eliglustat-tartrate and Proteinuria

Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement.. To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease.. Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial.. 41 referral centers in 9 countries.. 82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent.. Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months).. The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point.. Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group.. The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event.. Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit.

Topics: Adult; Aged; alpha-Galactosidase; Cardiovascular Diseases; Cerebrovascular Disorders; Disease Progression; Double-Blind Method; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Isoenzymes; Kidney Diseases; Male; Middle Aged; Proteinuria; Treatment Outcome

This report describes an open-label, nonrandomized, prospective evaluation of the effects of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy on patients who have Fabry disease and also received enzyme replacement therapy with agalsidase-beta, given at 1 mg/kg body wt every 2 wk. Previous placebo-controlled phase III and phase IV trials with agalsidase-beta demonstrated clearing of globotriaosylceramide from vascular endothelia but little effect on proteinuria or progressive loss of kidney function in patients with Fabry disease and severe chronic kidney disease marked by overt proteinuria and/or estimated GFR <60 ml/min per 1.73 m2. Angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker therapy is the standard of care for patients with proteinuric kidney diseases, but their use is challenging in patients with Fabry disease and low or low-normal baseline systemic BP. A group of patients with Fabry disease were treated with antiproteinuric therapy, in conjunction with agalsidase-beta; sustained reductions in proteinuria with stabilization of kidney function were achieved in a group of six patients who had severe Fabry nephropathy; the progression rate was -0.23 +/- 1.12 ml/min per 1.73 m2 per yr with 30 mo of follow-up.

Topics: Adult; alpha-Galactosidase; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Isoenzymes; Kidney; Kidney Diseases; Male; Middle Aged; Prospective Studies; Proteinuria; Severity of Illness Index; Treatment Outcome

Fabry disease is an X-linked glycosphingolipidosis caused by deficient synthesis of the enzyme α-galactosidase A, which results in accumulations of globotriaosylceramide (GL-3) in systemic tissues. Nephropathy is a dominant feature of Fabry disease. It still remains unclear how the nephropathy progresses. Recombinant agalsidase replacement therapy is currently the only approved, specific therapy for Fabry disease. The optimal dose of replacement enzyme also still remains unclear. The worldwide shortage of agalsidase-β in 2009 forced dose reduction of administration. It showed that the proteinuria emerged like surges, followed by temporary plasma GL-3 elevations in the early stages of classic Fabry disease. Additionally, it also showed that 1 mg/kg of agalsidase-β every other week could clear the GL-3 accumulations from podocytes and was required to maintain negative proteinuria and normal plasma GL-3 levels.. This observation of a young patient with classic Fabry disease about 5 years reveals that the long-term, low-dose agalsidase-β caused proteinuria surges, but not persistent proteinuria, followed by temporary plasma GL-3 elevations, and agalsidase-β at 1 mg/kg every other week could clear accumulated GL-3 from podocytes and was required to maintain normal urinalysis and plasma GL-3 levels.

Topics: Adolescent; alpha-Galactosidase; Enzyme Replacement Therapy; Fabry Disease; Humans; Isoenzymes; Kidney Diseases; Male; Podocytes; Proteinuria; Trihexosylceramides

Proteinuria suggests kidney involvement in Fabry disease. We assessed podocyturia, an early biomarker, in controls and patients with and without enzyme therapy, correlating podocyturia with proteinuria and renal function.. Cross-sectional study (n = 67): controls (Group 1, n = 30) vs. Fabry disease (Group 2, n = 37) subdivided into untreated (2A, n = 19) and treated (2B, n = 18). Variables evaluated: age, gender, creatinine, CKD-EPI, proteinuria, podocyte count/10 20× microscopy power fields, podocytes/100 ml urine, podocytes/g creatininuria (results expressed as median and range).. Group 1 vs. 2 did not differ concerning age, gender and CKD-EPI, but differed regarding proteinuria and podocyturia. Group 2A vs. 2B: age: 29 (18-74) vs. 43 (18-65) years (p = ns); gender: males n = 3 (16 %) vs. n = 9 (50 %). Proteinuria was significantly higher in Fabry treated patients, while CKD-EPI and podocyturia were significantly elevated in untreated individuals. Significant correlations: group 2A: age-proteinuria, ρ = 0.62 (p = 0.0044); age-CKD-EPI, ρ = -0.84 (p < 0.0001); podocyturia-podocytes/100 ml urine, ρ = 0.99 (p = 0.0001); podocyturia-podocytes/g creatininuria ρ = 0.86 (p = 0.0003), podocytes/100 ml urine-podocytes/g urinary creatinine, ρ = 0.84 (p = 0.0004); proteinuria-CKD-EPI, ρ = -0.68 (p = 0.0013). Group 2B: podocyturia-podocytes/100 ml urine, ρ = 0.88 (p < 0.0001); podocyturia-podocytes/g creatininuria, ρ = 0.84 (p < 0.0001); podocytes/100 ml urine-podocytes/g creatininuria, ρ = 0.94 (p < 0.0001); CKD-EPI-proteinuria, ρ = -0.66 (p = 0.0028).. Patients with Fabry disease display heavy podocyturia; those untreated present significantly higher podocyturia, lower proteinuria and better renal function than those who are treated, suggesting that therapy may be started at advanced stages. Podocyturia may antedate proteinuria, and enzyme therapy may protect against podocyte loss.

Topics: Adolescent; Adult; Aged; alpha-Galactosidase; Biomarkers; Case-Control Studies; Creatinine; Cross-Sectional Studies; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Isoenzymes; Male; Middle Aged; Podocytes; Proteinuria; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome; Urinalysis; Urine; Young Adult

Between 2009 and 2012, there was a worldwide shortage of agalsidase-β for the treatment of Fabry disease. Therefore, alternative treatments were needed, including switching to a different enzyme-replacement therapy.. This is an ongoing observational study assessing the effects of switching from agalsidase-β (1.0 mg/kg every other week) to agalsidase-α (0.2 mg/kg every other week) in 11 patients with Fabry disease.. Clinical data were collected for 5 years-2 years before switching and 3 years after switching.. Measures of renal function such as estimated glomerular filtration rate remained stable during the 3 years after switching to agalsidase-α. Improvements in cardiac mass were recorded in both male and female patients 12 months after switching to agalsidase-α, and the benefit was maintained during 36 months of follow-up. There was no significant difference in the severity of pain experienced by patients before and after switching enzyme-replacement therapy, and no difference in quality-of-life parameters. Agalsidase-α was generally well tolerated, and no patients experienced allergy or developed antibodies to agalsidase-α.. This observational study supports the safety of switching from agalsidase-β to agalsidase-α at the approved doses, with no loss of efficacy. It also suggests that if an infusion-related allergic reaction occurs in a patient receiving agalsidase-β, switching to agalsidase-α may be a viable option.

Topics: Adult; Aged; alpha-Galactosidase; Creatinine; Enzyme Replacement Therapy; Fabry Disease; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Isoenzymes; Male; Middle Aged; Proteinuria; Time Factors; Treatment Outcome

The effect of early-onset enzyme replacement therapy on renal morphologic features in Fabry disease is largely unknown. Here, we evaluated the effect of 5 years of treatment with agalsidase alfa or agalsidase beta in 12 consecutive patients age 7-33 years (median age, 16.5 years). We performed renal biopsies at baseline and after 5 years of enzyme replacement therapy; 7 patients had additional biopsies after 1 and 3 years. After a median of 65 months, biopsy findings from all patients showed total clearance of glomerular endothelial and mesangial cell inclusions, and findings from 2 patients showed complete clearance of inclusions from epithelial cells of the distal tubule. The 4 patients who received the highest dose of agalsidase exhibited substantial clearance of podocyte inclusions, and the youngest patient had nearly complete clearance of these inclusions. Linear regression analysis showed a highly significant correlation between podocyte globotriaocylceramide clearance and cumulative agalsidase dose (r=0.804; P=0.002). Microalbuminuria normalized in five patients. In summary, long-term enzyme replacement therapy in young patients can result in complete globotriaocylceramide clearance of mesangial and glomerular endothelial cells across all dosage regimens, and clearance of podocyte inclusions is dose-dependent.

Topics: Adolescent; Adult; alpha-Galactosidase; Biopsy; Child; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Isoenzymes; Kidney; Kidney Function Tests; Male; Proteinuria; Recombinant Proteins; Trihexosylceramides; Young Adult

The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta.. 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.. 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).. 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.

Topics: Adult; alpha-Galactosidase; Creatinine; Disease Progression; Enzyme Replacement Therapy; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Isoenzymes; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Prognosis; Proteinuria; Time Factors

Topics: alpha-Galactosidase; Disease Progression; Fabry Disease; Humans; Isoenzymes; Proteinuria; Randomized Controlled Trials as Topic

Topics: alpha-Galactosidase; Creatinine; Disease Progression; Fabry Disease; Fatal Outcome; Glomerular Filtration Rate; Humans; Isoenzymes; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria