Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study.

BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.

An expert consensus on practical clinical recommendations and guidance for patients with classic Fabry disease.

Fabry disease is an X-linked inherited lysosomal disorder that causes accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and reduced life expectancy. It can affect both males and females and can be classified into classic or later-onset phenotypes. In classic Fabry disease, α-galactosidase A (α-Gal A) activity is absent or severely reduced and disease manifestations have an early onset that can affect multiple organs. In contrast, in later-onset Fabry disease, patients have residual α-Gal A activity and clinical features are primarily confined to the heart. Individualized therapeutic goals in Fabry disease are required due to varying phenotypes and patient characteristics, and the wide spectrum of disease severity. An international group of expert physicians convened to discuss and develop practical clinical recommendations for disease- and organ-specific therapeutic goals in Fabry disease, based on expert consensus and evidence identified through a structured literature review. Biomarkers reflecting involvement of various organs in adult patients with classic Fabry disease are discussed and consensus recommendations for disease- and organ-specific therapeutic goals are provided. These consensus recommendations should support the establishment of individualized approaches to the management of patients with classic Fabry disease by considering identification, diagnosis, and initiation of disease-specific therapies before significant organ involvement, as well as routine monitoring, to reduce morbidity, optimize patient care, and improve patient health-related quality of life.

Fabry disease: diagnostic methods in nephrology practice.

Fabry disease (FD; OMIM 301500) is a rare X-linked systemic disease caused by a mutation of the GLA gene. Consequently, there is very low, or even absent, activity of the lysosomal enzyme α-galactosidase A (α-Gal A), resulting in the progressive accumulation of glycosphingolipids (predominantly, globotriaosylceramide (GL-3)) in various cells of different organs. Chronic progressive proteinuric kidney disease is one of the hallmarks of this disease, and it constitutes an important component of this condition's clinical picture. Many patients with FD develop advanced chronic kidney disease, and half of them progress to end-stage renal disease. Most male patients die before the age of 60 years. Specific treatment with enzyme replacement therapy (ERT) has been shown to be effective when treatment is started early enough, before irreversible changes can occur. Therefore, the early diagnosis of FD has become very important. However, in nephrology practice, too many patients are still being diagnosed in late and very advanced stages of the disease. Also, the number of diagnosed patients varies among different countries and regions. The reasons for this are numerous and diverse, and they mostly depend on the knowledge, awareness, and availability of diagnostic procedures.
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Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy.

BACKGROUND: Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant agalsidase-beta therapy. METHODS AND DESIGN: The goal was maintenance of urine protein to creatinine ratio (UPCR) <0.5 g/g or a 50% reduction in baseline UPCR for 24 patients at eight study sites. The change in estimated glomerular filtration rate (eGFR) was assessed over 21 months of treatment. RESULTS: 18 out of 24 patients achieved the UPCR goal with eGFR slopes that were significantly better than six patients who did not achieve the UPCR goal (-3.6 (-4.8 to -1.1) versus -7.0 (-9.0 to -5.6) mL/min/1.73 m(2)/year, respectively, p=0.018). Despite achieving the UPCR goal, 67% (12/18 patients) still progressed with an eGFR slope <-2 mL/min/1.73 m(2)/year. Regression analysis showed that increased age at initiation of agalsidase-beta therapy was significantly associated with worsened kidney outcome. Hypotension and hyperkalaemia occurred in seven and eight patients, respectively, which required modification of antiproteinuric therapy but was not associated with serious adverse events. CONCLUSIONS: This study documents the effectiveness of agalsidase-beta (1 mg/kg/2 weeks) and antiproteinuric therapy with ACE inhibitors and/or ARB in patients with severe Fabry nephropathy. Patients had preservation of kidney function if agalsidase-beta treatment was initiated at a younger age, and UPCR maintained at or below 0.5 g/g with antiproteinuric therapy. TRIAL REGISTRATION NUMBER: NCT00446862.

Dynamics of Leukocyte Telomere Length in Patients with Fabry Disease.

Fabry disease (FD) leads to significant morbidity and mortality, which may indicate accelerated ageing. However, it is still unclear whether there is a relationship between telomere length (TL), a marker of biological ageing, and disease outcome. We aimed to examine the relationship between leukocyte TL (LTL) dynamics and the presence of advanced disease stages and/or late complications of FD, including hypertrophic cardiomyopathy, nephropathy and stroke, both cross-sectionally and longitudinally. DNA was extracted from peripheral blood leukocytes and quantitative PCR was utilized to determine relative LTL in 99 Fabry patients. In the longitudinal analysis, we included 50 patients in whom at least three measurements were performed over a period of 5-10 years. The results showed a significant inverse correlation between LTL and age (ρ = -0.20, p = 0.05). No significant differences in LTL were found between females and males (p = 0.79) or between patients receiving disease-specific therapy and those without (p = 0.34). In a cross-sectional analysis, no association was found between the presence (p = 0.15) or number (p = 0.28) of advanced stages of the disease and/or late complications and LTL. Similarly, in a longitudinal analysis, no difference in LTL dynamics was found regarding the presence (p = 0.16) of advanced stage organ involvement and/or late complications or their number. These findings indicate that LTL dynamics in adulthood may not be a reliable indicator of disease outcomes in Fabry patients. Therefore, LTL may more accurately reflect the disease burden in early life, when TL is primarily determined.

Urinary-derived extracellular vesicles reveal a distinct microRNA signature associated with the development and progression of Fabry nephropathy.

Introduction: Early initiation is essential for successful treatment of Fabry disease, but sensitive and noninvasive biomarkers of Fabry nephropathy are lacking. Urinary extracellular vesicles (uEVs) represent a promising source of biomarkers of kidney involvement. Among them, microRNAs (miRNAs) are important post-transcriptional regulators of gene expression that contribute to the development and progression of various kidney diseases. We aimed to identify uEV-derived miRNAs involved in the development and/or progression of Fabry nephropathy. Methods: Patients with genetically confirmed Fabry disease and matched control subjects were included. EVs were isolated from the second morning urine by size exclusion chromatography, from which miRNAs were extracted. miRNA urine exosome PCR panels were used to characterize the miRNA signature in a discovery cohort. Individual qPCRs were performed on a validation cohort that included chronological samples. We identified the target genes of dysregulated miRNAs and searched for potential hub genes. Enrichment analyses were performed to identify their potential function. Results: The expression of miR-21-5p and miR-222-3p was significantly higher in patients with stable renal function and those with progressive nephropathy compared with the corresponding controls. In addition, the expression of miR-30a-5p, miR-10b-5p, and miR-204-5p was significantly lower in patients with progressive nephropathy, however, in the chronological samples, this was only confirmed for miR-204-5p. Some of the identified hub genes controlled by the dysregulated miRNAs have been associated with kidney impairment in other kidney diseases. Conclusion: The miRNA cargo in uEVs changes with the development and progression of Fabry nephropathy and, therefore, represents a potential biomarker that may provide a new option to prevent or attenuate the progression of nephropathy. Furthermore, dysregulated miRNAs were shown to be potentially associated with pathophysiological pathways in the kidney.

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study.

BACKGROUND: Pegunigalsidase alfa is a novel, PEGylated α-galactosidase-A enzyme-replacement therapy approved in the EU and US to treat patients with Fabry disease (FD). OBJECTIVE/METHODS: BRIDGE is a phase 3 open-label, switch-over study designed to assess safety and efficacy of 12 months of pegunigalsidase alfa (1 mg/kg every 2 weeks) treatment in adults with FD who had been previously treated with agalsidase alfa (0.2 mg/kg every 2 weeks) for ≥ 2 years. RESULTS: Twenty-seven patients were screened; 22 met eligibility criteria; and 20 (13 men, 7 women) completed the study. Pegunigalsidase alfa was well-tolerated, with 97% of treatment-emergent adverse events (TEAEs) being of mild or moderate severity. The incidence of treatment-related TEAEs was low, with 2 (9%) discontinuations due to TEAEs. Five patients (23%) reported infusion-related reactions. Overall mean (SD; n = 22) baseline estimated glomerular filtration rate (eGFR) was 82.5 (23.4) mL/min/1.73 m2 and plasma lyso-Gb3 level was 38.3 (41.2) nmol/L (men: 49.7 [45.8] nmol/L; women: 13.8 [6.1] nmol/L). Before switching to pegunigalsidase alfa, mean (standard error [SE]) annualized eGFR slope was - 5.90 (1.34) mL/min/1.73 m2/year; 12 months post-switch, the mean eGFR slope was - 1.19 (1.77) mL/min/1.73 m2/year; and mean plasma lyso-Gb3 reduced by 31%. Seven (35%) out of 20 patients were positive for pegunigalsidase alfa antidrug antibodies (ADAs) at ≥ 1 study timepoint, two of whom had pre-existing ADAs at baseline. Mean (SE) changes in eGFR slope for ADA-positive and ADA-negative patients were + 5.47 (3.03) and + 4.29 (3.15) mL/min/1.73 m2/year, respectively, suggesting no negative impact of anti-pegunigalsidase alfa ADAs on eGFR slope. CONCLUSION: Pegunigalsidase alfa may offer a safe and effective treatment option for patients with FD, including those previously treated with agalsidase alfa. TRN: NCT03018730. Date of registration: January 2017.

Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation.

BACKGROUND: The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. METHODS: Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. RESULTS: Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m(2)/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m(2)/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m(2)/year). CONCLUSIONS: Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.

Podocyturia in Fabry disease: a 10-year follow-up.

BACKGROUND: Fabry disease (FD) is a rare X-linked disorder of sphingolipid metabolism that results in chronic proteinuric nephropathy. Podocytes are one of the most affected renal cells and play an important role in the development and progression of kidney disease. Detached podocytes found in urine (podocyturia) are considered as a non-invasive early marker of kidney injury; however, the dynamics of podocyte loss remains unknown. METHODS: In this 10-year follow-up study, podocyturia and other renal clinical data were evaluated in 39 patients with FD. From 2009 to 2019, podocyturia was assessed in 566 fresh urine samples from 13 male and 26 female FD patients using immunocytochemical detection of podocalyxin. RESULTS: Podocyturia (number of podocytes per 100 mL of urine) was found in 311/566 (54.9%) of the samples, more frequently (68.9 ± 21.9% versus 50.6 ± 25.9%; P = 0.035) and with higher values (364 ± 286 versus 182 ± 180 number of podocytes per gram of creatinine (Cr) in urine; P = 0.020) in males compared with females. The mean number of assessed samples for each patient was 14.5 (range 3-40) and the frequency of samples with podocyturia ranged from 0% to 100% (median 57%). Podocyturia was already present in 42.9% of patients <20 years of age and in 89.5% of normoalbuminuric patients. Podocyturia correlated with albuminuria (urine albumin:Cr ratio) (r = 0.20, P < 0.001) and a higher incidence and values of podocyturia were observed in patients with lower estimated glomerular filtration rate. CONCLUSIONS: Our data demonstrated that podocyturia is an early clinical event in the development of nephropathy. In addition, we found podocyturia to be a discontinuous event with wide variability.

Renoprotective Effect of Agalsidase Alfa: A Long-Term Follow-Up of Patients with Fabry Disease.

Fabry disease is a rare lysosomal storage disorder caused by mutations in the GLA gene, which, without treatment, can cause significant renal dysfunction. We evaluated the effects of enzyme replacement therapy with agalsidase alfa on renal decline in patients with Fabry disease using data from the Fabry Outcome Survey (FOS) registry. Male patients with Fabry disease aged >16 years at agalsidase alfa start were stratified by low (≤0.5 g/24 h) or high (>0.5 g/24 h) baseline proteinuria and by 'classic' or 'non-classic' phenotype. Overall, 193 male patients with low (n = 135) or high (n = 58) baseline proteinuria were evaluated. Compared with patients with low baseline proteinuria, those with high baseline proteinuria had a lower mean ± standard deviation baseline eGFR (89.1 ± 26.2 vs. 106.6 ± 21.8 mL/min/1.73 m2) and faster mean ± standard error eGFR decline (−3.62 ± 0.42 vs. −1.61 ± 0.28 mL/min/1.73 m2 per year; p < 0.0001). Patients with classic Fabry disease had similar rates of eGFR decline irrespective of baseline proteinuria; only one patient with non-classic Fabry disease had high baseline proteinuria, preventing meaningful comparisons between groups. In this analysis, baseline proteinuria significantly impacted the rate of eGFR decline in the overall population, suggesting that early treatment with good proteinuria control may be associated with renoprotective effects.

Do clinical guidelines facilitate or impede drivers of treatment in Fabry disease?

BACKGROUND: Variable disease progression confounds accurate prognosis in Fabry disease. Evidence supports the long-term benefit of early intervention with disease-specific therapy, but current guidelines recommend treatment initiation based on signs that may present too late to avoid irreversible organ damage. Findings from the 'PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease' (PREDICT-FD) initiative included expert consensus on 27 early indicators of disease progression in Fabry disease and on drivers of and barriers to treatment initiation in Fabry disease. Here, we compared the PREDICT-FD indicators with guidance from the European Fabry Working Group and various national guidelines to identify differences in signs supporting treatment initiation and how guidelines themselves might affect initiation. Finally, anonymized patient histories were reviewed by PREDICT-FD experts to determine whether PREDICT-FD indicators supported earlier treatment than existing guidance. RESULTS: Current guidelines generally aligned with PREDICT-FD on indicators of renal involvement, but most lacked specificity regarding cardiac indicators. The prognostic significance of neurological indicators such as white matter lesions (excluded by PREDICT-FD) was questioned in some guidelines and excluded from most. Some PREDICT-FD patient-reported signs (e.g., febrile crises) did not feature elsewhere. Key drivers of treatment initiation in PREDICT-FD were: (A) male sex, young age, and clinical findings (e.g., severe pain, organ involvement), (B) improving clinical outcomes and preventing disease progression, and (C) a family history of Fabry disease (especially if outcomes were severe). All guidelines aligned with (A) and several advocated therapy for asymptomatic male patients. There was scant evidence of (B) in current guidance: for example, no countries mandated ancillary symptomatic therapy, and no guidance advocated familial screening with (C) when diagnosis was confirmed. Barriers were misdiagnosis and a lack of biomarkers to inform timing of treatment. Review of patient histories generally found equal or greater support for treatment initiation with PREDICT-FD indicators than with other guidelines and revealed that the same case and guideline criteria often yielded different treatment recommendations. CONCLUSIONS: Wider adoption of PREDICT-FD indicators at a national level could promote earlier treatment in Fabry disease. Clearer, more concise guidance is needed to harmonize treatment initiation in Fabry disease internationally.

Urinary total globotriaosylceramide and isoforms to identify women with Fabry disease: a diagnostic test study.

BACKGROUND: Fabry disease is a treatable X-linked lysosomal storage disorder caused by alterations in the structural gene (GLA) of α-galactosidase A (AGAL), manifesting with cardiovascular and/or kidney disease and decreased life span. Although males as well as females can be affected, females cannot be identified using AGAL activity. We evaluated urinary total globotriaosylceramide (Gb3) and single N-acyl isoforms for the detection of Fabry disease in female patients with and without chronic kidney disease (CKD). STUDY DESIGN: Diagnostic accuracy study. SETTING & PARTICIPANTS: 28 untreated women with Fabry disease and 335 female outpatients without Fabry disease with (n = 213) and without CKD (n = 122). INDEX TEST: Assessment of urinary Gb3 using electrospray ionization tandem mass spectrometry, including 6 N-acyl isoforms, total Gb3 related to urinary creatinine, and ratios of Gb3-24 to Gb3-18 and Gb3-24 to urinary AGAL. REFERENCE TEST: Fabry disease, diagnosed by identification of known pathogenic GLA mutations in patients or their male relatives. RESULTS: 6 parameters (ratio of Gb3-24 to urinary AGAL activity; Gb3-24; ratio of Gb3-24 to Gb3-18; Gb3-22; Gb3-16; and total Gb3) were highly informative for the diagnosis of Fabry disease independent of the presence or absence of CKD (area under the receiver operating characteristic curve, 0.876-0.927; all P < 0.001). LIMITATIONS: Because of low signal-to-noise ratios, 15.8% of samples had to be excluded. CONCLUSION: Total urinary Gb3 and Gb3 isoforms can be used for the diagnosis of Fabry disease in women.

Characteristics of Vascular Phenotype in Fabry Patients.

Fabry disease is a rare X-linked lysosomal disorder. Alpha-galactosidase A deficiency caused by mutation leads to accumulation of glycosphingolipids predominantly in endothelial cells, leading to impairment of vascular wall morphology and function. We assessed vascular wall hypertrophy (carotid artery intima-media thickness, cIMT), endothelial function (brachial artery flow-mediated dilation, FMD), presence of atherosclerotic plaques in the carotid and femoral arteries, and levels of endothelial adhesion and inflammatory biomarkers in 33 Fabry patients compared with 66 healthy matched controls. Fabry patients had thicker cIMT (0.07 ± 0.02 vs 0.06 ± 0.02 cm; P = .021), as well as dilated common carotid arteries (0.80 ± 0.12 vs 0.70 ± 0.06 cm; P < .001), and aortic annulus than controls (3.07 ± 0.48 vs 2.7 ± 0.48 cm; P = .001). Flow-mediated dilation was reduced (4.48 ± 8.80 vs 10.67 ± 8.72%; P = .001) and atherosclerotic plaques were less present in Fabry patients (9.10% vs 43.94%; P < .001). Vascular cell adhesion molecule-1, interleukin-6, tumor necrosis factor α, and high-sensitivity CRP were significantly higher and E-selectin lower in Fabry patients. Our results suggest that a complex vascular phenotype is present in Fabry patients. This represents a challenge for further research that could have important clinical applications.

Urinary Extracellular Vesicles and Their miRNA Cargo in Patients with Fabry Nephropathy.

Current biomarkers of Fabry nephropathy lack sensitivity in detecting early kidney damage and do not predict progression of nephropathy. Urinary extracellular vesicles (uEVs) and their molecular cargo could reflect early changes in renal impairment as they are secreted by the cells lining the urinary tract. We aimed to conduct a proof-of-concept study to investigate whether analysis of uEV characteristics and expression of uEV-derived microRNAs (miRNAs) could be applicable in studies to predict the development and progression of nephropathy in Fabry disease. A total of 20 Fabry patients were divided into two groups, depending on the presence of nephropathy. Chronological urine samples collected during 10-year follow-up were used for uEVs isolation with size exclusion chromatography. Nanoparticle tracking analysis was used to determine concentration and size of uEVs. We evaluated the expression of five uEV-derived miRNAs by qPCR (miR-23a-3p, miR-29a-3p, miR-30b-5p, miR-34a-5p, miR-200a-3p). There was no difference in the concentration and size of uEVs between patients with and without nephropathy at last follow-up or longitudinally. However, we found increased expression of miR-29a-3p and miR-200a-3p in uEVs isolated from chronological samples of patients with Fabry nephropathy. This may indicate an attempt by the organism to prevent the progression of renal damage leading to end-stage renal disease as previously reported in type 1 diabetes. In addition, we found an increased expression of miR-30b-5p in the 10-year period in uEVs of patients without renal dysfunction. miR-30b-5 was reported to have a protective role in podocyte injury and may possibly be important in Fabry nephropathy. These findings indicate that uEVs and their molecular cargo could be a promising target of studies focusing on elucidation of Fabry nephropathy. Nevertheless, total concentration and size of uEVs were neither indicative of the presence nor progression of Fabry nephropathy, while the role of the analyzed miRNAs in Fabry nephropathy progression was merely indicated and needs further in-depth studies.

End-stage renal disease in patients with Fabry disease: natural history data from the Fabry Registry.

BACKGROUND: Fabry disease, an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase activity, is associated with progressive loss of kidney function. This study was undertaken to characterize Fabry disease among patients who reached end-stage renal disease. METHODS: Data from 2,712 patients in the Fabry Registry were analysed to identify clinical characteristics of patients who received renal replacement therapy (RRT) during the natural history period (i.e. prior to any enzyme replacement therapy). RESULTS: A total of 213 patients [186 of 1,359 males (14%) and 27 of 1,353 females (2%)] received RRT at a median age of 38 years in both males and females. Males who received RRT were diagnosed at a median age of 35 years, compared to 23 years for non-RRT males. Sixty-one males and 10 females were not diagnosed with Fabry disease until after they had received RRT. Compared to other Fabry Registry patients, a higher percentage of RRT patients also experienced either a serious cardiovascular event or a stroke. Ninety-two of 186 males who had RRT (50%) experienced a cardiac event or stroke, compared to 230 of 1,173 non-RRT males (20%). Ten of 27 RRT females (37%) had experienced a cardiac event or stroke, compared to 226 of 1,326 non-RRT females (17%). Patients who had RRT experienced cardiovascular events and strokes at earlier ages than did patients who had not received RRT, and most received RRT before having a cardiac event or stroke. CONCLUSIONS: While all Fabry patients are at risk of cardiovascular events and strokes, patients with Fabry nephropathy who develop kidney failure appear to have concurrent involvement of other major organ systems. It is important that Fabry patients are diagnosed early and that their renal function is monitored carefully.

Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN).

BACKGROUND: In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. METHODS: An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. RESULTS: We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. CONCLUSIONS: The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Biomarkers of Fabry Nephropathy: Review and Future Perspective.

Progressive nephropathy is one of the main features of Fabry disease, which largely contributes to the overall morbidity and mortality burden of the disease. Due to the lack of specific biomarkers, the heterogeneity of the disease, and unspecific symptoms, diagnosis is often delayed. Clinical presentation in individual patients varies widely, even in patients from the same family carrying the same pathogenic GLA variant. Therefore, it is reasonable to anticipate that additional genomic, transcriptomic, proteomic, and metabolomics factors influence the manifestation and progression of the disease. The aim of this article is to provide an overview of nephropathy in Fabry patients and the biomarkers currently used in the diagnosis and follow-up. Current biomarkers are associated with late signs of kidney damage. Therefore, there is a need to identify biomarkers associated with early stages of kidney damage that would enable early diagnosis, which is crucial for effective treatment and prevention of severe irreversible complications. Recent advances in sequencing and -omics technologies have led to several studies investigating new biomarkers. We will provide an overview of the novel biomarkers, critically evaluate their clinical utility, and propose future perspectives, which we believe might be in their integration.

Aging in Fabry Disease: Role of Telomere Length, Telomerase Activity, and Kidney Disease.

INTRODUCTION: The lifespan of patients with Fabry disease (FD) is shorter than that seen in the general population. Leukocyte telomere length (LTL) and telomerase activity (TA) are potential markers of biologic aging. The aim of the current study was to determine the LTL and TA in FD patients and to assess the correlation between LTL and TA and renal involvement. METHODS: We included 33 FD patients and 66 healthy matched controls. LTL and TA were measured using a quantitative PCR assay and gene expression assay. FD patients were stratified by renal function (estimated glomerular filtration rate [eGFR] higher or lower than 60 mL/min/1.73 m2) and proteinuria (urine protein creatinine ratio higher or lower than 0.5 g/g). RESULTS: LTL was significantly shorter (0.69 vs. 0.73, p = 0.015) and TA significantly higher (1.55 vs. 1.19, p = 0.047) in FD patients compared to controls. Males with FD had significantly shorter LTL (p = 0.020) and lower, but non-significant, TA compared to male controls (p = 0.333). Female FD patients had similar LTL (p = 0.285) but significantly higher TA compared to female controls (p = 0.005). LTL was not influenced by eGFR, but TA was significantly lower in the low eGFR group (p = 0.003). CONCLUSIONS: FD patients have significantly shorter LTL, but significantly higher TA compared to healthy controls. Increased TA activity in FD patients could be the compensation mechanism to prevent LTL decrease (and accelerated ageing), which seems to be exhausted at the advanced stage of renal disease.

Cardiomyopathy and kidney function in agalsidase beta-treated female Fabry patients: a pre-treatment vs. post-treatment analysis.

AIMS: Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes. METHODS AND RESULTS: Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9-1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = -0.41 [-0.68, -0.15] mm/year, Ppre-post difference  <0.01; IVST: n = 38, slope difference = -0.32 [-0.67, 0.02] mm/year, Ppre-post difference  = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m2 /year, Ppre-post difference  = 0.80). CONCLUSIONS: Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function.

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative.

OBJECTIVES: The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. DESIGN AND SETTING: Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. RESULTS: A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. CONCLUSIONS: PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.