14. Munoz Mendoza J, Sun S, Chertow GM, Moran J, Doss S, Schiller B:Dialysate sodium and sodium gradient in maintenance hemodialysis: Aneglected sodium restriction approach? Nephrol Dial Transplant 26:1281–1287, 2011

15. Oberleithner H, Riethmüller C, Schillers H, MacGregor GA, deWardener HE, Hausberg M: Plasma sodium stiffens vascular endothe-lium and reduces nitric oxide release. Proc Natl Acad Sci U S A 104:16281–16286, 2007

See related article, “Predialysis Systolic BP Variability and Outcomes inHemodialysis Patients,” on pages 799–809.

Fabry Disease: Dose Matters

David G. Warnock* and Michael Mauer†*Department of Medicine, University of Alabama at Birmingham,Birmingham, Alabama; and †Departments of Pediatrics and Medicine,University of Minnesota, Minneapolis, Minnesota

J Am Soc Nephrol 25: 653–655, 2014.doi: 10.1681/ASN.2013121322

Fabry disease is an X-linked disorder resulting frommutations ofthe gene that encodes the lysosomal hydrolasea-galactosidase A,and leads to progressive lysosomal accumulation ofglobotriaosylceramide (GL-3) and related glycosphingolipids.1

In classically affected male patients, clinical onset occurs inchildhood or adolescence and is characterized by several symp-toms as well as kidney failure, cerebrovascular manifestations,heart failure, and eventually premature death.

Nephropathy is a dominant feature in Fabry disease. Pro-teinuria predicts and may also contribute to the progressivedecline inGFR, whichmay eventually lead to ESRD in the thirdto fifth decade of life.2 Fabry nephropathy is generally lesssevere in women than in men; however, heterozygous femalepatients with progressive kidney involvement reach ESRD atthe same median age as hemizygous male patients.3

Enzyme replacement therapy (ERT) with recombinanta-galactosidase, including agalsidase-a (Replagal; Shire Phar-maceuticals) and agalsidase-b (Fabrazyme; Genzyme Corpo-ration), is currently the only approved, specific treatment forFabry disease.4,5 ERT stabilizes or slows the progression ofFabry nephropathy in patients with Fabry disease,6–8 espe-cially if proteinuria can be controlled to ,0.5 g/d.9 Patientsare treated with 1 mg/kg agalsidase-b intravenously everyother week or 0.2 mg/kg agalsidase-a every other week; otherthan the amount of infused protein, there appears to be verylittle difference between the two products.10,11 There may

be differences in the response to ERT, and it appears that the5-fold difference in the delivered dose could affect the stabili-zation of renal function, at least in some patients.12,13 Theissue of effective ERT dosing for Fabry disease was broughtinto sharp focus by an unfortunate lapse in manufacturingpractices that resulted in aworldwide shortage of the Genzymeproduct (Fabrazyme) between June 2009 and January 2012.

In this issue of JASN, Weidemann and a collaboratinggroup in Germany report their patient experiences duringthe period of the Fabrazyme shortage that resulted in a changeof treatment regimen in many patients.14 Systematic and com-plete data collections were obtained before any change in ERTdose, at the time of dosing adjustment, and 1 year after thechange in dosing. This is an especially impressive effort con-sidering that the dose reductions caused by the shortage wereunanticipated and acutely imposed with very little warning. AsWeidemann et al. fully acknowledge in their article, decisionsabout dosing regimens during the shortage were based onconsensus-based clinical criteria and not on a randomized pro-spective study design, which substantially limits comparisonsbetween the treatment arms. More severely affected patientswere in the stable agalsidase-b group, and more mildly affectedpatients were in the agalsidase-a group. Approximately onethird of the 105 patients were maintained on standard ERT dos-ing at 1 mg/kg every 2 weeks, whereas the remainder receivingreduced dosing of agalsidase-b (0.3–0.5mg/kg every 2 weeks) orwere switched to agalsidase-a at 0.2 mg/kg every 2 weeks.

Although patients in the standard dosing group remainedstable, patients in the dose reduction group self-reportedworsened pain attacks, pain crises, and disease severity scoresand patients in the switch group reported worsened pain at-tacks, chronic pain, gastrointestinal symptoms, and diseaseseverity scores. The eGFRdecreased by approximately 3ml/minper 1.73 m2 in both male and female participants in the dosereduction group and showed a similar trend in themoremildlyaffected switch group (P50.09), but the eGFR was unchangedin the group maintained on standard dosing. However, thealbumin/creatinine ratio increased only in the switch group.Although there were no major target organ events during the1-year follow-up, this was a short follow-up time for such anal-yses and most patients had been on stable ERT dosing for atleast a year before the shortage.

Two much smaller studies—with 10 patients15 and 11 pa-tients,16 respectively, and with no comparison groups main-tained on full dose ERT—reported no increases in symptomsor organ injury indicators 12 months after the switch to0.2 mg/kg agalsidase-a every other week. The study byWeidemann et al.,14 with very different outcomes of dose re-duction, illustrates the risk of coming to potentially incorrect con-clusions on the basis of statistically underpowered observations.

The licensed dose of agalsidase-b (1 mg/kg every 2 weeks)was based primarily on the findings that 20 weeks of treatmentin adults substantially cleared endothelial cells of accumulatedGL-3 primarily in renal peritubular capillaries, but also in theheart and skin.4 This was sustained at 11 months although

Published online ahead of print. Publication date available at www.jasn.org.

Correspondence: Dr. Michael Mauer, Departments of Pediatrics and Medi-cine, University of Minnesota, 2450 Riverside Avenue, East Building, MB681,Minneapolis, MN 55454. Email: mauer002@umn.edu

Copyright © 2014 by the American Society of Nephrology

J Am Soc Nephrol 25: 647–655, 2014 Editorials 653

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there were fewer effects on distal tubular and vascular smoothmuscle cells and on podocytes. After 54 months of this dose ofERT, repeat renal biopsies showed that podocytes were onlypartially cleared of GL-3 in four patients and were unchangedGL-3 in two patients.8 In Europe, the approval of agalsidase-a(Replagal) at 0.2 mg/kg every other week was based on 6-monthdata from placebo controlled trials as well as 18-month data froman open-label maintenance study. The primary endpoint in theTKT003 study was the effect of the enzyme replacement on seri-ous debilitating pain. The regulatory summary reported that thestudy demonstrated improvement in kidney function and reduc-tions in pain, cardiacmass, andGL-3 content in kidney, heart, andliver cells (http://www.fda.gov/ohrms/dockets/ac/03/briefing/3917b2_02_fda-backgrounder.pdf).

It is noteworthy that there is no progressive increase inglomerular endothelial cell GL-3 accumulation with age inchildren with Fabry disease, whereas podocyte GL-3 accumu-lation is not only progressive with increasing age but alsocorrelates with podocyte foot process width, and both footprocess width and podocyte GL-3 deposits are correlated withproteinuria.17 Similar findings are emerging in patients stud-ied into adulthood while average glomerular endothelial cellGL-3 remains constant (B. Najafian and M. Mauer, unpub-lished observations). A recent case report describes podocyteGL-3 deposits and foot process effacement in a young Japanesemale patient with severe neuropathic pain and confirmedFabry disease with normal kidney function but with verylow levels of proteinuria.18

Proteinuria in adults was previously recognized as an impor-tant risk factor for progression of Fabry nephropathy, especiallyif proteinuria is .1 g/d.19,20 ERT appears not to have beneficialeffect on overt proteinuria in adults,7,21 especially in men, butstabilization of renal functionmay be seenwith ERT if proteinuriacan be controlled using renin-angiotensin system blockers.9

Recent studies in younger patients and female patients havedescribed effects of ERT on lower levels of proteinuria (spe-cifically, reductions in albumin excretion in patients withrelatively mild or early onset renal involvement treated withhigher doses of ERT [1 mg/kg every 2 weeks]). The study byTøndel et al. is especially notable because systematic renal biop-sies were carried out before and 5 years after ERT.22 Tøndelet al. described a reduction in and even clearing of podocyteGL-3 deposits that was related to the cumulative dose of ERTreceived, and the reductions in urinary albumin excretion par-alleled the reductions in podocyte GL-3 deposits. At lowerdoses of administered ERT, neither podocyte GL-3 scoringnor albuminuria decreased. Similarly, women with Fabry dis-ease whose glomerular and tubular protein excretion de-creased had received 1 mg/kg per 2 weeks of agalsidase-bfor at least 1 year.23 These studies emphasize the importanceof starting ERTearly, before there is major, irreversible organdamage, and illustrate the importance of systematic histologicevaluation to assess the adequacy of response to ERTas well asthe importance of the podocyte in relation to proteinuria, animportant indicator of disease progression in Fabry

nephropathy. We are hopeful that additional biomarkerswill be validated in the future that will assist in the treatmentdecisions (e.g., when to start, what dose); however, for now,histologic evaluation should be seriously considered in everypatient.

What lessons were learned from the 2.5-year shortage ofagalsidase-b? Clinical trials are difficult to carry out in raredisorders, such as Fabry disease, especially with already ap-proved treatments resulting in a paucity of treatment-naïvepatients. Thus, albeit an imperfect set-up, studies such asthat of Weidemann et al.,14 which took advantage of an un-fortunate and quite prolonged drug shortage, are important.Using the patients as their own controls, important effects ofdose reductions were noted even though these reductions werenot below the levels approved in Europe for agalsidase-a.These effects were primarily on patient-reported outcomesand renal function, and did not include major target organevents during the relative short-term follow-up period de-scribed by Weidemann et al. Patient-reported outcomes re-quire more systematic evaluation as important aspects of theresponse to ERT and other future treatments for Fabry disease.Finally, there may be instances of Fabry disease in which thecurrently approved maximal ERT doses may be suboptimal be-cause of individual pathophysiologic variables, the presence ofrelatively more advanced disease, or both. In these patients,more personalized care approaches with dose adjustments forinadequate clinical or tissue responses might be considered andnew add-on treatment modalities need to be explored for pa-tients with residual risks despite current standards of care.

DISCLOSURESD.G.W. is a consultant for Genzyme Corporation, has received research

support from Genzyme Corporation and Amicus Pharmaceuticals, and has

served on advisory boards for Shire Pharmaceuticals and the Fabry Registry

Advisory Board for Genzyme Corporation. M.M. is a consultant for Genzyme

Corporation and Amicus Pharmaceuticals, has received investigator-initiated

research support fromGenzymeCorporation, and serves on the FabryRegistry

Advisory Board for Genzyme Corporation. These interests with Genzyme

Corporation have been reviewed and managed by the University of Minnesota

in accordance with its conflict of interest policies.

REFERENCES

1. Desnick RJ, Ioannou YA, Eng CM: Alpha-galactosidase A deficiency:Fabry disease. In: The Metabolic Bases of Inherited Disease, edited byScriver C, Beaudet A, Sly W, Valle D, 8th Ed., New York, McGraw-Hill,2001, pp 3733–3774

2. Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G,Goldfarb L, Brady RO, Balow JE, Austin Iii HA, Kopp JB: Natural history ofFabry renal disease: Influence of alpha-galactosidase A activity and geneticmutations on clinical course.Medicine (Baltimore) 81: 122–138, 2002

3. Ortiz A, Oliveira JP, Waldek S, Warnock DG, Cianciaruso B, Wanner C;Fabry Registry: Nephropathy in males and females with Fabry disease:Cross-sectional description of patients before treatment with enzymereplacement therapy. Nephrol Dial Transplant 23: 1600–1607, 2008

4. EngCM,GuffonN,WilcoxWR, Germain DP, Lee P,Waldek S, Caplan L,Linthorst GE, Desnick RJ; International Collaborative Fabry Disease

654 Journal of the American Society of Nephrology J Am Soc Nephrol 25: 647–655, 2014

EDITORIALS www.jasn.org

Study Group: Safety and efficacy of recombinant human alpha-galactosidase A—replacement therapy in Fabry’s disease. N EnglJ Med 345: 9–16, 2001

5. Schiffmann R, Kopp JB, Austin HA 3rd, Sabnis S, Moore DF, Weibel T,Balow JE, Brady RO: Enzyme replacement therapy in Fabry disease: Arandomized controlled trial. JAMA 285: 2743–2749, 2001

6. Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO: Long-termtherapy with agalsidase alfa for Fabry disease: Safety and effects on renalfunction in a home infusion setting. Nephrol Dial Transplant 21: 345–354, 2006

7. Banikazemi M, Bultas J, Waldek S, WilcoxWR, Whitley CB, McDonald M,Finkel R, Packman S, Bichet DG, Warnock DG, Desnick RJ; Fabry DiseaseClinical Trial Study Group: Agalsidase-beta therapy for advanced Fabrydisease: A randomized trial. Ann Intern Med 146: 77–86, 2007

8. Germain DP, Waldek S, Banikazemi M, Bushinsky DA, Charrow J,Desnick RJ, Lee P, Loew T, Vedder AC, Abichandani R, Wilcox WR,Guffon N: Sustained, long-term renal stabilization after 54 months ofagalsidase beta therapy in patients with Fabry disease. J Am SocNephrol 18: 1547–1557, 2007

9. Tahir H, Jackson LL, Warnock DG: Antiproteinuric therapy and Fabrynephropathy: Sustained reduction of proteinuria in patients receivingenzyme replacement therapy with agalsidase-beta. J Am Soc Nephrol18: 2609–2617, 2007

10. Desnick RJ: Enzyme replacement therapy for Fabry disease: Lessonsfrom two alpha-galactosidase A orphan products and one FDA ap-proval. Expert Opin Biol Ther 4: 1167–1176, 2004

11. Linthorst GE, Hollak CE, Donker-Koopman WE, Strijland A, Aerts JM:Enzyme therapy for Fabry disease: Neutralizing antibodies towardagalsidase alpha and beta. Kidney Int 66: 1589–1595, 2004

12. Schiffmann R, Askari H, Timmons M, Robinson C, Benko W, Brady RO,Ries M: Weekly enzyme replacement therapy may slow decline ofrenal function in patients with Fabry disease who are on long-termbiweekly dosing. J Am Soc Nephrol 18: 1576–1583, 2007

13. Fervenza FC, Torra R, Warnock DG: Safety and efficacy of enzyme re-placement therapy in the nephropathy of Fabry disease. Biologics 2:823–843, 2008

14. Weidemann F, Krämer J, Duning T, Lenders M, Canaan-Kühl S, Krebs A,Gonzáles HG, Sommer C, Üçeyler N, Niemann M, Störk S, Schelleckes M,Reiermann S, Stypmann J, Brand SM, Wanner C, Brand E: Patients withFabry disease after enzyme replacement therapy dose reduction versustreatment switch. J Am Soc Nephrol 25: 837–849, 2014

15. Tsuboi K, Yamamoto H: Clinical observation of patients with Fabrydisease after switching from agalsidase beta (Fabrazyme) to agalsidasealfa (Replagal). Genet Med 14: 779–786, 2012

16. Pisani A, Spinelli L, ViscianoB,Capuano I, SabbatiniM, Riccio E,MessalliG,Imbriaco M: Effects of switching from agalsidase beta to agalsidase alfain 10 patients with Anderson-Fabry disease. JIMD Rep 9: 41–48, 2013

17. NajafianB,SvarstadE,BostadL,GublerMC,TøndelC,WhitleyC,MauerM:Progressive podocyte injury and globotriaosylceramide (GL-3) accumula-tion in young patients with Fabry disease. Kidney Int 79: 663–670, 2011

18. Kanai T, Yamagata T, Ito T, Odaka J, Saito T, Aoyagi J, Kobayashi M,Ohashi T, Ueda Y, Momoi MY: Foot process effacement with normalurinalysis in classic Fabry disease. JIMD Rep 1: 39–42, 2011

19. Schiffmann R, Warnock DG, Banikazemi M, Bultas J, Linthorst GE,Packman S, Sorensen SA, Wilcox WR, Desnick RJ: Fabry disease: Pro-gression of nephropathy, and prevalence of cardiac and cerebrovas-cular events before enzyme replacement therapy. Nephrol DialTransplant 24: 2102–2111, 2009

20. Wanner C,Oliveira JP, Ortiz A,MauerM,Germain DP, Linthorst GE, SerraAL, Maródi L, Mignani R, Cianciaruso B, Vujkovac B, Lemay R, Beitner-JohnsonD,Waldek S,WarnockDG: Prognostic indicators of renal diseaseprogression in adults with Fabry disease: Natural history data from theFabry Registry. Clin J Am Soc Nephrol 5: 2220–2228, 2010

21. Warnock DG, Ortiz A, Mauer M, Linthorst GE, Oliveira JP, Serra AL,Maródi L,Mignani R, Vujkovac B, Beitner-JohnsonD, Lemay R, Cole JA,Svarstad E, Waldek S, Germain DP, Wanner C; Fabry Registry: Renaloutcomes of agalsidase beta treatment for Fabry disease: Role ofproteinuria and timing of treatment initiation. Nephrol Dial Transplant27: 1042–1049, 2012

22. Tøndel C, Bostad L, Larsen KK, Hirth A, Vikse BE, Houge G, Svarstad E:Agalsidase benefits renal histology in young patients with Fabry dis-ease. J Am Soc Nephrol 24: 137–148, 2013

23. Prabakaran T, Birn H, Bibby BM, Regeniter A, Sørensen SS, Feldt-Rasmussen U, Nielsen R, Christensen EI: Long-term enzyme re-placement therapy is associated with reduced proteinuria and preservedproximal tubular function in women with Fabry disease [published onlineahead of print November 8, 2013].Nephrol Dial Transplant doi:10.1093/ndt/gft452

See related article, “Patients with Fabry Disease after Enzyme ReplacementTherapy Dose Reduction Versus Treatment Switch,” on pages 837–849.

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