Screening, Diagnosis, And Management Of Patients With .
meeting reportwww.kidney-international.orgScreening, diagnosis, and management of patientswith Fabry disease: conclusions from a “KidneyDisease: Improving Global Outcomes” (KDIGO)Controversies ConferenceOPENRaphael Schiffmann1, Derralynn A. Hughes2, Gabor E. Linthorst3, Alberto Ortiz4, Einar Svarstad5,6,David G. Warnock7, Michael L. West8 and Christoph Wanner9; for Conference Participants101Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA; 2Department of Haematology, Royal Free London NHSFoundation Trust, & University College London, UK; 3Department of Endocrinology and Metabolism, Academic Medical Center,Amsterdam, Netherlands; 4Unidad de Dialisis, IIS-Fundacion Jimenez Diaz/UAM, IRSIN, Madrid, Spain; 5Department of Clinical Medicine,University of Bergen, Bergen, Norway; 6Department of Medicine, Haukeland University Hospital, Bergen, Norway; 7Division of Nephrology,Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; 8Department of Medicine, DalhousieUniversity, Halifax, Canada; and 9Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Würzburg, GermanyPatients with Fabry disease (FD) are at a high risk fordeveloping chronic kidney disease and cardiovasculardisease. The availability of specific but costly therapy haselevated the profile of this rare condition. This KDIGOconference addressed controversial areas in the diagnosis,screening, and management of FD, and included enzymereplacement therapy and nonspecific standard-of-caretherapy for the various manifestations of FD. Despitemarked advances in patient care and improved overalloutlook, there is a need to better understand thepathogenesis of this glycosphingolipidosis and todetermine the appropriate age to initiate therapy in alltypes of patients. The need to develop more effectivespecific therapies was also emphasized.Kidney International (2017) 91, 284–293; DS: chronic kidney disease; enzyme replacement therapy; Fabrydisease; Fabry nephropathy; standard of careCopyright ª 2016, International Society of Nephrology. Published byElsevier Inc. This is an open access article under the CC BY-NC-SA sa/4.0/).Fabry disease (FD; OMIM entry number: 301500) is anX-linked lysosomal storage disorder caused by deficientactivity of a-galactosidase A resulting in accumulationof glycosphingolipids with terminal a-D-galactosyl residue,particularly globotriaosylceramide (GL-3, Gb3, CTH) andglobotriaosylsphingosine (Lyso-GL-3, lyso-Gb3).1 Theselipids progressively accumulate in the circulation and invirtually all cell types and organs, resulting in the development of a multisystem disorder. Affected patients are at highrisk of developing a small-fiber neuropathy, progressive proteinuric kidney disease, fibrotic cardiac disease resulting inrhythm and conduction disturbances, progressive hypertrophic cardiomyopathy, and mostly ischemic cerebrovascularstroke.2 Though this disease is X-linked, both males and females are affected by it.Although diagnosis and management of FD have markedlyimproved over the years, the disease has no cure, and currenttherapy is suboptimal.3 Our goal was to summarize the current knowledge and knowledge gaps regarding screening,diagnosis, and therapy, and to propose a research agenda toresolve outstanding controversial issues.SCREENING AND DIAGNOSISClinical presentation and diagnostic testingCorrespondence: Raphael Schiffmann, Institute of Metabolic Disease,Baylor Research Institute, 3812 Elm Street, Dallas, TX 75226, USA. E-mail:raphael.schiffmann@baylorhealth.edu; and Christoph Wanner, University ofWürzburg, University Hospital, Renal Division, 97080 Würzburg, Germany.E-mail: wanner c@ukw.de10See Appendix for list of other conference participants.Received 13 September 2016; revised 8 October 2016; accepted 13October 2016; published online 18 December 2016284The clinical characteristics of FD are described in Table 1. Thediagnosis is established in males by a-galactosidase A–specificactivity that is below 25% to 30% of mean control in peripheral white blood cells.2,4–7 Alpha-galactosidase A activityis somewhat predictive of classic or later-onset manifestations.Classically affected hemizygotes have undetectable or very low(#3%) enzymatic activity.2 As with many genetic diseases,there is a wide phenotypic variability even among patientswith the same GLA mutation. A late-onset phenotype of FDexists mainly with cardiac-variant disease forms.8 These patients present with typical disease in their fifth or sixth decadebut often lack the early alerting clinical features of angiokeratoma, acroparesthesia, corneal opacities, and sweatingabnormalities. Patients with milder variants typically haveKidney International (2017) 91, 284–293
meeting reportR Schiffmann et al.: Fabry disease: a KDIGO conference reportTable 1 Manifestations in Fabry diseaseChildhood and adolescence ( 16 years)Acroparesthesia/pain crisis: chronic or episodic, burning sensation inthe palms of hands or soles of feet, exacerbated by temperaturechanges, fever, stress, physical exercise, and alcoholAngiokeratomas: small, raised, dark red spots that develop slowly andcan be found on the buttocks, genitalia, inner thighs, back, and oralcavityOphthalmologic abnormalities: cornea verticillata (whorl-shapedopacity), posterior subcapsular cataracts, tortuous vascular lesionsin the retina and conjunctiva, dilated vessels on upper lid marginSensorineural hearing lossHypohidrosis or anhidrosismake the correct diagnosis. Where enzyme activity is low andno mutation is found by Sanger sequencing of exons andexon-intron boundaries, further investigations includingmultiplex ligation-dependent probe amplification analysisand assessment of specific intronic mutations should beperformed.11Substrate accumulation including Gb3and lyso-Gb3 mayoccur in plasma and urine. While glycolipid urinalysis may behelpful in attributing pathogenicity or phenotype, it may beless useful in screening because increased urinary Gb3 hasbeen described in cohorts of patients with cardiac disease ornephrotic syndrome without a diagnosis of FD.12Increased albuminuriaHistory of nonspecific bowel disturbancesHistory of lethargy and fatigueEarly adulthood (17–30 years)More extensive angiokeratomasHigh albuminuria ( 1g/24 hours)Edema or lymphedemaFeverHypohidrosis or anhidrosisLymphadenopathyHeat sensitivityDiarrhea, abdominal painCardiac: bradycardia, short PR interval, left ventricular hypertrophy,conduction defectsLater adulthood (age 30 years)Heart disease: fibrotic, left and right ventricular hypertrophy, heartvalve abnormalities and dysrhythmias, sudden cardiac death,angina, diastolic heart failure, cardiac transplantationChronic kidney disease: including end-stage renal disease requiringrenal replacement therapy with dialysis or renal transplantationStroke or transient ischemic attacksDeafness, of acute or chronic onsetmissense GLA mutations and variable residual enzymeactivity. For example, the N215S mutation may have residualenzyme activity in plasma and/or leucocytes close to thenormal range. One exception is a splice mutation common inTaiwanese patients with FD who have 10% residual enzymeactivity and develop left ventricular hypertrophy in theirfourth or fifth decade of life.4In heterozygous females, random X-inactivation mayresult in expression of a-galactosidase A activity in the plasmaor leucocytes within the normal range in up to 60% ofwomen.9 Sequencing of the GLA gene is necessary for adiagnosis of FD in most females. In addition to point mutations, frameshift mutations and small deletions withinexons and exon-intron boundaries, large deletions, andintronic mutations have been described.2 The finding ofelevated globotriaosylceramide (Gb3) in relevant tissuesshould be the ultimate requirement when confronted withGLA variants of unknown significance.10 Erroneous attribution of pathogenicity to a mutation may lead to a costly andinappropriate use of specific therapy such as enzymereplacement therapy (ERT) and a missed opportunity toKidney International (2017) 91, 284–293Screening strategies for Fabry diseaseBased on recent newborn screening studies each including atleast 30,000 newborns, the prevalence of FD was found to bemarkedly higher than previously expected with 1 in 3100males reported in northwestern Italy,13 1 in 3000 males inAustria, 1 in 1300 males in Taiwan, 1 in 7800 males inWashington state (USA), and 1 in 1500 males in Missouri(USA). Before these studies, the prevalence was expected to bemuch lower: 1 in 117,000 in Australia,14 1 in 468,000 in theNetherlands,15 and only 1 in 833,000 in Portugal.16High-risk screening. Screening for stroke in the young hasshown definite FD in 0.5%,17 in 0.9% of the hypertensivepopulation with left ventricular hypertrophy,18 in 0.5% to 1%of patients with idiopathic hypertrophic cardiomyopathy5,19but 4% of males,20 and in 0.11% to 0.17% of dialysispatients.21–23 Only 0.2% of unselected patients with commonheart disease have FD.12 Prevalence screening studies mayinadvertently indicate falsely higher prevalence due to benignpolymorphisms (e.g., D313Y).24,25FD should be considered and tested in patients withchronic kidney disease (CKD) with no definitive cause ofnephropathy and when no biopsy has been performed,especially in familial cases. The difficulty in recognizing thiscondition due to a highly variable and nonspecific phenotype,lack of positive family history in at least 5% of cases, and alow prevalence rate in many regions of the world signifies thatmany patients are diagnosed late or never diagnosed.26 Thissituation can only be reversed by the introduction of widespread screening of at-risk patients.Family screening. The X-linked nature of FD inheritancerenders cascade screening of families efficient and of highdiagnostic yield over on average 3 generations surroundingan index case. All index patients should meet with a geneticcounselor or a physician to produce an informative familytree and facilitate communication with predicted affectedfamily members so they may be referred to a medicalgeneticist for genetic counseling and testing. Consideringthe privacy of the index case is important and must beweighed against the risk of delayed diagnosis in familymembers.27Many patients find it valuable to discuss implications oftesting with a clinical geneticist and may wish to considerpreconception genetic diagnosis, prenatal testing, or postnatal285
meeting reportdiagnosis. Diagnosis in a Fabry male has particular diagnosticimplications for his mother and daughters, who will all, in theabsence of new mutations or nonpaternity, have positive testresults. The risk of FD in any male or female offspring of awoman with FD is 50%.27 Once a genetic diagnosis has beenmade, patients should undergo a full clinical evaluation andtreatment as described in Supplementary Table S1.Knowledgegapsandresearchrecommendations(Table 2). The true prevalence of FD is not known, butfuture systematic screening for the disease in the generalpopulation may help determine it. Another challenge is topredict the pathogenicity of some GLA variants. Becausenewborn screening for FD has effectively begun in certainjurisdictions, future research must evaluate the ethical andpsychological ramifications of early diagnosis of a disorderthat may or may not manifest itself until years or decadeslater.ENZYME REPLACEMENT THERAPYERT with recombinant human a-galactosidase A (agalsidase)is the only currently available therapy aimed at the etiology ofFD (Supplementary Table S2). Agalsidase-a and agalsidase-bhave been studied in clinical trials with different primaryendpoints, hampering comparison of effectiveness. However,surrogate endpoints were evaluated on both enzymes inplacebo-controlled trials that led to regulatory approval(Supplementary Table S3). These trials have reported on shortperiods of ERT, with different clinical endpoints, predominantly in (male) typical patients. As FD is a rare chronic,slowly progressive disease with a 4-decade natural history andbroad heterogeneous presentation, this evidence is incomplete. Extrapolating results to long-term patient managementor other Fabry populations is challenging. Based on ethicaland feasibility considerations, it is very unlikely that furtherevidence from placebo-controlled trials will become available.Additional knowledge is provided by case series and postmarketing surveillance databases that, despite their limitations, suggest that the earlier therapy is started, the better theoutcome may be. This observation is in accordance with thehypothesis that glycolipid clearance is most therapeuticallyeffective before secondary, irreversible tissue injury hasoccurred.Initiation of ERTExpert opinion-based recommendations on initiation andcessation of ERT are available.28,29 However, there is noscientific evidence as to the optimal age of ERT initiation.Therefore, there are no uniform guidelines, and conditionsand age to start ERT differ in various countries. In general,development of signs or symptoms related to FD is an indication to start ERT. For the kidney, this implies the development of CKD (i.e., pathological albuminuria or decreasedglomerular filtration rate [GFR]) or progressive decreasein GFR) if ERT has not already been started earlier fornonrenal manifestations such as pain.30 The benefits of earlytreatment, before irreversible tissue injury occurs, should be286R Schiffmann et al.: Fabry disease: a KDIGO conference reportTable 2 Knowledge gaps and research recommendationsScreening and diagnosis Elucidate role of gene variants of uncertain significance Investigate potential genotype–phenotype relations Determine when to initiate specific treatment as a function of GLAmutation severity Ascertain response to specific therapy as a function of GLA mutationseverity Establish an independent, transparent, and freely accessible registry ofconsenting FD patients including phenotype, genotype data, and fullannotation of phenotypes Evaluate utility of cardiology screening of patients with a short PRinterval Identify optimal screening tools Follow the outcome of FD newborn screening programs Elucidate role of skewed X-inactivation in heterozygotes Investigate the mechanism of organ injury in female patients Pursue the use of biomarkers for diagnosis Acquire better understanding of glycosphingolipid pathogenesis andbasic cellular pathologyInitiation of therapy Determine when to start treatment in asymptomatic or paucisymptomatic patients, females, with nonclassic disease Obtain expanded information on the natural history of FD in classicfemale patients and nonclassic FD patients, and the effects of ERT inthese groups Undertake X-linked inactivation studies and early initiation of therapy infemalesTherapeutic regimens Establish criteria and biomarkers for dose individualization Evaluate combination therapy: substrate synthesis reduction combinedwith ERT or with a pharmacological chaperone Develop standardized assessment of neutralizing antibodies and evaluate impact on treatment regimens – utilize experience from Pompedisease interventionsOutcomes Define therapeutic failure. Does progression of FD while undergoingERT indicate therapeutic failure? Define long-term outcomes of different dosing schemes in differentpatient populations Define very long-term outcomes of patients starting ERT in childhood,both on clinical manifestations and glycolipid burden(e.g., cardiomyocytes, podocytes, vascular smooth muscle cells) Ascertain impact of ERT on heart and central nervous system disease,valvular abnormalities and aortic root dilatation, and lymphedema Identify outcome of ERT in nonclassic FD Understand pathophysiology of lung involvement and treatment withERT as well as the role of b2-agonists86,114 Provide uniform description and categorization of study populations infuture reports on the efficacy of therapy, including genotype, phenotype, sex, and age at initiation of therapy Conduct long-term outcome studies of (pediatric) patients who startedERT when asymptomatic or paucisymptomatic Collect histologic evidence of ERT-induced clearance of Gb3 in longlived cells: vascular smooth muscle cells, cardiomyocytes, podocytes Conduct studies on the pathophysiology and treatment of gastrointestinal involvement and lymphedema Develop more sensitive patient-reported outcome measuresERT, enzyme replacement therapy; FD, Fabry disease.balanced against the burden of biweekly infusions in veryyoung individuals. In a recent pediatric randomizedcontrolled trial (RCT), Fabry arteriopathy and segmentaleffacement of podocyte foot processes were found in allbiopsied FD patients with normal GFR and urinary albuminto-creatinine ratio (UACR) 30 mg/g,31 suggesting earlyKidney International (2017) 91, 284–293
R Schiffmann et al.: Fabry disease: a KDIGO conference reportrenal involvement and by inference an indication for initiation of ERT before kidney injury, marked by proteinuria orreduced GFR, become clinically apparent. There is lack ofagreement on cessation criteria.Glycolipid deposits. Placebo-controlled RCTs in classic FDhave consistently shown that within 6 months, ERT reducesplasma and urinary Gb3 and capillary endothelial Gb3(Supplementary Table S3). Clearance of Gb3 in other slowlydividing cells may take years. In young patients, there is somelimited evidence of a dose-dependent clearance of podocytesover 5 years of follow-up.32 This finding has not yet beenestablished as an acceptable surrogate for beneficial renaltherapeutic effect.Kidney, cardiac, and cerebral disease. Overall, there is asuggestion that ERT slows the progression of kidneyinvolvement in FD and results in reduction of hypertrophiccardiomyopathy, especially when started prior to establishedfibrosis. However, there is no reduction in the rate of strokewith ERT. Though there are limited data and only fewcomparative studies, it is suggested that dose may have animpact. Only 1 placebo-controlled study addressed the effectof ERT (1.0 mg/kg/2 weeks agalsidase-b) on severe renal,cardiac, or central nervous system events. A small decrease inclinical events was observed after a prespecified correction forimbalances at baseline (Supplementary Table S3).33 Onepatient registry study shows a decline in clinical event rateafter the first 6 months of agalsidase-b, but in general there isno indication that the event rate on ERT is lower than thenatural history of the disease.34,35 The clinical event rate forpatients taking agalsidase-a has not been published, althoughmorbidity may be delayed in these patients.36 The observeddifferences in ERT outcomes may be caused by the profoundclinical heterogeneity of studied patients (SupplementaryTable S3).Proteinuria is a well-recognized factor associated withprogressive loss of kidney function in many forms of CKD.37In the phase 3 trial with agalsidase-b, classic FD patientspresenting with 1.0 g/day (d) of proteinuria had stabilization of their renal function during 5 years of follow-up.38 Incontrast, classic patients presenting with 1 g/d of proteinuria, usually associated with fibrosis and scarring in morethan half of the glomeruli on baseline renal biopsies, hadprogressive loss of kidney function, many reaching CKD stage5.38 These results have been extended with 10 years of followup. The important factors related to progressive loss of kidneyfunction were age at which ERT was initiated and averagedratio of urinary protein to creatinine 0.5 g/g ( 0.5 g/d, 50mg/mmol) during the follow-up period.39,40 In those withuncontrolled proteinuria or a reduced GFR ( 60 ml/min/1.73 m2), ERT alone does not seem to prevent further deterioration of renal function.The phase 3 follow-up results have been incorporated intovarious treatment recommendations, with the suggestion thatERT be withheld if there is clinical evidence
Although diagnosis and management of FD have markedly improved over the years, the disease has no cure, and current therapy is suboptimal.3 Our goal was to summarize the cur-rent knowledge and knowledge gaps regarding screening, diagnosis, and therapy, and to propose a research agenda to resolve outstanding controversial issues. SCREENING AND .
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