Fabry Disease Chronic Kidney Disease - PDF document

Fabry Disease Chronic Kidney Disease IntroductionFabry disease (FD) arises from an X-linked defect in lipid storage, whereby deicient or -galactosidase A (-gal A) activity leads to systemic deposition of glyco-sphingolipids, mainly globotriaosylceramide (known as Gb3 or GL3).Deposition mainly af-fects the cardiovascular, renal, and neurologic systems, but can occur in all organs, and de-spite speciic enzyme replacement therapy (ERT) with human recombinant -galactosidase, Etiology and Pathophysiology The inborn error of metabolism in FD is deicient lysosomal hydrolase enzyme, -galactosidase A (galA; EC 3.2.1.22), which catalyzes the hydrolytic cleavage of the terminal galactose from Gb3.8,14The enzyme is encoded by the GLA gene on Xq22, with more than 600 dierent mutations identiied so far. Residual enzyme activity ranges from 0% to about 30% of mean normal value; newly idenGLA gene variants have higher residual enzyme activity, and may therefore be benign. Even in accepted FD mutations, however, it is not known how the disease will be expressed.Without suicient -gal A activity, Gb3 accumulates in cells and tissues, which causes inlammation, ischemia, hypertrophy, and the development of ibrosis, thus promoting cellular damage and progressive organ dysfunction.Many cell types are aected, including vascular (endothelial and smooth muscle cells), cardiac and renal (tubular and glomerular cells, and podocytes), and nerve cells. Because of impaired autonomic function, vasculop-athy, myopathy, and gastrointestinal symptoms are some of the most frequently reported symptoms.16,17Progressive endothelial accumulation of glycosphingolipids such as Gb3 accounts for the associated clinical abnormalities of skin, eye, kidney, heart, brain, and peripheral nervous system.lular process starts early in life and, if untreated, eventually leads to organ failure and premature death. However, Gb3 deposition may only be partly responsible for the manifestations of FD, since signs and symptoms may occur without the presence of severe Another molecule, lyso-Gb3 is also found to be circu-lating in high concentrations in FD, and reproduces some of the eects of high glucose in podocytes.20,21Clinical manifestations of FD can include skin lesions (angiokeratomas, Figure 1), pain and burning in the hands and feet (acroparaesthesia), fatigue, impaired sweating, and gastrointestinal problems such as diarrhea, constipation, nausea, and vomiting.Corneal opacities that progress to a characteristic “whorled” pattern are found in most hemizygotes, but generally do not impact vision. Many of these symptoms are observed during childhood and adolescence, and tend to be prominent in hemizygous males. Heterozygous females were believed to be asymptomatic carriers, however, it is now acknowledged that heterozygous females can also be aected and may develop either a partial or full spectrum of clinical manifestations associated with FD. In adulthood, progressive Gb3 accumulation in the microvasculature causes ischemic damages that can result in cardiovascular disease, stroke and kidney failure. 15,18 Cardiac symptoms include left ventricular hypertrophy (LVH), arrhythmia, angina, and dyspnea.Kidney disease is a major complication of FD related to glyco-sphingolipid accumulation throughout the nephron. Approxi-mately 50% of men and 20% of women by the age of 35 years have proteinuria in the presence of FD. Regular assessments of kidney function in FD should include estimates of the glomerular iltration rate (eGFR), total protein and albumin excretion, and urinary sodium excretion.23,24 Biopsy studies have shown that glomerular and vascular changes are present before progression to proteinuria.25,26 Podocyturia has been observed in patients before the appearance of albuminuria and proteinuria, and there-fore researchers suggest that it be considered an even earlier biomarker of kidney damage, and as an indication to begin ERT at a younger age.2,13,27 Patients who start treatment later in life still have disease progression. Aside from these established eects on kidney pathology and function, parapelvic kidney cysts have also been found in some patients, but their cause is unknown.Identifying these cysts may help with earlier recognition of FD.Figure 1. Angiokeratoma in Fabry disease. Note the multiple periumbilical angiokeratomas. Courtesy Dr. S. Waldek. Reprinted with permission from: Kashtan CE. “Alport’s and other familial glomerular syndromes,” in Comprehensive Clinical Nephrolo-gy. Feehally J, Floege J, Johnson RJ, eds, pp. 543548, Mosby Elsevier. Philadel-phia, PA, USA, 3rd edition, 2007.The classic epidemiology of FD based on enzyme activity has estimated prevalence at 1:17,000 - 1:117,000 in Caucasian males, and 1:40,000 in males and females.3,7 However, evidence suggests that atypical and late-onset phenotypes are underdiagnosed, so the actual prevalence is most likely higher.15,30The results from large genetic screening programs, which are based on DNA sequencing and do not rely upon the development of clinical symptoms, indicate that FD is more prevalent than previously thought.3,8Mutations that cause classic manifestations of FD are found in approximately 1:22,000 to 1:40,000 males, and mutations that cause atypical presentations are found in approximately 1:1000 to 1:3000 males and 1:6000 to 1:40,000 females.8,30,31The incidence of FD is being reevaluated because variant forms of FD and newborn screening numbers challenge classic epide-miology.Incidence ranges are derived from the high prevalence of a presumed cardiac Fabry mutation (IVS4+919G), reported at 1:1,600 males in Taiwan to the 1:3,000 reported from newborn screening data in Illinois and 1:10,000 (males and females) in Washington state.7,32 Studies also suggest an increased incidence of FD in patients with

cryptogenic strokes, hypertrophic cardio-myopathy, and dialysis patients, ranging from 1:20 to 1:1000.7,18,33Newly identiied GLA gene variants have higher residual enzyme activity, but it is questionable if these variants are clinically signif-For example, the IVS4 + 919G mutation presents with 10% residual enzyme activity but not all patients are symptomatic.3,33Onset of the signs and symptoms associated with FD should warrant prompt diagnosis and intervention. However, observed symptoms are heterogeneous among many patients, making a timely diagnosis a challenge. In addition, some symptoms can resemble other more common diseases. Diagnostic delays have been estimated at ~15 years for both genders.diagnosis is frequently inaccurate. In the 366 European patients from the Fabry Outcome Survey, the mean delay until correct di-agnosis after symptom onset was estimated at 13.7 and 16.3 years for males and females, respectively.8,34Appropriate biochemical and/or genetic conirmation could be considered for conirma-tion if physical and clinical examination raises a suspicion of FD.When there is a clear family history and classic phenotype, FD can be conirmed in males if there is low -gal A activity in leuko-cytes or plasma. Assays of plasma alpha-galactosidase activity may be less sensitive than in leukocytes.36,37Mutation analysis of -Gal A gene is needed to diagnose female carriers (unless the woman is an obligate heterozygote, whereby the father 3 4 is known to have FD), and in males and females with atypical presentations or marginal -gal A levels.rarely made by skin or kidney biopsy, however, FD may be found incidentally if a kidney biopsy is performed to diagnose chronic kidney disease (CKD).8,39Although not required for the diagnosis in most patients, genotyping is recommended for all FD families since it may be helpful for future therapies utilizing synthetic chaperones.Only one member from an aected family needs genotyping. More than 600 mutations have been identiied so far; therefore, inding a mutation in a new family requires com-plete resequencing of the gene.Prenatal diagnosis of FD can be made using amniocytes and chorionic villi for enzymatic and molecular testing, but only molecular testing is routinely performed in the United States. Preimplantation genetic diagnosis for families with a known familial mutation is also possible through assisted reproduction centers.7,40Earlier diagnosis promotes timely interventions and the potential to slow the progression of complications such as kidney failure. For this reason, newborn screening programs for FD have begun in Taiwan, Missouri, and Illinois, and is being pilot tested in New York and Washington state.4042 Legislation for screening has been passed in New Mexico, Pennsylvania, and New Jersey, and has been introduced in Minnesota, Kentucky, Tennessee, Ohio, Arizona, and California.Because eective treatments are now available and evidence points to beneits from earlier intervention, along with the additional beneit of identifying aected older family members, newborn screening is now viewed more favorably among health care providers. With the expansion of newborn screening for FD, issues regarding pediatric management and timing for the initiation of ERT have come more to the forefront.The role of biopsy is central to the early diagnosis and manage-ment of FD nephropathy. Since clinical parameters alone do not conirm a diagnosis of early FD nephropathy, a kidney biopsy will do so, along with detecting the early kidney damage that pre-cedes albuminuria/proteinuria.26,44,45In addition, biopsy is a useful tool to exclude non FD kidney diseases in cases with atypical clinical course, such as rapid decline of renal function or very early development of heavy proteinuria.Podocyte zebra bodies or glycosphingolipid deposits in concentric whorls are pathogno-monic for FD. (Figure 2) Glycosphingolipid is deposited in cytoplasmic vacuoles in glomerular visceral epithelial cells. Insert: Cytoplasmic vacu-oles contain electron-dense material in parallel arrays (zebra bodies) and in concentric whorls (myelin igures). Courtesy of J. Carlos Manivel, MD. Reprinted with permission from: Kashtan CE. “Alport’s and other familial glomerular syndromes,” in Comprehensive Clinical Nephrology. Feehally J, Floege J, Johnson RJ, eds, pp. 543548, Mosby Elsevier. Philadelphia, PA, USA, 3rd edition, 2007. Dierential Diagnosis Although FD is considered highly penetrant in males and females, its expression can vary greatly, thus contributing to its high rate of misdiagnosis. It is therefore necessary to begin with a comprehensive medical and family history, and to include FD in the dierential diagnosis according to the hallmark clinical and familial features in Table 1.Table 1: Test ANY patient who has:1. amily history of Fabry disease OR2. al verticillata (“whorls”) on slit lamp examIn the absence of above two factors, test patients with at least two of the features below:1. eased sweating (anhidrosis or hypohidrosis)2. eddish-purple skin rash in the bathing trunk area (angiokeratomas)3. ersonal and/or family history of kidney failure4. ersonal or family history of “burning” or “hot” pain in the hands and feet, particularly during fevers (acroparesthesias)5. ersonal or family history of exercise, heat, or cold intolerance6. atients with sporadic or non-autosomal dominant (no male-to-male) transmission of unexplained cardiac hypertrophyAdapted from: Laney DA, Bennett RL, Clarke V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Counsel. 2013;22:555564.Additionally, FD must be considered in dierential diagnoses when a young male presents with signs and symptoms of stroke, along with other characteri

stic lesions. Conditions that mimic the symptoms of FD include the following: acute stroke; basilar artery thrombosis; cardioembolic stroke; cavernous, dissection and lacunar syndromes; posterior cerebral artery stroke; transient global amnesia. Consider FD in adults with unexplained pro-teinuria or kidney failure, especially if LVH is present or there is a history of stroke. In children, other possible causes of pain such as rheumatoid arthritis, rheumatic fever, systemic lupus erythe-matosus, Raynaud’s disease, and “growing pains” (a frequent mis-diagnosis in children with FD) must be ruled out. In adults, celiac disease and multiple sclerosis are the most common dierential diagnoses, particularly in females. Likewise, when no mutation GLA gene has been found, the possibility of a phenocopy mimicking FD should be considered.There are cases of hemizygous males with disease manifesta-tions seen only in the kidney. These renal variants have been found among Japanese dialysis patients whose kidney disease had been misdiagnosed as chronic glomerulonephritis. These -galactosidase A activity, and were then found to have GLA gene mutations. These indings suggest that FD may be underdiagnosed among dialysis and kidney transplant patients.48,49 Early detection of these renal vari-ants is important, since these patients may later develop vascular disease of the heart or brain.TreatmentSupportive Care and Antiproteinuric TherapySupportive care usually consists of pain relief, blood pressure control/nephroprotection, antiarrhythmic agents, gastrointestinal agents, and lifestyle modiications. Renal replacement therapy (dialysis or kidney transplantation) is available for patients with kidney failure. Patients with neuropathic pain may beneit from avoiding any possible triggers of their acute pain attacks. Certain antidepressants and anticonvulsants can be considered. 4 Analgesics are also an option, but nonsteroidal anti-inlammatory drugs are generally are not considered eective, and can nega-tively impact kidney function. Treatments for gastrointestinal symptoms can include changes in eating habits (e.g., smaller, more frequent meals), H2 blockers, and metoclopramide.Hypertension is not common during earlier onset of FD, but more so as the disease progresses, particularly in the presence of kidney disease.38,51,52 Hypertension, along with LVH, is most strongly associated with cardiovascular events in FD. Angioten-sin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) can be considered, particularly in the presence of proteinuria, given their antiproteinuric eect.30,53One pro-spective observational study examined the safety and eicacy of controlling proteinuria with ACEi or ARB therapy in FD patients who were receiving ERT with agalsidase beta.Results showed that proteinuria in most classical FD patients was controlled, but that kidney function was not preserved in patients who did not achieve the urine protein to creatinine ratio (UPCR) treatment goal of 0.5 g/g.Kidney function was preserved in a minority of patients who started ERT at a younger age, and who maintained a UPCR .5 g/g with antiproteinuric therapy.Enzyme Replacement TherapyTo address the underlying metabolic error in FD, ERT was made available in 2001. Agalsidase beta is the only currently available ERT in the United States, whereas agalsidase alfa and agalsi-dase beta are both available in Europe. Agalsidase alfa has not been approved for use in the United States.No strong evidence demonstrates superiority of either one in the treatment of FD.5456A 10-year observational study of 52 patients with classic FD demonstrated the eectiveness of agalsidase beta thera-py (1mg/kg/2 weeks) in regards to renal, cardiac, and overall outcomes.Mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal in patients who had less kidney damage and had started ERT at a younger age (mean 25 years versus 38 years).Patients who began ER&#x 045;T at age 40 years exhibited signiicant increase in left ventricular posterior wall thickness and interventricular septum thickness.Most patients remained alive and event-free, and mean plasma Gb3 normalized within 6 months.Mean slopes for estimated glomerular iltration rate (eGFR) were -1.89 mL/min/1.73 m/year and -6.82 mL/min/1.73 m/year for starting ERT with less and greater kidney damage, respectively.Proteinuria is an early marker of kidney disease, but it may also relect an already damaged and denuded iltration barrier due to a decreased number of podocytes; under this circumstance, proteinuria could be considered a late biomarker of glomerular damage.Research shows that the presence of increased podocyturia in the absence of proteinuria and CKD may indicate that the detachment of damaged podocytes in FD precedes proteinuria.2,26,44,45 In the irst morphologic study to show relationships between proteinuria and early glomerular lesions of FD nephropathy in young patients, podocyte Gb3 inclusion volume density increased progressively with age, but there were no signiicant relationships between age and endothelial or mesangial inclusion volume densities.Foot process width, greater in male patients, also progressively increased with age and correlated directly with proteinuria.This is important because once proteinuria presents, the response to ERT may be inadequate, and proteinuria usually does not abate.ERT produces a rapid and signiicant decrease in mesangial and endothelial cell Gb3 inclusions, whereas podocyte inclusions and proteinuria persist despite treatment. Some experts have therefore advocated for initiating ERT at an earlier age before podocyturia and eacement have begun. In order to determine the eect of early ERT on renal morphology in FD, one study evaluat

ed the eect of 5 years of treatment with agalsidase alfa or agalsidase beta in 12 consecutive patients, age 733 years (median age of 16.5 years). Results showed that long-term ERT in young patients with either drug can result in complete Gb3 clearance of mesangial and glomerular endothelial cells across all dosage regimens, and that eective clearance of podocyte inclusions is possible, and that it is dose-dependent.Only one placebo-controlled trial has studied the prevention of end organ complications with ERT; after a per-protocol analysis that adjusted for baseline proteinuria, a reduction in complications using agalsidase beta as compared with placebo was found in patients with advanced disease at baseline.9,15,59Interpreting long-term studies is diicult because a control arm is usually absent, or because only historical controls are used for comparison with treatment groups. Aside from potential in reducing end organ complications, agalsidase beta has been associated with symptomatic beneits, including pain and health-related quality of life.60,61 Deriving beneit from ERT must be balanced by individual patient needs, along with the consideration that the burdens of treatment may be too great to either initiate or continue treatment. The European Fabry Working Group has therefore examined risks versus beneits of ERT in patient groups, and has created a consensus document on when to initiate, not initiate, or stop ERT.62 Pharmacological ChaperonesPharmacological chaperones (PCs) bind to and stabilize some mutant forms of -gal A in the endoplasmic reticulum, which fa-cilitates proper protein folding, and allows for correct traicking.Migalastat hydrochloride, currently in clinical trials, is an analog of the terminal galactose of Gb3 that binds and stabilizes wild type and mutant forms of -gal A. The beneits of PCs include: being non-invasive because they are taken orally, exhibiting broad tissue distribution, and gaining access to the central nervous system.However, PCs are genotype speciic, and it is estimated that only one-third to one-half of mutations may be amenable to currently available PCs.Aside from stabilizing misfolded proteins, PCs may improve the physical stability, and maybe the eicacy, of the recombinant enzymes in ERT.Pre-clin-ical studies have suggested that combination therapy of PCs and ERT maybe be helpful in FD, but such combination therapy has not yet been developed.Substrate Reduction TherapySubstrate reduction therapy (SRT) aims at decreasing synthesis of the substrate Gb3 by targeting the enzymes involved in the production of cellular Gb3.An investigational drug that is in clinical trials is the glucosylceramide synthase (GCS) inhibitor, Genz-682452. In preclinical studies, GCS inhibition by Genz-682452 reduced the tissue level of Gb3 in mice.SRT most likely will not be used as a monotherapy, but maybe in combination with ERT.54,63Stem Cell Transplant and Gene TherapyDiiculties with inding a matching donor and treatment related side eects limit the use of stem cell transplants.Additionally, enzymes secreted by non-modiied transplanted cells and their progeny do not attain therapeutic levels that could inluence uncorrected cells in other organs.No gene therapies have yet been approved by the FDA, although many clinical trials are underway.Gene therapy can provide a non-immunogenic, sustained, and balanced supply of -gal A. Pre-clinical studies of gene therapy in FD have reported produc--Gal A and reduction of Gb3 in Fabry mice and patient bone marrow mononuclear cells.54,64,65Expanded newborn screening with advanced diagnostic tech-niques has led to identifying more FD patients.The advent of ERT has heralded a new era in treatment and improved outcomes for more patients.Morphological studies have pointed to the importance of kidney biopsy in conirming or ruling out FD, while also allowing for earlier ERT and hopefully preventing damage to podocytes.This constitutes a paradigm shift from inding patients much later on after a series of misdiagnoses and having missed a window of opportunity for optimizing ERT therapy.Study of other therapeutic targets such as lyso-Gb3 may lead to more individualized therapies, along with reinement of therapies already under investigation, such as PCs and SRT. The availabil-ity of combination therapies and earlier biomarkers of kidney damage such as podocyturia will likely enhance renal and overall outcomes, but large randomized controlled trials are required in order to determine the long-term beneits of ERT and other inter-ventions.Newborn screening, along with earlier diagnosis and treatment will require greater involvement from neonatologists, pediatricians, and genetic counselors. References1. snick RJ, Ioannou YA, Eng CM. “-Galactosidase A deiciency;Fabry dis-ease,” in The Metabolic and molecular Bases of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, Valle D, eds., pp. 37333774, McGraw-Hill. New York, NY, USA, 8th edition, 2001.2. rimarchi H, Canzonieri R, Muryan A, et al. Copious podocyturia without proteinuria and with normal renal function in a young adult with Fab-ry disease. Case Rep in Nephrol. 2015;Article ID 257628. http://dx.doi.org/10.1155/2015/257628.3. . 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Correction in trans for Fabry disease: expression, secretion and uptake of alpha-galactosidase A in patient-derived cells driven by a high-titer recombinant retroviral vector. Proc Natl Acad Sci. 1996;93:79177922.65. Park J, Murray GJ, Limaye A, et al. Long-term correction of globotriao-sylceramide storage in Fabry mice by recombinant adeno-associated virus-mediated gene transfer. Proc Natl Acad Sci. 2003;100:3450-3454.30 East 33rd StreetNew York, NY 10016 800.622.9010 www.kidney.org upported byDISCLAIMER Information contained in this National Kidney Foundation educational resource is based upon current data available at the time of publication. Information is intended to help clinicians become aware of new scientiic indings and developments. This clinical bulletin is not intended to set out a preferred standard of care and should not be construed as one. Neither should the information be interpreted as prescribing an exclusive course of management.2016 National Kidney Foundation, Inc. 02107244_