and 6–12 months thereafter |
| Albuminuria (preferred, more sensitive) and/or proteinuria | Pre-treatment and at least annually thereafter (every 6 months if moderate risk and every 3 months if high risk) |
| Serum creatinine | Pre-treatment and at least annually thereafter (every 6 months if moderate risk and every 3 months if high risk) |
| eGFR | Pre-treatment and at least annually thereafter (every 6 months if moderate risk and every 3 months if high risk) |
| Immunogenicity (anti-drug antibodies) | At a frequency based on the individual patients’ need for medical care and routine follow-up |
| Symptomatic improvement (pain scores cold and heat intolerance, vibratory thresholds) | Annually |
| QoL, work performance, level of depression/anxiety | Every clinic visit |
| Disease course – organ involvement | |
| Cardiac | |
| Blood pressure and cardiac rhythm | Every clinic visit |
| ECG and echocardiography | Annually and as clinically indicated |
| Cardiac MRI | MRI with gadolinium: regularly (>2 year interval) or when disease clinical progression is evident |
| MRI with T1 mapping: used as an investigational tool | |
| Cerebrovascular | |
| Brain MRI | Regularly (every 3 years) or when clinically needed |
DBS, dried blood spot; Lyso-Gb3, globotriaosylsphingosine; eGFR, estimated glomerular filtration rate; ECG, electrocardiogram; MRI, magnetic resonance imaging, QoL: Quality of life.
Neutralizing Antibodies (ADAs)
The neutralizing antibodies should also be monitored alongside lyso-Gb3 levels in patients receiving ERT, at a frequency based on the individual patients’ need for medical care and routine follow-up [26, 156, 157] (Table 3). Currently, there are no universal standards for antibody testing to assess antibody development in response to ERT as standardized, commercially available assays or protocols for measuring IgG levels have not yet been established [26].
Symptomatic Improvement and QoL
The monitoring should also include the assessment of symptomatic improvement (pain scores, cold and heat intolerance, vibratory thresholds) and the QoL, work performance, and level of depression/anxiety (every clinic visit) [76, 149, 158] (Table 3).
Patients with FD have a lower QoL compared with the general population due to several factors, such as Fabry-related chronic pain and pain crises, gastrointestinal symptoms, hearing loss, physical inactivity, fatigue, poor psychosocial functioning, the burden of organ damage, and the therapy-related burden (travel long distances to clinics for infusions) [26, 108, 158, 159]. Therefore, QoL should be carefully addressed by physicians along with the use of adjunctive therapies or psychological support [26, 108, 158, 159]. Renal involvement, cardiac complications, stroke, and pain were reported to be significantly related to QoL in patients with FD, supporting that the management requires a multidisciplinary approach with the exchange of views between nephrologists, cardiologists, and neurologists [158, 160]. Notably, even simply receiving a diagnosis of FD and being placed on a treatment plan may improve QoL in some patients, likely due to the psychological reassurance of having a care team and ongoing health monitoring [105].
Cardiac and Cerebrovascular Involvement
Follow-up should also include assessment of cardiac involvement, including blood pressure and cardiac rhythm at each clinic visit, annual ECG and echocardiography, and cardiac MRI with gadolinium or T1 mapping at intervals greater than 2 years or when clinical progression is suspected, while cerebrovascular involvement should be monitored with brain MRI performed regularly, typically every 3 years or as clinically indicated [4, 10, 69, 76, 161] (Table 3). T1 mapping reflects glycosphingolipid accumulation and enables noninvasive tissue characterization; together with echocardiographic parameters such as myocardial strain, it can be used to evaluate disease progression in FD [162].
In addition, clinical stability in treated patients suggests treatment efficacy, whereas clinical deterioration in untreated patients may indicate the need to initiate ERT [163]. Hence, utilization of dynamic tools based on a composite scoring of different organ involvements (i.e., FASTEX) is considered of utmost importance to reliably assess clinical stability over time [163].
Similarly, there is a need to develop a composite scoring system for Fabry nephropathy that incorporates different monitoring parameters (i.e., reduction in plasma and/or DBS lyso-Gb3, albuminuria/proteinuria and eGFR) with a final cutoff value to reliably estimate the renal functional status under treatment in terms of stabilization, progression of nephropathy, response to treatment, and need for treatment switch.
| Key messages VI – monitoring |
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Conclusion
The participating experts considered the indispensable role of heightened disease awareness among nephrologists, the maintenance of a high diagnostic index in symptomatic individuals, and the importance of systematic screening of at-risk populations to enable prompt identification of Fabry nephropathy. This is particularly important in the current availability of enzymatic and genetic screening tests and the specific disease-modifying treatments capable of decelerating kidney function deterioration when initiated at an early disease stage. Implementation of a multidisciplinary approach with an experienced team of clinicians, and continued monitoring and assessment of clinical status are considered critical to optimal patient care, as well as the timely initiation of ERT in conjunction with appropriately selected adjunctive treatments within a care plan individualized to the patient’s clinical signs and symptoms.
The renal biopsy (diagnostic and prognostic role of histological changes become evident before clinical and laboratory indicators of disease), proteinuria (an independent risk factor for disease progression and poor treatment response), podocyturia (as a potential earlier biomarker of clinically silent kidney damage), and plasma lyso-Gb3 (as a diagnostic biomarker also helping stratification of phenotypes) are considered particularly valuable tools in the diagnosis and monitoring. Nonetheless, the considerable phenotypic and clinical variability of Fabry nephropathy emphasizes the likelihood of additional factors participating in the secondary mechanisms that perpetuate and amplify the initial kidney injury initiated by Gb3 deposition and drive progression toward fibrosis, and thus, the novel biomarkers elucidating these pathways and enabling consistent, reproducible assessments of kidney function are indispensable for optimal disease management. Regarding the comparative efficacy of agalsidase preparations, while the available data do not definitively establish the superiority of either preparation for Fabry nephropathy treatment, five times higher treatment dosage for agalsidase beta seems to be the most prominent difference providing certain advantages in terms of dose-dependent outcomes such as the higher chance of clearance of Gb3 in podocytes, benefits in terms of GFR decline and levels of lyso-Gb3, and overcoming the negative effects of antibody formation on lysoGb3 during treatment. Accordingly, the proposed expert opinion is expected to increase awareness among nephrologists regarding the conceptual, clinical, and therapeutic aspects of Fabry nephropathy, which would assist them in recognizing Fabry nephropathy in their clinical practice and providing the best practice in the management and monitoring of the disease.
Conflict of Interest Statement
N. Eren has received honoraria from Sanofi Turkey for participation in the expert panel meetings that led to this manuscript, also receives advisory board fees from Takeda and speaker honoraria from Abdi İbrahim Otsuka, Biofarma, Takeda, Alexion, Boehringer Ingelheim, Nobel, and AstraZeneca. K. Turkmen has received honoraria from Sanofi Turkey for participation in the expert panel meetings that led to this manuscript and also receives advisory board fees from Takeda and speaker honoraria from Alexion, Abdi İbrahim Otsuka, and Takeda. F.H. Turgut has received honoraria from Sanofi Turkey for participation in the expert panel meetings that led to this manuscript and also receives speaker honoraria from Abdi İbrahim Otsuka, Takeda, and AstraZeneca. B. Tokgoz has received honoraria from Sanofi Turkey for participation in the expert panel meetings that led to this manuscript and also receives advisory board fees from Takeda and speaker honoraria from Vantive. A. Inci has received honoraria from Sanofi Turkey for participation in the expert panel meetings that led to this manuscript and has also received speaker honoraria from Abdi İbrahim Otsuka, Biofarma, and AstraZeneca. N. Seyahi has received honoraria from Sanofi Turkey for participation in the expert panel meetings that led to this manuscript and also receives advisory board fees from Takeda and speaker honoraria from Abdi İbrahim Otsuka, Biofarma, Takeda, Alexion, and AstraZeneca.
Funding Sources
This work was supported by Sanofi Turkey, which provided funding for the organization of expert panel meetings, including participant invitations and compensation for the experts’ time and travel expenses. Sanofi Turkey was given the opportunity to review the manuscript for factual accuracy; however, all decisions regarding the intellectual content, conclusions, and submission for publication were made solely by the authors, who maintained full editorial independence throughout the process. Editorial support, including manuscript formatting and referencing, was provided by Kappa Training Consultancy Research LLC, Izmir, Turkey (funded by Sanofi Turkey), under the direction of the authors.
Author Contributions
Necmi Eren: conceptualization, literature search, writing – original draft preparation, and writing – review and editing. Kultigin Turkmen, Faruk Hilmi Turgut, Bulent Tokgoz, and Ayca Inci: conceptualization, literature search, and writing –review and editing. Nurhan Seyahi: conceptualization, literature search, writing – review and editing, and supervision. All authors have read and approved the final manuscript.
Funding Statement
This work was supported by Sanofi Turkey, which provided funding for the organization of expert panel meetings, including participant invitations and compensation for the experts’ time and travel expenses. Sanofi Turkey was given the opportunity to review the manuscript for factual accuracy; however, all decisions regarding the intellectual content, conclusions, and submission for publication were made solely by the authors, who maintained full editorial independence throughout the process. Editorial support, including manuscript formatting and referencing, was provided by Kappa Training Consultancy Research LLC, Izmir, Turkey (funded by Sanofi Turkey), under the direction of the authors.
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