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Antiproteinuric Therapy and Fabry Nephropathy

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Antiproteinuric Therapy and Fabry Nephropathy Phenotypes J Med Genet: first published as 10.1136/jmedgenet-2015-103471 on 21 October 2015. Downloaded from ORIGINAL ARTICLE Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy David G Warnock,1 Christie P Thomas,2 Bojan Vujkovac,3 Ruth C Campbell,4 Joel Charrow,5 Dawn A Laney,6 Leslie L Jackson,1 William R Wilcox,6 Open Access Scan to access more 7 free content Christoph Wanner ▸ Additional material is ABSTRACT women may be affected as severely as male Fabry – published online only. To view Background Nephropathy is an important feature of patients,2 4 especially with skewed X-chromosome please visit the journal online 56 (http://dx.doi.org/10.1136/ classical Fabry disease, which results in inactivation. jmedgenet-2015-103471). alpha-galactosidase A deficiency and cellular Enzyme replacement therapy (ERT) and support- 1 globotriaosylceramide accumulation. We report the safety ive care (eg, renal replacement therapy) have Division of Nephrology, fi Department of Medicine, and ef cacy of antiproteinuric therapy with ACE changed the natural history of Fabry disease; car- University of Alabama at inhibitors or angiotensin II receptor blockers (ARBs) in a diovascular events now account for the majority of Birmingham, Birmingham, study of classical Fabry patients receiving recombinant deaths.78Agalsidase-beta given at 1 mg/kg every Alabama, USA agalsidase-beta therapy. two weeks reduced endothelial GL-3 deposits from 2Department of Internal Medicine, University of Iowa Methods and design The goal was maintenance of kidney, skin and heart biopsies in a randomised, Carver College of Medicine, urine protein to creatinine ratio (UPCR) <0.5 g/g or a placebo-controlled phase III trial with 58 Iowa City, Iowa, USA 50% reduction in baseline UPCR for 24 patients at eight patients.910In an open-label, 54-month extension 3 General Hospital, Slovenj study sites. The change in estimated glomerular filtration study, renal function was stabilised in most Gradec, Slovenia rate (eGFR) was assessed over 21 months of treatment. patients.11 However, baseline proteinuria (>1g/ 4Department of Medicine, Medical University of South Results 18 out of 24 patients achieved the UPCR goal 24 h) and >50% glomerulosclerosis on kidney Caroline, Charleston, South with eGFR slopes that were significantly better than six biopsies were important risk factors for continued Carolina, USA patients who did not achieve the UPCR goal (−3.6 loss of renal function despite ERT.11 With an add- 5 Departments of Pediatrics- (−4.8 to −1.1) versus −7.0 (−9.0 to −5.6) mL/min/ itional 5 years of follow-up, patients who main- Genetics, Northwestern 2 University Feinberg School of 1.73 m /year, respectively, p=0.018). Despite achieving tained urinary protein-to-creatinine ratios (UPCR) Medicine and Ann & Robert the UPCR goal, 67% (12/18 patients) still progressed <0.5 g/24 h on agalsidase-beta had low risk for H. Lurie Children’s Hospital of with an eGFR slope <−2 mL/min/1.73 m2/year. renal progression, while those with UPCR >0.5 g/ Chicago, Chicago, Illinois, USA 12 6 Regression analysis showed that increased age at 24 h had progressive loss of renal function. Mean Department of Human initiation of agalsidase-beta therapy was significantly estimated glomerular filtration rate (eGFR) slopes Genetics, Emory University, − − http://jmg.bmj.com/ Atlanta, Georgia, USA associated with worsened kidney outcome. Hypotension for the two groups were 1.89 and 6.82 mL/min/ 2 12 7Department of Nephrology, and hyperkalaemia occurred in seven and eight patients, 1.73 m /year, respectively. The age at which University Klinik Würzburg, respectively, which required modification of patients started agalsidase-beta emerged as an Würzburg, Germany antiproteinuric therapy but was not associated with important factor that differentiated the two groups Correspondence to serious adverse events. (mean 25 vs 38 years, respectively). Dr David G Warnock, Room Conclusions This study documents the effectiveness of Another randomised, placebo-controlled study 614 ZRB, UAB, 1720 2nd agalsidase-beta (1 mg/kg/2 weeks) and antiproteinuric with agalsidase-beta was conducted with Fabry on September 28, 2021 by guest. Protected copyright. Avenue South, Birmingham, therapy with ACE inhibitors and/or ARB in patients with patients and more advanced renal involvement AL 34294-0007, USA; severe Fabry nephropathy. Patients had preservation of (baseline eGFR <80 mL/min/1.73 m2/year).13 The [email protected] kidney function if agalsidase-beta treatment was initiated overall results were similar for the two randomised Received 22 August 2015 at a younger age, and UPCR maintained at or below studies; patients with higher baseline eGFR and Accepted 25 September 2015 0.5 g/g with antiproteinuric therapy. lower UPCR had significant preservation of renal – Published Online First Trial registration number NCT00446862. function when treated with agalsidase-beta.11 13 21 October 2015 We previously demonstrated in a small, open-label single-centre study that treatment with ACE inhibi- INTRODUCTION tors or angiotensin receptor blocker (ARB) to main- Fabry disease (OMIM #301500) is an X-linked tain UPCR <0.5 g/24 h was associated with disorder caused by lysosomal alpha-galactosidase stabilisation of renal function even in Fabry patients A(α-Gal A) deficiency. Classical patients with muta- at high risk for progression of nephropathy.14 This tions in the α-Gal A gene accumulate globotriaosyl- background provides the rationale for prospectively ceramide (GL-3) and become symptomatic in evaluating the control of proteinuria in Fabry childhood with pain, gastrointestinal disturbances, nephropathy. angiokeratoma and hypohidrosis.1 Classical patients The objective of the present study was to investi- fi To cite: Warnock DG, experience progressive loss of renal function and gate the safety and ef cacy of antiproteinuric Thomas CP, Vujkovac B, hypertrophic cardiomyopathy, with severe clinical therapy with ACE inhibitor and/or ARB therapy in et al. J Med Genet events including end-stage renal disease, stroke, adults with Fabry nephropathy. We hypothesised – 2015;52:860 866. arrhythmias and premature death.12Heterozygous that patients with UPCR maintained <0.5 g/g 860 Warnock DG, et al. J Med Genet 2015;52:860–866. doi:10.1136/jmedgenet-2015-103471 Phenotypes J Med Genet: first published as 10.1136/jmedgenet-2015-103471 on 21 October 2015. Downloaded from throughout the study would have preservation of their renal Laboratory using isotope-dilution mass-spectroscopy traceable function. Participants over 21 months in 24 patients (15 males calibration.18 and 9 females) with classic Fabry disease treated with agalsidase- We compared characteristics of patients using χ2 and analysis beta at eight different study sites. Also, 18 of the 24 participants of variance. Duncan and Dunnett tests were used for multiple achieved the UPCR goal during the study, but only 6 out of 18 comparisons, with statistical significance set at p≤0.05. Values had preservation of kidney function (eGFR slopes better than are presented as ±1 SD; median values are presented with 25th −2.0 mL/min/1.73 m2/year). The age at which agalsidase-beta and 75th centiles (IQR). The eGFR slopes and intercepts were was started was the most significant factor associated with loss calculated with linear regression for individual patient treatment of kidney function despite control of UPCR to the defined treat- visits, and patient-specific intercepts and slopes were extracted ment goal of 0.5 g/g or 50% reduction from the baseline level. from mixed effect linear regression models for the entire group. Statistical and graphical analyses were done with Stata V.13.1 METHODS (Stata, College Station, Texas, USA). Study design, participants and setting The Fabrazyme+Arbs+ACE inhibitor Treatment (FAACET) RESULTS study evaluated the safety and efficacy proteinuria control with Characteristics at qualification and baseline evaluation ACE inhibitor and/or ARB therapy Fabry patients who were Thirty-two subjects were enrolled at 10 different study sites, and receiving ERT with agalsidase-beta at 1 mg/kg every two weeks. 24 subjects (15 males and 9 females) completed the study proto- FAACET was registered as a prospective observational study col. The study sites, principal investigators, number of subjects (NCT00446862), sponsored by the University of Alabama at enrolled, number of subjects completing the protocol and Birmingham. Enrolment was based on local study site records, reasons for discontinuation are shown in online supplementary and included adult males and females with Fabry nephropathy table 1. For the 24 subjects who completed the study, the base- associated with reduced eGFR and/or significant proteinuria. line median age was 43.1 years (IQR 38.3–50.2); 15 were males After a 3-month initial baseline phase, the patients were fol- and 3 self-identified themselves as black (table 1). lowed during a 21-month treatment phase. The primary object- The median duration of ERT therapy before the first visit was ive (UPCR goal) was reduction of the UPCR to <0.5 g/g for all 3.1 years (IQR 0.3–4.4), and the median age at which ERT was treatment visits or the averaged treatment UPCR values to started was 42.8 years (IQR 36.1–47.5). Median values for <50% of the first baseline value. ACE inhibitor and/or ARB qualifying UPCR (1.5 g/g (IQR 1.1–2.3)) and eGFR (71 mL/ doses were adjusted during the visits according to the local stan- min/1.73 m2 (IQR 56–95)) were obtained 1.0 year (IQR 0.1– dards for care, with the goal of reaching and maintaining the 2.2) before enrolment. Baseline values for vital signs, serum UPCR goal. The primary outcome measure was the regression potassium, UPCR, albumin to creatinine ratio (ACR) and eGFR slope of eGFR (mL/min/1.73 m2/year).
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