- Email: [email protected]
Diagnosis and Management of Kidney Involvement in Fabry Disease
Diagnosis and Management of Kidney Involvement in Fabry Disease David G. Warnock and Michael L. West Interest in the diagnosis and treatment of Fabry disease has been greatly stimulated by the availability of Food and Drug Administration–pproved, effective enzyme replacement therapy. This review will update the progress in this area since enzyme replacement therapy has become available. Fabry disease is often associated with proteinuric chronic kidney disease (CKD), and it appears that the treatment paradigms that have proven to be so effective in diabetes mellitus and other forms of proteinuric kidney disease are also effective in conjunction with enzyme replacement therapy for treating the kidney manifestations of Fabry disease. As such, Fabry disease represents an interesting example of progressive proteinuric kidney disease in which the usual blood pressure is lower than in other forms of CKD. This makes the use of effective antiproteinuric therapy challenging, especially considering the autonomic dysfunction that appears to be part of the disease. Comprehensive therapy for Fabry disease includes enzyme replacement therapy and all of the adjunctive therapies that are currently used to treat all forms of proteinuric CKD. It is anticipated that this approach will preserve kidney function and also benefit the cardiac and cerebrovascular systems in patients with Fabry disease. © 2006 by the National Kidney Foundation, Inc. Key Words: Enzyme replacement therapy; Proteinuria; Chronic kidney disease
C
hronic kidney disease (CKD) and proteinuria are prominent features of Fabry disease. This condition is a rare cause of endstage renal disease (ESRD) and is characterized by deficiency of the lysosomal enzyme alpha-galactosidase A with accumulation of glycosphinglolipids, mainly globotriaosylceramide (GL-3) in all tissues.1 Death in the fifth decade was the usual common outcome in affected males before the advent of dialysis and transplantation.2 Enzyme replacement therapy (ERT) with human recombinant alpha-galactosidase is an exciting advance, which has now made Fabry disease a treatable cause of CKD. Efforts are underway to define the course, and understand the causes of progressive CKD in Fabry disease. From the Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; and Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. Dr Warnock serves on the Speakers Bureau and as a Consultant for Genzyme Corporation. He has received research funding for participation in the phase III and phase IV trials of agalsidase beta. Dr West is a consultant for Genzyme Corporation and Shire Pharmaceuticals Ltd. He has received research funding and speakers honoraria from both companies. Address correspondence to David G. Warnock, MD, Room 647 THT,1530 3rd Avenue South, Birmingham, AL 352940006.E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 1548-5595/06/1302-0009$32.00/0 doi:10.1053/j.ackd.2006.01.013
138
In the context of effective ERT, it is also important to identify the role and use of optimal adjunctive therapy (eg, statins and antiproteinuric agents) to slow the progression of disease, taking full advantage of what is known about the management of other proteinuric kidney diseases like diabetic nephropathy. Pedigree and population screening efforts need to be carefully considered, especially because the currently available screening based on serum enzyme activity may misclassify as many as 33% of heterozygote (eg, female) patients.3 Nephrologists can play a critical role in the diagnosis and management of Fabry disease and, in addition to their role in provision of dialysis and transplantation in advanced Fabry disease, may also provide ERT to patients with early Fabry disease. Although the necessity for a multidisciplinary approach to the management of this disease is well recognized, it is equally important that the individual patient have a welldefined entry into the health care system with a readily identifiable physician who has primary responsibility for coordinating the overall care. Over 300 well-defined mutations in the GLA gene coding for alpha-galactosidase A on the X chromosome have been described4,5 and include point mutations, short-length rearrangements, splice-site mutations, and dele-
Advances in Chronic Kidney Disease, Vol 13, No 2 (April), 2006: pp 138-147
Kidney Manifestations of Fabry Disease
tions. The spectrum of disease is being better defined.6,7 Even though this is an X-linked disease, female heterozygotes are not merely “carriers,” but often have some clinical manifestations, ranging from trivial to severe, although generally the onset of symptoms is at a later age than affected male hemizygotes. A homozygous female has been described who had severe onset of classical disease at 8 years of age similar to affected males.8 The severity and extent of disease can be related to the specific mutation in the GLA gene,9 but even within the same family, a surprising spectrum of disease can exist.10,11
Diagnosis of Kidney Involvement in Fabry Disease Although rare, accounting for only 0.02% of the ESRD patients in the USRDS cohort of 1995 to 1998,12 Fabry disease has generated increasing attention because of the availability of ERT. With increasing recognition of the disease and characteristic findings on kidney biopsy,13–15 serendipitous diagnoses of Fabry disease have been described in patients who underwent kidney biopsy for proteinuria.16,17 The utility of diagnostic kidney biopsy cannot be overemphasized. Kidney sonographic and magnetic resonance imaging findings have also been described with a surprising prevalence of peripelvic cysts,18,19 but the sensitivity and specificity of these approaches have not been defined. A renal variant has been described in males, in which the usual systemic manifestations are minimal, yet kidney involvement can progress to ESRD.20 –22 Screening efforts can be performed in subpopulations thought to be at higher risk of disease than the general population. Dialysis screening efforts would seem to be worthwhile because kidney failure is an important outcome in Fabry disease. Nakao et al22 screened 514 consecutive males and found 6 who had low levels of serum alphagalactosidase, for a prevalence of 1.2%. Mutational analysis confirmed the diagnosis in all 6 patients, and 1 turned out to have classical disease that had not been previously appreciated. The other 5 had very mild extrarenal manifestations, raising the possibility of a kidney variant. Another
139
screening effort involving 450 male Japanese dialysis patients discovered a single patient with Fabry disease confirmed by mutational analysis.21 Taken together, these 2 screening studies in male Japanese hemodialysis patients defined 7 patients in a population of 964, for a prevalence of 0.73%. Other large-scale screening efforts of hemodialysis populations have been performed in Holland and Austria.23,24 These studies found very low prevalence of undiagnosed Fabry disease 0.13% (4/2,988) in these populations, consistent with significant geographic variability in the prevalence of Fabry disease. However, even in areas with an extremely high prevalence of Fabry disease such as Nova Scotia, Canada, mass screening of the ESRD population has failed to reveal a single new case (0/820) (West ML, personal communication; January 1, 2006). Several technical issues have to be considered in all such screening efforts. Mutational confirmation has to be done, and some cases will be missed if only exon screening is performed.25,26 More importantly, the stability and method of enzyme analysis are critical. Leukocytes or whole blood assays (“spot” test) appear more accurate than serum assays because leukocytes are the primary source of circulating enzyme, and the enzyme is more stable on storage with whole blood samples on filter paper rather than stored plasma.27 An important limitation to widespread screening is the false-negative rate in females that can approach 33%.3 DNA mutational analysis, although the gold standard for the diagnosis of Fabry disease in females, is too expensive and slow for use in mass screening. Recent advances with tandem mass spectroscopy methods may well be able to separate heterozytoges from normal females based on analysis of urinary glycosphingolipids.28,29 Although not readily applicable to mass population screening, these approaches do address the uncomfortably high false-negative rate of serum enzyme assays in females. Whether screening for Fabry disease in ESRD populations should be performed will depend on the local disease prevalence, experience, and the type of assay available.
140
Warnock and West
Clinical Trials: Safety and Efficacy of Enzyme Replacement Therapy in Fabry Disease The trials that led to regulatory approval for ERT have recently been reviewed.30 –32 Approval for 2 forms of alpha-Gal A (gene-activated human alpha-galactosidase A [agalsidase alpha, Replagal; Shire Pharmaceuticals, Cambridge, MA] and recombinant human alpha-galactosidase A [agalsidase beta, Fabrazyme; Genzyme Corp, Cambridge, MA]) has been obtained in most European countries, as well as Brazil, Argentina, Australia, and Canada; only the Fabrazyme version is approved in the United States.33 Claims that differences in their glycosylation patterns could account for differences in clinical effectiveness34 have not been confirmed by prospective studies. Both products are very similar, with comparable specific activities, glycosylation, and immunogenicity.35,36 The only notable difference relates to the approved dose for intravenous administration: agalsidase alpha at 0.2 mg/kg and agalsidase beta at 1 mg/kg. Agalsidase beta at 1 mg/kg was given every 2 weeks for 20 weeks in a phase III study in 58 patients. The primary endpoint was clearance of GL-3 deposits from glomerular capillary endothelial cells. In 69% of the patients treated with agalsidase beta, GL-3 was cleared from the vascular endothelium in kidney, heart, and skin after 6 months of ERT. None of the placebo-treated controls had any changes in their endothelial deposits.37 All of the patients who completed the phase III trial continued to receive agalsidase beta at 1 mg/kg every 2 weeks in an open-label extension study. After 6 months of the open-label therapy, all 22 patients formerly in the placebo group and 20 of 21 patients who were initially started on agalsidase beta in the initial phase (42/43, 98%) achieved or maintained normal or near-normal kidney capillary endothelial histology on repeat biopsy.37 The benefits of enzyme replacement therapy at 1 mg/kg every 2 weeks were confirmed in a 36-month extension study of the phase III trial.32 A detailed histological assessment of these results examined the posttreatment kidney biopsies.38 GL-3 accumulation was present in nearly all cell types in the pretreatment biop-
sies, including vascular endothelial cells, vascular smooth-muscle cells, mesangial cells, and interstitial cells, with particularly dense accumulations in podocytes and distal tubular epithelial cells. After 11 months of agalsidase beta treatment, there was complete clearance of GL-3 from the vascular endothelium, glomerular mesangial cells, and cortical interstitial cells. Moderate clearance was noted from the smooth-muscle cells of arterioles and small arteries. GL-3 clearance from podocytes and distal tubular epithelium was limited as compared with that observed in other cell types.38 Agalsidase alpha (0.2 mg/kg) has also been reported to reduce plasma, urine, and tissue GL-3 in liver and kidney in short-term trials in 26 patients.39,40 Use of ERT in children with Fabry disease is limited to date, but treatment agalsidase alpha has been positive and well tolerated with no undue safety concerns in 1 randomized controlled trial.41 To date, all published randomized controlled trials of ERT in Fabry disease have used surrogate markers such as tissue GL-3 rather than clinical outcomes such as kidney failure, cardiac death, and stroke. The difficulty of performing an outcomes study in a rare disease with variable phenotype is a significant barrier to achieving a more solid scientific basis of ERT in Fabry disease. Fortunately, a phase III to IV placebo-controlled randomized trial in 82 Fabry patients of agalsidase beta was recently concluded, and promising clinical outcomes data are to be published very shortly. These results are eagerly awaited. Observational studies on European Fabry registry patients have reported stabilization in kidney function after 2 and 3 years of ERT as estimated by the modified MDRD formula or calculated by creatinine clearance.42 Although these data are suggestive of ERT benefit in Fabry disease, they are not conclusive because of the small numbers of patients, lack of a central reference laboratory, relatively short follow-up period, and the selective nature of the patient inclusion because of incomplete registry data. Safety of ERT in Fabry disease is of some concern. In the initial trials, from 57% to 59% of patients experienced a moderate infusion
Kidney Manifestations of Fabry Disease
reaction to agalsidase beta and agalsidase alpha, with fever, chills, or edema.37,39 Such reactions are not uncommon in patients receiving infusions of other foreign proteins. The majority of patients receiving ERT develop IgG antibodies to infused recombinant human alpha-galactosidase even in the short term with 88% of patients positive after agalsidase beta and 64% after agalsidase alpha37,39; this difference is likely related to the 5-fold higher dose of the former drug. However, the presence of antibodies does not correlate with infusion reactions and antibody titers tend to fall over time, eventually becoming negative in many patients. Because females tend to have some degree of residual enzyme activity, they rarely develop such antibodies. Although the significance of such antibodies is questioned, concerns about possible neutralizing effects on infused ERT have been raised.36 Although IgE antibody to agalsidase beta has been rarely reported, anaphylaxis has never occurred and some patients have been successfully rechallenged with enzyme.
Optimal Dosing of ERT Unfortunately, long-term dosing studies will probably not be performed now that ERT therapy has been approved, similar to the situation that has occurred with ERT for Gaucher disease. In Fabry disease, there remains an important question about the effective dose because the 2 available forms of ERT differ in their approved dosage (0.2 mg/kg for agalsidase alpha and 1.0 mg/kg for agalsidase beta). Patients who are switched from one form to the other provide an important opportunity to deduce possible dose-related effects. Kidney biopsy results have been reported for 2 brothers with Fabry disease who were initially treated with agalsidase alpha at 0.2 mg/kg for 16 and 60 months, respectively.11 Biopsies were performed at the time of switching from agalsidase alpha (0.2 mg/kg) to agalsidase beta (1.0 mg/kg), and both showed persisting vascular endothelial deposits despite agalsidase alpha therapy,11 in contrast to the prospective studies with agalsidase beta, which reported complete resolution of these deposits.38 A recent autopsy re-
141
port, however, described clearing of vascular endothelial cells with agalsidase alpha (0.2 mg/kg) given for 2 years but with persisting deposits in other vascular cells.43 This situation will only be clarified by more comparative data. In the current postapproval era, repeated kidney biopsies need to be justified on clinical grounds rather than by protocol. Alternatively, assessments of urinary glycosphingolipids may be useful for assessing the adequacy of ERT dose as well as the effects of any potentially neutralizing antibodies that develop during the course of ERT.36,44
Assessment of Kidney Function in Patients With Fabry Disease Progressive decline in kidney function is a cardinal manifestation of Fabry disease, usually in the setting of overt proteinuria. As is true of all other forms of CKD, serum creatinine is a relatively insensitive index of kidney function, especially in relatively early stages of kidney involvement. Therefore, more quantitative estimates of glomerular filtration rate (GFR) are needed to define the severity of the kidney involvement.45 Although some debate persists about the optimal methods for assessing kidney function,46 it does not appear that these challenges are any different in patients with Fabry disease than in any other form of proteinuric CKD. The dilemma is especially well defined when ERT is instituted early on in the disease course before there is any significant decline in measured kidney function. An initial baseline evaluation of kidney function needs to be performed in every patient with Fabry disease. This assessment should include estimate of the GFR and urine protein, albumin, and sodium excretion. The frequency of subsequent assessments of kidney function will be determined by the baseline assessment, with more frequent follow-up assessment for more severe CKD. Patients who have significant proteinuria despite relatively “normal” kidney function should be treated with ERT and antiproteinuric therapy Initiation of ERT in patients with multisystem manifestations of Fabry disease is a straightforward decision on clinical grounds.
142
Warnock and West
Complicating factors include the logistics of biweekly infusions, and the availability of comprehensive insurance coverage for the cost of the drug. Extrapolating from studies in other forms of proteinuric kidney disease, any patient who has persistent proteinuria (urine protein/creatinine ⬎200 mg/g) should be offered ERT and antiproteinuric therapy, irrespective of the stage of CKD in the hope of preventing disease progression.47,48 If there is any doubt about the origin of the proteinuria, then a kidney biopsy can be very useful. Patients with milder kidney involvement (CKD stage 1 or 2) but without proteinuria should be offered ERT if the other multisystem manifestations of Fabry disease are evident. In this setting, an argument can be advanced for performing kidney biopsies on clinical grounds so as to assess the degree of interstitial and glomerular fibrosis and scaring. Although the podocyte deposits with GL-3 are easily recognized, the underlying pathophysiology is thought to involve ischemic changes that are associated with fibrosis, scarring, and even segmental sclerosis.14,49 Although the knockout mouse model of Fabry disease has associated vascular thrombosis,50 this has not been reported in human Fabry disease. A betterdefined approach to the description of the histologic changes and even development of a formal “chronicity” score would be important advances in management of the kidney manifestations of Fabry disease. The optimal goal of ERT is to preserve normal kidney function by early clearing of the endothelial deposits and prevention of further deposits. In this context, the sooner ERT is started, the more likely the long-term outcome will be favorable. However, the optimal time to start ERT remains undefined. If GFR has already been compromised, the goal is stabilization of the kidney function. As with other forms of CKD, it may not be realistic to expect absolute improvement in kidney function if the GFR has already been compromised, but the reduction in the rate at which the CKD progresses is a salutary outcome.51 At present, it is not established if there is a “point of no return” at which enzyme replacement therapy will not halt the progression of CKD to kidney failure requiring dialysis or transplantation. Stabilization of kidney func-
tion has been described in patients with relatively advanced CKD because of Fabry disease, but such patients treated with either agalsidase beta or agalsidase alpha have also received aggressive adjunctive therapy with reduction of proteinuria as integral parts of their therapy.42,51
Comprehensive Management of the Nephropathy of Fabry Disease Progression rates of chronic kidney involvement can be as high or higher in Fabry disease as that seen in diabetic nephropathy.2 Before the availability of dialysis, death from kidney failure occurred in early the fifth decade in classically affected males.1,2,31 The outcome may be related to interstitial and glomerular fibrosis and scarring rather than GL-3 deposits in parietal and visceral glomerular epithelia cells. Attention to the control of blood pressure, lipids, and proteinuria are important aspects in the modern approach to treatment of any form of CKD.52,53 Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are now recognized as mainstays in the therapy of all forms of proteinuric kidney disease. However, their aggressive application in conjunction with ERT has yet not been fully embraced as the standard of care. One of the obstacles to this approach is the relatively low blood pressures and substandard exercise tolerance that is seen, especially in males with Fabry disease. These hemodynamic factors may reflect the autonomic dysfunction and impaired autoregulation that has recently been described.54 –56 Unless there are compelling indications, betablockers should be avoided because of the autonomic dysfunction in these patients, and their adverse effects on exercise tolerance and diastolic blood pressure, which paradoxically may fall during exercise in patients with Fabry disease.57 The reason for adding adjunctive therapy to enzyme replacement therapy is not reduction of the systemic blood pressure to a preset goal, but the stabilization of kidney function and reduction of urinary protein and albumin excretion to the absolute minimum. The combination of ACEi and ARB may have unique
Kidney Manifestations of Fabry Disease
effects over either class by itself.58,59 Recent studies of type II diabetes have identified reduction of urinary protein excretion as well as blood pressure control as critical elements in stabilizing kidney function.47,48,60,61 At present, there are no controlled studies that show the utility of reducing urinary protein excretion as part of the management of the Fabry disease with ERT. In fact, reduced urinary protein excretion has not even been a defined secondary endpoint in any of the ERT trials. In addition, because disease progression in Fabry disease may be genetically programmed, it is possible that there is not beneficial effect on the progression of the kidney involvement with ACEi therapy, as has been observed in polycystic kidney disease.62 Nevertheless, it would not be surprising if baseline urinary protein excretion at the start of ERT predicts the outcome of the kidney involvement, as it has been shown in type II diabetes trials.47,48 In the case described by De Schoenmakere et al,51 the favorable response to ERT was associated with lisinopril treatment and maintenance of urinary protein excretion at 0.4 to 0.6 g/d. We have had a similar experience in our patients with advanced CKD because of Fabry disease.11,63 It does not appear that ERT, with either form of agalsidase, has any effect on urinary protein excretion.64 Whether higher doses of ERT, earlier onset of treatment and the addition of adjunctive antiproteinuric therapy with ACEi and/or ARB will favorably impact on the overall course of Fabry disease are important questions that need to be addressed with prospective studies.
Management of During Dialysis and Transplantation The provision of renal replacement therapy is important in the management of a patient with Fabry disease who has reached kidney failure. Although these issues should be readily addressed, the long-term outcome of these patients will obviously be related to their cardiovascular and cerebrovascular events. The impact of ERT on these outcomes needs to be carefully assessed in patients who are receiving dialysis or have had kidney transplants.
143
The 3-year survival of Fabry dialysis patients was 63% compared with 74% in a nondiabetic cohort but significantly better than a diabetic cohort of dialysis patients in a careful case-control study (53%).12 This difference in outcomes from the nondiabetic dialysis patients may be attributable to cerebrovascular and cardiovascular events in the Fabry dialysis patients and provides an important rationale for providing these patients with ERT, even though kidney function is irreversibly compromised. Peritoneal dialysis patients can also successfully be treated with ERT.65 A careful pharmacokinetic study organized by Kosch et al66 has shown that agalsidase-beta is not lost during hemodialysis and that these patients can be successfully treated with ERT during the course of their routine hemodialysis. There is some debate concerning the utility of giving these patients ERT23 that will have to be addressed when the long-term efficacy studies become available. Kidney transplantation appears to improve symptoms and may even benefit patient outcomes in Fabry disease, perhaps to increased renal clearance of GL-3.67 Transplanted patients with Fabry disease do at least as well as those with other causes of kidney failure who have been transplanted.67–70 Mignani et al67 have reported improvement in cardiac function in several kidney transplant patients treated with agalsidase beta.
Future Directions Surrogate Markers At present, there is not an accepted biomarker for following the response to ERT in Fabry disease. Organ function, long-term outcomes, and tissue-based examination of the extent of GL-3 deposits are important but not useful for making dosing decisions in an individual patient. Urinary and plasma GL-3 levels have not been widely used to monitor the response to ERT, although this may change as these assays are refined.44,71 A similar interest related to individualized ERT dosing is the presence of neutralizing antibodies, especially in male patients.36 For the present, the recommended treatment doses for agalsidase alpha and agalsidase beta are 0.2 and 1.0 mg/kg,
144
Warnock and West
respectively, every 2 weeks, but these recommendations may be modified as acceptable measures of the response to ERT are developed, and the natural history of the disease is defined in the ERT era through the active participation of ERT- treated patients in prospective registries. Epithelial Podocyte Deposits Although the degree of proteinuria may well be an important prognostic determinant and may directly contribute to the progression of kidney disease, GL-3 deposits in podocytes have not been directly related to the magnitude of proteinuria or the rates of progression or severity of the kidney involvement in Fabry disease. GL-3 deposits in podocytes may represent a lifetime of accumulation and have been shown in glomerular epithelial cells as early as the second trimester in a male fetus.72 Epithelial deposits have been shown in heterozygous females with little derangement in kidney function,11,73–75 in a kidney from a heterozygous donor 20 years after transplantation into an unaffected recipient,76 as a subclinical finding in hemizygous males with other forms of kidney disease,77 and in a 23year-old man with isolated low-grade protein.78 Although acknowledging the universality of podocyte GL-3 deposits in both males and females with Fabry disease, there have not been any specific changes that can be associated with the degree of proteinuria. The development of a scoring system for glomerular and interstitial fibrosis (“chronicity” index) could be a helpful tool for staging kidney biopsy results and predicting the response to antiproteinuric and ERT in patients with Fabry disease. Other Therapies The role of additional treatments for Fabry disease such as chaperone therapy79 and gene therapy80 and their specific impact on the kidney manifestations of Fabry disease still needs to be determined.
Conclusions The ERT era is upon us for Fabry disease, and the natural history of the disease will need to
be defined. Effective therapy for this disease is being defined, with the kidney involvement paramount with respect to the documented morbidity of the disease and the ease with which kidney function and urinary protein excretion can be measured. Fabry disease represents a form of progressive proteinuric kidney disease that is not necessarily associated with overt hypertension. In fact, the presence of autonomic dysfunction can complicate the provision of effective antiproteinuric therapy. Future work will need to better define the mechanisms of proteinuria and define the optimal measures of the response to maximal, comprehensive therapy for this disease. Although this review has focused on the current status of the kidney involvement, the cardiovascular and cerebrovascular systems are also important targets for the disease that should also respond to ERT.
References 1. Desnick R, Ioannou Y, Eng C: Alpha-Galactosidase A deficiency: Fabry disease, in Scriver C, Beaudet A, Sly W, et al (eds): The Metabolic Bases of Inherited Disease (ed 8). New York, NY, McGraw-Hill, 2001, pp 3733-3774 2. Branton MH, Schiffmann R, Sabnis SG, et al: Natural history of Fabry renal disease: influence of alphagalactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore) 81:122-138, 2002 3. Linthorst GE, Vedder AC, Aerts JM, et al: Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta 353:201-203, 2005 4. Garman SC, Garboczi DN: The molecular defect leading to Fabry disease: Structure of human alpha-galactosidase. J Mol Biol 337:319-335, 2004 5. Schafer E, Baron K, Widmer U, et al: Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease. Hum Mutat 25:412, 2005 6. Hauser AC, Lorenz M, Sunder-Plassmann G: The expanding clinical spectrum of Anderson-Fabry disease: A challenge to diagnosis in the novel era of enzyme replacement therapy. J Intern Med 255:629636, 2004 7. Schaefer E, Mehta A, Gal A: Genotype and phenotype in Fabry disease: Analysis of the Fabry Outcome Survey. Acta Paediatr Suppl 94:87-92, 2005; discussion 79 8. Rodriguez-Mari A, Coll MJ, Chabas A: Molecular analysis in Fabry disease in Spain: Fifteen novel GLA mutations and identification of a homozygous female. Hum Mutat 22:258, 2003 9. Maki N, Komatsuda A, Wakui H, et al: A nonsense mutation (R220X) in the alpha-galactosidase A gene
Kidney Manifestations of Fabry Disease
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
causes typical Fabry disease in both genders. Clin Nephrol 61:185-190, 2004 Verovnik F, Benko D, Vujkovac B, et al: Remarkable variability in renal disease in a large Slovenian family with Fabry disease. Eur J Hum Genet 12:678-681, 2004 Warnock DG: Fabry disease: Diagnosis and management, with emphasis on the renal manifestations. Curr Opin Nephrol Hypertens 14:87-95, 2005 Thadhani R, Wolf M, West ML, et al: Patients with Fabry disease on dialysis in the United States. Kidney Int 61:249-255, 2002 Grunfeld JP, Lidove O, Joly D, et al: Renal disease in Fabry patients. J Inherit Metab Dis 24(Suppl 2):71-74, 2001; discussion 65 Gubler MC, Lenoir G, Grunfeld JP, et al: Early renal changes in hemizygous and heterozygous patients with Fabry’s disease. Kidney Int 13:223-235, 1978 Sessa A, Meroni M, Battini G, et al: Renal pathological changes in Fabry disease. J Inherit Metab Dis 24(Suppl 2):66-70, 2001; discussion 65 Thamboo TP, Sivaraman P, Chan NH: Pathologic quiz case: an unsuspected cause of nephrotic syndrome. Heterozygous Fabry disease. Arch Pathol Lab Med 128:593-594, 2004 Torra R, Del Pozo C, Yague J, et al: Treatment of three Fabry patients with moderate renal failure and description of the renal variant. Nephrol Dial Transplant 18:634, 2003 (abstr) Glass RB, Astrin KH, Norton KI, et al: Fabry Disease: Renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes. J Comput Assist Tomogr 28:158-168, 2004 Ries M, Bettis KE, Choyke P, et al: Parapelvic kidney cysts: A distinguishing feature with high prevalence in Fabry disease. Kidney Int 66:978-982, 2004 Cybulla M, Schaefer E, Wendt S, et al: Chronic renal failure and proteinuria in adulthood: Fabry disease predominantly affecting the kidneys. Am J Kidney Dis 45:e82-89, 2005 Ichinose M, Nakayama M, Ohashi T, et al: Significance of screening for Fabry disease among male dialysis patients. Clin Exp Nephrol 9:228-232, 2005 Nakao S, Kodama C, Takenaka T, et al: Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int 64:801-807, 2003 Kotanko P, Kramar R, Devrnja D, et al: Results of a nationwide screening for Anderson-Fabry disease among dialysis patients. J Am Soc Nephrol 15:13231329, 2004 Linthorst GE, Hollak CE, Korevaar JC, et al: alphaGalactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease. Nephrol Dial Transplant 18:1581-1584, 2003 Lai LW, Whitehair O, Wu MJ, et al: Analysis of splice-site mutations of the alpha-galactosidase A gene in Fabry disease. Clin Genet 63:476-482, 2003 Yasuda M, Shabbeer J, Osawa M, et al: Fabry disease: Novel alpha-galactosidase A 3=-terminal mutations result in multiple transcripts due to aberrant 3=-end formation. Am J Hum Genet 73:162-173, 2003
145
27. Fuller M, Lovejoy M, Brooks DA, et al: Immunoquantification of alpha-galactosidase: Evaluation for the diagnosis of Fabry disease. Clin Chem 50:1979-1985, 2004 28. Fuller M, Sharp PC, Rozaklis T, et al: Urinary lipid profiling for the identification of fabry hemizygotes and heterozygotes. Clin Chem 51:688-694, 2005 29. Mills K, Morris P, Lee P, et al: Measurement of urinary CDH and CTH by tandem mass spectrometry in patients hemizygous and heterozygous for Fabry disease. J Inherit Metab Dis 28:35-48, 2005 30. Brenner BM, Grunfeld JP: Renoprotection by enzyme replacement therapy. Curr Opin Nephrol Hypertens 13:231-241, 2004 31. Desnick RJ, Brady R, Barranger J, et al: Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 138: 338-346, 2003 32. Wilcox WR, Banikazemi M, Guffon N, et al: Longterm safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet 75:65-74, 2004 33. Desnick RJ: Enzyme replacement therapy for Fabry disease: Lessons from two alpha-galactosidase A orphan products and one FDA approval. Expert Opin Biol Ther 4:1167-1176, 2004 34. Barbey F, Hayoz D, Widmer U, et al: Efficacy of enzyme replacement therapy in Fabry disease. Curr Med Chem Cardiovasc Hematol Agents 2:277-286, 2004 35. Lee K, Jin X, Zhang K, et al: A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology 13:305-313, 2003 36. Linthorst GE, Hollak CE, Donker-Koopman WE, et al: Enzyme therapy for Fabry disease: Neutralizing antibodies toward agalsidase alpha and beta. Kidney Int 66:1589-1595, 2004 37. Eng CM, Guffon N, Wilcox WR, et al: Safety and efficacy of recombinant human alpha-galactosidase A—Replacement therapy in Fabry’s disease. N Engl J Med 345:9-16, 2001 38. Thurberg BL, Rennke H, Colvin RB, et al: Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int 62:1933-1946, 2002 39. Schiffmann R, Kopp JB, Austin HA 3rd, et al: Enzyme replacement therapy in Fabry disease: A randomized controlled trial. JAMA 285:2743-2749, 2001 40. Schiffmann R, Murray GJ, Treco D, et al: Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci U S A 97:365-370, 2000 41. Ries M, Gupta S, Moore DF, et al: Pediatric Fabry disease. Pediatrics 115:e344-e355, 2005 42. Beck M, Ricci R, Widmer U, et al: Fabry disease: Overall effects of agalsidase alfa treatment. Eur J Clin Invest 34:838-844, 2004 43. Schiffmann R, Rapkiewicz A, Abu-Asab M, et al: Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement. Virchows Arch 29:1-7, 2005
146
Warnock and West
44. Whitfield PD, Calvin J, Hogg S, et al: Monitoring enzyme replacement therapy in Fabry disease—Role of urine globotriaosylceramide. J Inherit Metab Dis 28:21-33, 2005 45. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 39:S1-S266, 2002 46. Kleinert J, Lorenz M, Hauser AC, et al: Measurement of renal function in patients with Fabry disease. Acta Paediatr Suppl 94:9-23, 2005; discussion 9-10 47. de Zeeuw D, Remuzzi G, Parving HH, et al: Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110:921-927, 2004 48. de Zeeuw D, Remuzzi G, Parving HH, et al: Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int 65:2309-2320, 2004 49. Svarstad E, Bostad L, Kaarboe O, et al: Focal and segmental glomerular sclerosis (FSGS) in a man and a woman with Fabrs disease. Clin Nephrol 63:394-401, 2005 50. Eitzman DT, Bodary PF, Shen Y, et al: Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. J Am Soc Nephrol 14:298-302, 2003 51. De Schoenmakere G, Chauveau D, Grunfeld JP: Enzyme replacement therapy in Anderson-Fabry’s disease: Beneficial clinical effect on vital organ function. Nephrol Dial Transplant 18:33-35, 2003 52. Gaede P, Vedel P, Larsen N, et al: Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348:383-393, 2003 53. Remuzzi G, Schieppati A, Ruggenenti P: Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med 346:1145-1151, 2002 54. Hilz MJ, Brys M, Marthol H, et al: Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy. Neurology 62:1066-1072, 2004 55. Hilz MJ, Kolodny EH, Brys M, et al: Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease. J Neurol 251: 564-570, 2004 56. Stemper MDB, Hilz MDPDMJ: Postischemic cutaneous hyperperfusion in the presence of forearm hypoperfusion suggests sympathetic vasomotor dysfunction in Fabry disease. J Neurol 250:970-976, 2003 57. Bierer G, Kamangar N, Balfe D, et al: Cardiopulmonary exercise testing in Fabry disease. Respiration 72:504-511, 2005 58. Campbell R, Sangalli F, Perticucci E, et al: Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int 63:1094-1103, 2003 59. Nakao N, Yoshimura A, Morita H, et al: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial. Lancet 361:117-124, 2003 60. Keane WF, Brenner BM, de Zeeuw D, et al: The risk of developing end-stage renal disease in patients with
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
type 2 diabetes and nephropathy: The RENAAL study. Kidney Int 63:1499-1507, 2003 Ruggenenti P, Perna A, Remuzzi G: Retarding progression of chronic renal disease: The neglected issue of residual proteinuria. Kidney Int 63:22542261, 2003 Levey AS, Greene T, Beck GJ, et al: Dietary protein restriction and the progression of chronic renal disease: What have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group. J Am Soc Nephrol 10:2426-2439, 1999 Tahir I, Alldredge L, Warnock DG: Sustained decrease in urine protein excretion in Fabry patients treated with ACE ihibitors and ARBs while receiving agalsidase-beta therapy. J Am Soc Nephrol 16:142, 2005 (abstr) Schiffmann R, Ries M, Timmons M, et al: Long-term therapy with agalsidase alfa for Fabry disease: Safety and effects on renal function in a home infusion setting. Nephrol Dial Transplant 21:345-354, 2006 Siamopoulos KC: Fabry disease: Kidney involvement and enzyme replacement therapy. Kidney Int 65:744753, 2004 Kosch M, Koch HG, Oliveira JP, et al: Enzyme replacement therapy administered during hemodialysis in patients with Fabry disease. Kidney Int 66:12791282, 2004 Mignani R, Panichi V, Giudicissi A, et al: Enzyme replacement therapy with agalsidase beta in kidney transplant patients with Fabry disease: A pilot study. Kidney Int 65:1381-1385, 2004 Mignani R, Gerra D, Maldini L, et al: Long-term survival of patients with renal transplantation in Fabry’s disease. Contrib Nephrol 136:229-233, 2001 Ojo A, Meier-Kriesche HU, Friedman G, et al: Excellent outcome of renal transplantation in patients with Fabry’s disease. Transplantation 69:2337-2339, 2000 Tsakiris D, Simpson HK, Jones EH, et al: Report on management of renale failure in Europe, XXVI, 1995. Rare diseases in renal replacement therapy in the ERA-EDTA Registry. Nephrol Dial Transplant 11(Suppl 7):4-20, 1996 Roy S, Gaudin K, Germain DP, et al: Optimisation of the separation of four major neutral glycosphingolipids: Application to a rapid and simple detection of urinary globotriaosylceramide in Fabry disease. J Chromatogr B Analyt Technol Biomed Life Sci 805: 331-337, 2004 Tsutsumi O, Sato M, Sato K, et al: Early prenatal diagnosis of inborn error of metabolism: A case report of a fetus affected with Fabry’s disease. Asia Oceania J Obstet Gynaecol 11:39-45, 1985 Farge D, Nadler S, Wolfe LS, et al: Diagnostic value of kidney biopsy in heterozygous Fabry’s disease. Arch Pathol Lab Med 109:85-88, 1985 Marguery MC, Giordano F, Parant M, et al: Fabry’s disease: Heterozygous form of different expression in two monozygous twin sisters. Dermatology 187:9-15, 1993 Rodriguez FH Jr, Hoffmann EO, Ordinario AT Jr, et
Kidney Manifestations of Fabry Disease
al: Fabry’s disease in a heterozygous woman. Arch Pathol Lab Med 109:89-91, 1985 76. Grunfeld JP, Lidove O, Barbey F: Heterozygotes with Fabry’s disease. Contrib Nephrol 136:208-210, 2001 77. Kawamura O, Sakuraba H, Itoh K, et al: Subclinical Fabry’s disease occurring in the context of IgA nephropathy. Clin Nephrol 47:71-75, 1997 78. Meroni M, Spisni C, Tazzari S, et al: Isolated glomerular proteinuria as the only clinical manifestation of
147
Fabry’s disease in an adult male. Nephrol Dial Transplant 12:221-223, 1997 79. Frustaci A, Chimenti C, Ricci R, et al: Improvement in cardiac function in the cardiac variant of Fabry’s disease with galactose-infusion therapy. N Engl J Med 345:25-32, 2001 80. Siatskas C, Medin JA: Gene therapy for Fabry disease. J Inherit Metab Dis 24(Suppl 2):25-41, 2001;discussion 11-22
C
hronic kidney disease (CKD) and proteinuria are prominent features of Fabry disease. This condition is a rare cause of endstage renal disease (ESRD) and is characterized by deficiency of the lysosomal enzyme alpha-galactosidase A with accumulation of glycosphinglolipids, mainly globotriaosylceramide (GL-3) in all tissues.1 Death in the fifth decade was the usual common outcome in affected males before the advent of dialysis and transplantation.2 Enzyme replacement therapy (ERT) with human recombinant alpha-galactosidase is an exciting advance, which has now made Fabry disease a treatable cause of CKD. Efforts are underway to define the course, and understand the causes of progressive CKD in Fabry disease. From the Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; and Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. Dr Warnock serves on the Speakers Bureau and as a Consultant for Genzyme Corporation. He has received research funding for participation in the phase III and phase IV trials of agalsidase beta. Dr West is a consultant for Genzyme Corporation and Shire Pharmaceuticals Ltd. He has received research funding and speakers honoraria from both companies. Address correspondence to David G. Warnock, MD, Room 647 THT,1530 3rd Avenue South, Birmingham, AL 352940006.E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 1548-5595/06/1302-0009$32.00/0 doi:10.1053/j.ackd.2006.01.013
138
In the context of effective ERT, it is also important to identify the role and use of optimal adjunctive therapy (eg, statins and antiproteinuric agents) to slow the progression of disease, taking full advantage of what is known about the management of other proteinuric kidney diseases like diabetic nephropathy. Pedigree and population screening efforts need to be carefully considered, especially because the currently available screening based on serum enzyme activity may misclassify as many as 33% of heterozygote (eg, female) patients.3 Nephrologists can play a critical role in the diagnosis and management of Fabry disease and, in addition to their role in provision of dialysis and transplantation in advanced Fabry disease, may also provide ERT to patients with early Fabry disease. Although the necessity for a multidisciplinary approach to the management of this disease is well recognized, it is equally important that the individual patient have a welldefined entry into the health care system with a readily identifiable physician who has primary responsibility for coordinating the overall care. Over 300 well-defined mutations in the GLA gene coding for alpha-galactosidase A on the X chromosome have been described4,5 and include point mutations, short-length rearrangements, splice-site mutations, and dele-
Advances in Chronic Kidney Disease, Vol 13, No 2 (April), 2006: pp 138-147
Kidney Manifestations of Fabry Disease
tions. The spectrum of disease is being better defined.6,7 Even though this is an X-linked disease, female heterozygotes are not merely “carriers,” but often have some clinical manifestations, ranging from trivial to severe, although generally the onset of symptoms is at a later age than affected male hemizygotes. A homozygous female has been described who had severe onset of classical disease at 8 years of age similar to affected males.8 The severity and extent of disease can be related to the specific mutation in the GLA gene,9 but even within the same family, a surprising spectrum of disease can exist.10,11
Diagnosis of Kidney Involvement in Fabry Disease Although rare, accounting for only 0.02% of the ESRD patients in the USRDS cohort of 1995 to 1998,12 Fabry disease has generated increasing attention because of the availability of ERT. With increasing recognition of the disease and characteristic findings on kidney biopsy,13–15 serendipitous diagnoses of Fabry disease have been described in patients who underwent kidney biopsy for proteinuria.16,17 The utility of diagnostic kidney biopsy cannot be overemphasized. Kidney sonographic and magnetic resonance imaging findings have also been described with a surprising prevalence of peripelvic cysts,18,19 but the sensitivity and specificity of these approaches have not been defined. A renal variant has been described in males, in which the usual systemic manifestations are minimal, yet kidney involvement can progress to ESRD.20 –22 Screening efforts can be performed in subpopulations thought to be at higher risk of disease than the general population. Dialysis screening efforts would seem to be worthwhile because kidney failure is an important outcome in Fabry disease. Nakao et al22 screened 514 consecutive males and found 6 who had low levels of serum alphagalactosidase, for a prevalence of 1.2%. Mutational analysis confirmed the diagnosis in all 6 patients, and 1 turned out to have classical disease that had not been previously appreciated. The other 5 had very mild extrarenal manifestations, raising the possibility of a kidney variant. Another
139
screening effort involving 450 male Japanese dialysis patients discovered a single patient with Fabry disease confirmed by mutational analysis.21 Taken together, these 2 screening studies in male Japanese hemodialysis patients defined 7 patients in a population of 964, for a prevalence of 0.73%. Other large-scale screening efforts of hemodialysis populations have been performed in Holland and Austria.23,24 These studies found very low prevalence of undiagnosed Fabry disease 0.13% (4/2,988) in these populations, consistent with significant geographic variability in the prevalence of Fabry disease. However, even in areas with an extremely high prevalence of Fabry disease such as Nova Scotia, Canada, mass screening of the ESRD population has failed to reveal a single new case (0/820) (West ML, personal communication; January 1, 2006). Several technical issues have to be considered in all such screening efforts. Mutational confirmation has to be done, and some cases will be missed if only exon screening is performed.25,26 More importantly, the stability and method of enzyme analysis are critical. Leukocytes or whole blood assays (“spot” test) appear more accurate than serum assays because leukocytes are the primary source of circulating enzyme, and the enzyme is more stable on storage with whole blood samples on filter paper rather than stored plasma.27 An important limitation to widespread screening is the false-negative rate in females that can approach 33%.3 DNA mutational analysis, although the gold standard for the diagnosis of Fabry disease in females, is too expensive and slow for use in mass screening. Recent advances with tandem mass spectroscopy methods may well be able to separate heterozytoges from normal females based on analysis of urinary glycosphingolipids.28,29 Although not readily applicable to mass population screening, these approaches do address the uncomfortably high false-negative rate of serum enzyme assays in females. Whether screening for Fabry disease in ESRD populations should be performed will depend on the local disease prevalence, experience, and the type of assay available.
140
Warnock and West
Clinical Trials: Safety and Efficacy of Enzyme Replacement Therapy in Fabry Disease The trials that led to regulatory approval for ERT have recently been reviewed.30 –32 Approval for 2 forms of alpha-Gal A (gene-activated human alpha-galactosidase A [agalsidase alpha, Replagal; Shire Pharmaceuticals, Cambridge, MA] and recombinant human alpha-galactosidase A [agalsidase beta, Fabrazyme; Genzyme Corp, Cambridge, MA]) has been obtained in most European countries, as well as Brazil, Argentina, Australia, and Canada; only the Fabrazyme version is approved in the United States.33 Claims that differences in their glycosylation patterns could account for differences in clinical effectiveness34 have not been confirmed by prospective studies. Both products are very similar, with comparable specific activities, glycosylation, and immunogenicity.35,36 The only notable difference relates to the approved dose for intravenous administration: agalsidase alpha at 0.2 mg/kg and agalsidase beta at 1 mg/kg. Agalsidase beta at 1 mg/kg was given every 2 weeks for 20 weeks in a phase III study in 58 patients. The primary endpoint was clearance of GL-3 deposits from glomerular capillary endothelial cells. In 69% of the patients treated with agalsidase beta, GL-3 was cleared from the vascular endothelium in kidney, heart, and skin after 6 months of ERT. None of the placebo-treated controls had any changes in their endothelial deposits.37 All of the patients who completed the phase III trial continued to receive agalsidase beta at 1 mg/kg every 2 weeks in an open-label extension study. After 6 months of the open-label therapy, all 22 patients formerly in the placebo group and 20 of 21 patients who were initially started on agalsidase beta in the initial phase (42/43, 98%) achieved or maintained normal or near-normal kidney capillary endothelial histology on repeat biopsy.37 The benefits of enzyme replacement therapy at 1 mg/kg every 2 weeks were confirmed in a 36-month extension study of the phase III trial.32 A detailed histological assessment of these results examined the posttreatment kidney biopsies.38 GL-3 accumulation was present in nearly all cell types in the pretreatment biop-
sies, including vascular endothelial cells, vascular smooth-muscle cells, mesangial cells, and interstitial cells, with particularly dense accumulations in podocytes and distal tubular epithelial cells. After 11 months of agalsidase beta treatment, there was complete clearance of GL-3 from the vascular endothelium, glomerular mesangial cells, and cortical interstitial cells. Moderate clearance was noted from the smooth-muscle cells of arterioles and small arteries. GL-3 clearance from podocytes and distal tubular epithelium was limited as compared with that observed in other cell types.38 Agalsidase alpha (0.2 mg/kg) has also been reported to reduce plasma, urine, and tissue GL-3 in liver and kidney in short-term trials in 26 patients.39,40 Use of ERT in children with Fabry disease is limited to date, but treatment agalsidase alpha has been positive and well tolerated with no undue safety concerns in 1 randomized controlled trial.41 To date, all published randomized controlled trials of ERT in Fabry disease have used surrogate markers such as tissue GL-3 rather than clinical outcomes such as kidney failure, cardiac death, and stroke. The difficulty of performing an outcomes study in a rare disease with variable phenotype is a significant barrier to achieving a more solid scientific basis of ERT in Fabry disease. Fortunately, a phase III to IV placebo-controlled randomized trial in 82 Fabry patients of agalsidase beta was recently concluded, and promising clinical outcomes data are to be published very shortly. These results are eagerly awaited. Observational studies on European Fabry registry patients have reported stabilization in kidney function after 2 and 3 years of ERT as estimated by the modified MDRD formula or calculated by creatinine clearance.42 Although these data are suggestive of ERT benefit in Fabry disease, they are not conclusive because of the small numbers of patients, lack of a central reference laboratory, relatively short follow-up period, and the selective nature of the patient inclusion because of incomplete registry data. Safety of ERT in Fabry disease is of some concern. In the initial trials, from 57% to 59% of patients experienced a moderate infusion
Kidney Manifestations of Fabry Disease
reaction to agalsidase beta and agalsidase alpha, with fever, chills, or edema.37,39 Such reactions are not uncommon in patients receiving infusions of other foreign proteins. The majority of patients receiving ERT develop IgG antibodies to infused recombinant human alpha-galactosidase even in the short term with 88% of patients positive after agalsidase beta and 64% after agalsidase alpha37,39; this difference is likely related to the 5-fold higher dose of the former drug. However, the presence of antibodies does not correlate with infusion reactions and antibody titers tend to fall over time, eventually becoming negative in many patients. Because females tend to have some degree of residual enzyme activity, they rarely develop such antibodies. Although the significance of such antibodies is questioned, concerns about possible neutralizing effects on infused ERT have been raised.36 Although IgE antibody to agalsidase beta has been rarely reported, anaphylaxis has never occurred and some patients have been successfully rechallenged with enzyme.
Optimal Dosing of ERT Unfortunately, long-term dosing studies will probably not be performed now that ERT therapy has been approved, similar to the situation that has occurred with ERT for Gaucher disease. In Fabry disease, there remains an important question about the effective dose because the 2 available forms of ERT differ in their approved dosage (0.2 mg/kg for agalsidase alpha and 1.0 mg/kg for agalsidase beta). Patients who are switched from one form to the other provide an important opportunity to deduce possible dose-related effects. Kidney biopsy results have been reported for 2 brothers with Fabry disease who were initially treated with agalsidase alpha at 0.2 mg/kg for 16 and 60 months, respectively.11 Biopsies were performed at the time of switching from agalsidase alpha (0.2 mg/kg) to agalsidase beta (1.0 mg/kg), and both showed persisting vascular endothelial deposits despite agalsidase alpha therapy,11 in contrast to the prospective studies with agalsidase beta, which reported complete resolution of these deposits.38 A recent autopsy re-
141
port, however, described clearing of vascular endothelial cells with agalsidase alpha (0.2 mg/kg) given for 2 years but with persisting deposits in other vascular cells.43 This situation will only be clarified by more comparative data. In the current postapproval era, repeated kidney biopsies need to be justified on clinical grounds rather than by protocol. Alternatively, assessments of urinary glycosphingolipids may be useful for assessing the adequacy of ERT dose as well as the effects of any potentially neutralizing antibodies that develop during the course of ERT.36,44
Assessment of Kidney Function in Patients With Fabry Disease Progressive decline in kidney function is a cardinal manifestation of Fabry disease, usually in the setting of overt proteinuria. As is true of all other forms of CKD, serum creatinine is a relatively insensitive index of kidney function, especially in relatively early stages of kidney involvement. Therefore, more quantitative estimates of glomerular filtration rate (GFR) are needed to define the severity of the kidney involvement.45 Although some debate persists about the optimal methods for assessing kidney function,46 it does not appear that these challenges are any different in patients with Fabry disease than in any other form of proteinuric CKD. The dilemma is especially well defined when ERT is instituted early on in the disease course before there is any significant decline in measured kidney function. An initial baseline evaluation of kidney function needs to be performed in every patient with Fabry disease. This assessment should include estimate of the GFR and urine protein, albumin, and sodium excretion. The frequency of subsequent assessments of kidney function will be determined by the baseline assessment, with more frequent follow-up assessment for more severe CKD. Patients who have significant proteinuria despite relatively “normal” kidney function should be treated with ERT and antiproteinuric therapy Initiation of ERT in patients with multisystem manifestations of Fabry disease is a straightforward decision on clinical grounds.
142
Warnock and West
Complicating factors include the logistics of biweekly infusions, and the availability of comprehensive insurance coverage for the cost of the drug. Extrapolating from studies in other forms of proteinuric kidney disease, any patient who has persistent proteinuria (urine protein/creatinine ⬎200 mg/g) should be offered ERT and antiproteinuric therapy, irrespective of the stage of CKD in the hope of preventing disease progression.47,48 If there is any doubt about the origin of the proteinuria, then a kidney biopsy can be very useful. Patients with milder kidney involvement (CKD stage 1 or 2) but without proteinuria should be offered ERT if the other multisystem manifestations of Fabry disease are evident. In this setting, an argument can be advanced for performing kidney biopsies on clinical grounds so as to assess the degree of interstitial and glomerular fibrosis and scaring. Although the podocyte deposits with GL-3 are easily recognized, the underlying pathophysiology is thought to involve ischemic changes that are associated with fibrosis, scarring, and even segmental sclerosis.14,49 Although the knockout mouse model of Fabry disease has associated vascular thrombosis,50 this has not been reported in human Fabry disease. A betterdefined approach to the description of the histologic changes and even development of a formal “chronicity” score would be important advances in management of the kidney manifestations of Fabry disease. The optimal goal of ERT is to preserve normal kidney function by early clearing of the endothelial deposits and prevention of further deposits. In this context, the sooner ERT is started, the more likely the long-term outcome will be favorable. However, the optimal time to start ERT remains undefined. If GFR has already been compromised, the goal is stabilization of the kidney function. As with other forms of CKD, it may not be realistic to expect absolute improvement in kidney function if the GFR has already been compromised, but the reduction in the rate at which the CKD progresses is a salutary outcome.51 At present, it is not established if there is a “point of no return” at which enzyme replacement therapy will not halt the progression of CKD to kidney failure requiring dialysis or transplantation. Stabilization of kidney func-
tion has been described in patients with relatively advanced CKD because of Fabry disease, but such patients treated with either agalsidase beta or agalsidase alpha have also received aggressive adjunctive therapy with reduction of proteinuria as integral parts of their therapy.42,51
Comprehensive Management of the Nephropathy of Fabry Disease Progression rates of chronic kidney involvement can be as high or higher in Fabry disease as that seen in diabetic nephropathy.2 Before the availability of dialysis, death from kidney failure occurred in early the fifth decade in classically affected males.1,2,31 The outcome may be related to interstitial and glomerular fibrosis and scarring rather than GL-3 deposits in parietal and visceral glomerular epithelia cells. Attention to the control of blood pressure, lipids, and proteinuria are important aspects in the modern approach to treatment of any form of CKD.52,53 Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are now recognized as mainstays in the therapy of all forms of proteinuric kidney disease. However, their aggressive application in conjunction with ERT has yet not been fully embraced as the standard of care. One of the obstacles to this approach is the relatively low blood pressures and substandard exercise tolerance that is seen, especially in males with Fabry disease. These hemodynamic factors may reflect the autonomic dysfunction and impaired autoregulation that has recently been described.54 –56 Unless there are compelling indications, betablockers should be avoided because of the autonomic dysfunction in these patients, and their adverse effects on exercise tolerance and diastolic blood pressure, which paradoxically may fall during exercise in patients with Fabry disease.57 The reason for adding adjunctive therapy to enzyme replacement therapy is not reduction of the systemic blood pressure to a preset goal, but the stabilization of kidney function and reduction of urinary protein and albumin excretion to the absolute minimum. The combination of ACEi and ARB may have unique
Kidney Manifestations of Fabry Disease
effects over either class by itself.58,59 Recent studies of type II diabetes have identified reduction of urinary protein excretion as well as blood pressure control as critical elements in stabilizing kidney function.47,48,60,61 At present, there are no controlled studies that show the utility of reducing urinary protein excretion as part of the management of the Fabry disease with ERT. In fact, reduced urinary protein excretion has not even been a defined secondary endpoint in any of the ERT trials. In addition, because disease progression in Fabry disease may be genetically programmed, it is possible that there is not beneficial effect on the progression of the kidney involvement with ACEi therapy, as has been observed in polycystic kidney disease.62 Nevertheless, it would not be surprising if baseline urinary protein excretion at the start of ERT predicts the outcome of the kidney involvement, as it has been shown in type II diabetes trials.47,48 In the case described by De Schoenmakere et al,51 the favorable response to ERT was associated with lisinopril treatment and maintenance of urinary protein excretion at 0.4 to 0.6 g/d. We have had a similar experience in our patients with advanced CKD because of Fabry disease.11,63 It does not appear that ERT, with either form of agalsidase, has any effect on urinary protein excretion.64 Whether higher doses of ERT, earlier onset of treatment and the addition of adjunctive antiproteinuric therapy with ACEi and/or ARB will favorably impact on the overall course of Fabry disease are important questions that need to be addressed with prospective studies.
Management of During Dialysis and Transplantation The provision of renal replacement therapy is important in the management of a patient with Fabry disease who has reached kidney failure. Although these issues should be readily addressed, the long-term outcome of these patients will obviously be related to their cardiovascular and cerebrovascular events. The impact of ERT on these outcomes needs to be carefully assessed in patients who are receiving dialysis or have had kidney transplants.
143
The 3-year survival of Fabry dialysis patients was 63% compared with 74% in a nondiabetic cohort but significantly better than a diabetic cohort of dialysis patients in a careful case-control study (53%).12 This difference in outcomes from the nondiabetic dialysis patients may be attributable to cerebrovascular and cardiovascular events in the Fabry dialysis patients and provides an important rationale for providing these patients with ERT, even though kidney function is irreversibly compromised. Peritoneal dialysis patients can also successfully be treated with ERT.65 A careful pharmacokinetic study organized by Kosch et al66 has shown that agalsidase-beta is not lost during hemodialysis and that these patients can be successfully treated with ERT during the course of their routine hemodialysis. There is some debate concerning the utility of giving these patients ERT23 that will have to be addressed when the long-term efficacy studies become available. Kidney transplantation appears to improve symptoms and may even benefit patient outcomes in Fabry disease, perhaps to increased renal clearance of GL-3.67 Transplanted patients with Fabry disease do at least as well as those with other causes of kidney failure who have been transplanted.67–70 Mignani et al67 have reported improvement in cardiac function in several kidney transplant patients treated with agalsidase beta.
Future Directions Surrogate Markers At present, there is not an accepted biomarker for following the response to ERT in Fabry disease. Organ function, long-term outcomes, and tissue-based examination of the extent of GL-3 deposits are important but not useful for making dosing decisions in an individual patient. Urinary and plasma GL-3 levels have not been widely used to monitor the response to ERT, although this may change as these assays are refined.44,71 A similar interest related to individualized ERT dosing is the presence of neutralizing antibodies, especially in male patients.36 For the present, the recommended treatment doses for agalsidase alpha and agalsidase beta are 0.2 and 1.0 mg/kg,
144
Warnock and West
respectively, every 2 weeks, but these recommendations may be modified as acceptable measures of the response to ERT are developed, and the natural history of the disease is defined in the ERT era through the active participation of ERT- treated patients in prospective registries. Epithelial Podocyte Deposits Although the degree of proteinuria may well be an important prognostic determinant and may directly contribute to the progression of kidney disease, GL-3 deposits in podocytes have not been directly related to the magnitude of proteinuria or the rates of progression or severity of the kidney involvement in Fabry disease. GL-3 deposits in podocytes may represent a lifetime of accumulation and have been shown in glomerular epithelial cells as early as the second trimester in a male fetus.72 Epithelial deposits have been shown in heterozygous females with little derangement in kidney function,11,73–75 in a kidney from a heterozygous donor 20 years after transplantation into an unaffected recipient,76 as a subclinical finding in hemizygous males with other forms of kidney disease,77 and in a 23year-old man with isolated low-grade protein.78 Although acknowledging the universality of podocyte GL-3 deposits in both males and females with Fabry disease, there have not been any specific changes that can be associated with the degree of proteinuria. The development of a scoring system for glomerular and interstitial fibrosis (“chronicity” index) could be a helpful tool for staging kidney biopsy results and predicting the response to antiproteinuric and ERT in patients with Fabry disease. Other Therapies The role of additional treatments for Fabry disease such as chaperone therapy79 and gene therapy80 and their specific impact on the kidney manifestations of Fabry disease still needs to be determined.
Conclusions The ERT era is upon us for Fabry disease, and the natural history of the disease will need to
be defined. Effective therapy for this disease is being defined, with the kidney involvement paramount with respect to the documented morbidity of the disease and the ease with which kidney function and urinary protein excretion can be measured. Fabry disease represents a form of progressive proteinuric kidney disease that is not necessarily associated with overt hypertension. In fact, the presence of autonomic dysfunction can complicate the provision of effective antiproteinuric therapy. Future work will need to better define the mechanisms of proteinuria and define the optimal measures of the response to maximal, comprehensive therapy for this disease. Although this review has focused on the current status of the kidney involvement, the cardiovascular and cerebrovascular systems are also important targets for the disease that should also respond to ERT.
References 1. Desnick R, Ioannou Y, Eng C: Alpha-Galactosidase A deficiency: Fabry disease, in Scriver C, Beaudet A, Sly W, et al (eds): The Metabolic Bases of Inherited Disease (ed 8). New York, NY, McGraw-Hill, 2001, pp 3733-3774 2. Branton MH, Schiffmann R, Sabnis SG, et al: Natural history of Fabry renal disease: influence of alphagalactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore) 81:122-138, 2002 3. Linthorst GE, Vedder AC, Aerts JM, et al: Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta 353:201-203, 2005 4. Garman SC, Garboczi DN: The molecular defect leading to Fabry disease: Structure of human alpha-galactosidase. J Mol Biol 337:319-335, 2004 5. Schafer E, Baron K, Widmer U, et al: Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease. Hum Mutat 25:412, 2005 6. Hauser AC, Lorenz M, Sunder-Plassmann G: The expanding clinical spectrum of Anderson-Fabry disease: A challenge to diagnosis in the novel era of enzyme replacement therapy. J Intern Med 255:629636, 2004 7. Schaefer E, Mehta A, Gal A: Genotype and phenotype in Fabry disease: Analysis of the Fabry Outcome Survey. Acta Paediatr Suppl 94:87-92, 2005; discussion 79 8. Rodriguez-Mari A, Coll MJ, Chabas A: Molecular analysis in Fabry disease in Spain: Fifteen novel GLA mutations and identification of a homozygous female. Hum Mutat 22:258, 2003 9. Maki N, Komatsuda A, Wakui H, et al: A nonsense mutation (R220X) in the alpha-galactosidase A gene
Kidney Manifestations of Fabry Disease
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
causes typical Fabry disease in both genders. Clin Nephrol 61:185-190, 2004 Verovnik F, Benko D, Vujkovac B, et al: Remarkable variability in renal disease in a large Slovenian family with Fabry disease. Eur J Hum Genet 12:678-681, 2004 Warnock DG: Fabry disease: Diagnosis and management, with emphasis on the renal manifestations. Curr Opin Nephrol Hypertens 14:87-95, 2005 Thadhani R, Wolf M, West ML, et al: Patients with Fabry disease on dialysis in the United States. Kidney Int 61:249-255, 2002 Grunfeld JP, Lidove O, Joly D, et al: Renal disease in Fabry patients. J Inherit Metab Dis 24(Suppl 2):71-74, 2001; discussion 65 Gubler MC, Lenoir G, Grunfeld JP, et al: Early renal changes in hemizygous and heterozygous patients with Fabry’s disease. Kidney Int 13:223-235, 1978 Sessa A, Meroni M, Battini G, et al: Renal pathological changes in Fabry disease. J Inherit Metab Dis 24(Suppl 2):66-70, 2001; discussion 65 Thamboo TP, Sivaraman P, Chan NH: Pathologic quiz case: an unsuspected cause of nephrotic syndrome. Heterozygous Fabry disease. Arch Pathol Lab Med 128:593-594, 2004 Torra R, Del Pozo C, Yague J, et al: Treatment of three Fabry patients with moderate renal failure and description of the renal variant. Nephrol Dial Transplant 18:634, 2003 (abstr) Glass RB, Astrin KH, Norton KI, et al: Fabry Disease: Renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes. J Comput Assist Tomogr 28:158-168, 2004 Ries M, Bettis KE, Choyke P, et al: Parapelvic kidney cysts: A distinguishing feature with high prevalence in Fabry disease. Kidney Int 66:978-982, 2004 Cybulla M, Schaefer E, Wendt S, et al: Chronic renal failure and proteinuria in adulthood: Fabry disease predominantly affecting the kidneys. Am J Kidney Dis 45:e82-89, 2005 Ichinose M, Nakayama M, Ohashi T, et al: Significance of screening for Fabry disease among male dialysis patients. Clin Exp Nephrol 9:228-232, 2005 Nakao S, Kodama C, Takenaka T, et al: Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int 64:801-807, 2003 Kotanko P, Kramar R, Devrnja D, et al: Results of a nationwide screening for Anderson-Fabry disease among dialysis patients. J Am Soc Nephrol 15:13231329, 2004 Linthorst GE, Hollak CE, Korevaar JC, et al: alphaGalactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease. Nephrol Dial Transplant 18:1581-1584, 2003 Lai LW, Whitehair O, Wu MJ, et al: Analysis of splice-site mutations of the alpha-galactosidase A gene in Fabry disease. Clin Genet 63:476-482, 2003 Yasuda M, Shabbeer J, Osawa M, et al: Fabry disease: Novel alpha-galactosidase A 3=-terminal mutations result in multiple transcripts due to aberrant 3=-end formation. Am J Hum Genet 73:162-173, 2003
145
27. Fuller M, Lovejoy M, Brooks DA, et al: Immunoquantification of alpha-galactosidase: Evaluation for the diagnosis of Fabry disease. Clin Chem 50:1979-1985, 2004 28. Fuller M, Sharp PC, Rozaklis T, et al: Urinary lipid profiling for the identification of fabry hemizygotes and heterozygotes. Clin Chem 51:688-694, 2005 29. Mills K, Morris P, Lee P, et al: Measurement of urinary CDH and CTH by tandem mass spectrometry in patients hemizygous and heterozygous for Fabry disease. J Inherit Metab Dis 28:35-48, 2005 30. Brenner BM, Grunfeld JP: Renoprotection by enzyme replacement therapy. Curr Opin Nephrol Hypertens 13:231-241, 2004 31. Desnick RJ, Brady R, Barranger J, et al: Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 138: 338-346, 2003 32. Wilcox WR, Banikazemi M, Guffon N, et al: Longterm safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet 75:65-74, 2004 33. Desnick RJ: Enzyme replacement therapy for Fabry disease: Lessons from two alpha-galactosidase A orphan products and one FDA approval. Expert Opin Biol Ther 4:1167-1176, 2004 34. Barbey F, Hayoz D, Widmer U, et al: Efficacy of enzyme replacement therapy in Fabry disease. Curr Med Chem Cardiovasc Hematol Agents 2:277-286, 2004 35. Lee K, Jin X, Zhang K, et al: A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology 13:305-313, 2003 36. Linthorst GE, Hollak CE, Donker-Koopman WE, et al: Enzyme therapy for Fabry disease: Neutralizing antibodies toward agalsidase alpha and beta. Kidney Int 66:1589-1595, 2004 37. Eng CM, Guffon N, Wilcox WR, et al: Safety and efficacy of recombinant human alpha-galactosidase A—Replacement therapy in Fabry’s disease. N Engl J Med 345:9-16, 2001 38. Thurberg BL, Rennke H, Colvin RB, et al: Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int 62:1933-1946, 2002 39. Schiffmann R, Kopp JB, Austin HA 3rd, et al: Enzyme replacement therapy in Fabry disease: A randomized controlled trial. JAMA 285:2743-2749, 2001 40. Schiffmann R, Murray GJ, Treco D, et al: Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci U S A 97:365-370, 2000 41. Ries M, Gupta S, Moore DF, et al: Pediatric Fabry disease. Pediatrics 115:e344-e355, 2005 42. Beck M, Ricci R, Widmer U, et al: Fabry disease: Overall effects of agalsidase alfa treatment. Eur J Clin Invest 34:838-844, 2004 43. Schiffmann R, Rapkiewicz A, Abu-Asab M, et al: Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement. Virchows Arch 29:1-7, 2005
146
Warnock and West
44. Whitfield PD, Calvin J, Hogg S, et al: Monitoring enzyme replacement therapy in Fabry disease—Role of urine globotriaosylceramide. J Inherit Metab Dis 28:21-33, 2005 45. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 39:S1-S266, 2002 46. Kleinert J, Lorenz M, Hauser AC, et al: Measurement of renal function in patients with Fabry disease. Acta Paediatr Suppl 94:9-23, 2005; discussion 9-10 47. de Zeeuw D, Remuzzi G, Parving HH, et al: Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110:921-927, 2004 48. de Zeeuw D, Remuzzi G, Parving HH, et al: Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int 65:2309-2320, 2004 49. Svarstad E, Bostad L, Kaarboe O, et al: Focal and segmental glomerular sclerosis (FSGS) in a man and a woman with Fabrs disease. Clin Nephrol 63:394-401, 2005 50. Eitzman DT, Bodary PF, Shen Y, et al: Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. J Am Soc Nephrol 14:298-302, 2003 51. De Schoenmakere G, Chauveau D, Grunfeld JP: Enzyme replacement therapy in Anderson-Fabry’s disease: Beneficial clinical effect on vital organ function. Nephrol Dial Transplant 18:33-35, 2003 52. Gaede P, Vedel P, Larsen N, et al: Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348:383-393, 2003 53. Remuzzi G, Schieppati A, Ruggenenti P: Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med 346:1145-1151, 2002 54. Hilz MJ, Brys M, Marthol H, et al: Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy. Neurology 62:1066-1072, 2004 55. Hilz MJ, Kolodny EH, Brys M, et al: Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease. J Neurol 251: 564-570, 2004 56. Stemper MDB, Hilz MDPDMJ: Postischemic cutaneous hyperperfusion in the presence of forearm hypoperfusion suggests sympathetic vasomotor dysfunction in Fabry disease. J Neurol 250:970-976, 2003 57. Bierer G, Kamangar N, Balfe D, et al: Cardiopulmonary exercise testing in Fabry disease. Respiration 72:504-511, 2005 58. Campbell R, Sangalli F, Perticucci E, et al: Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int 63:1094-1103, 2003 59. Nakao N, Yoshimura A, Morita H, et al: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial. Lancet 361:117-124, 2003 60. Keane WF, Brenner BM, de Zeeuw D, et al: The risk of developing end-stage renal disease in patients with
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
type 2 diabetes and nephropathy: The RENAAL study. Kidney Int 63:1499-1507, 2003 Ruggenenti P, Perna A, Remuzzi G: Retarding progression of chronic renal disease: The neglected issue of residual proteinuria. Kidney Int 63:22542261, 2003 Levey AS, Greene T, Beck GJ, et al: Dietary protein restriction and the progression of chronic renal disease: What have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group. J Am Soc Nephrol 10:2426-2439, 1999 Tahir I, Alldredge L, Warnock DG: Sustained decrease in urine protein excretion in Fabry patients treated with ACE ihibitors and ARBs while receiving agalsidase-beta therapy. J Am Soc Nephrol 16:142, 2005 (abstr) Schiffmann R, Ries M, Timmons M, et al: Long-term therapy with agalsidase alfa for Fabry disease: Safety and effects on renal function in a home infusion setting. Nephrol Dial Transplant 21:345-354, 2006 Siamopoulos KC: Fabry disease: Kidney involvement and enzyme replacement therapy. Kidney Int 65:744753, 2004 Kosch M, Koch HG, Oliveira JP, et al: Enzyme replacement therapy administered during hemodialysis in patients with Fabry disease. Kidney Int 66:12791282, 2004 Mignani R, Panichi V, Giudicissi A, et al: Enzyme replacement therapy with agalsidase beta in kidney transplant patients with Fabry disease: A pilot study. Kidney Int 65:1381-1385, 2004 Mignani R, Gerra D, Maldini L, et al: Long-term survival of patients with renal transplantation in Fabry’s disease. Contrib Nephrol 136:229-233, 2001 Ojo A, Meier-Kriesche HU, Friedman G, et al: Excellent outcome of renal transplantation in patients with Fabry’s disease. Transplantation 69:2337-2339, 2000 Tsakiris D, Simpson HK, Jones EH, et al: Report on management of renale failure in Europe, XXVI, 1995. Rare diseases in renal replacement therapy in the ERA-EDTA Registry. Nephrol Dial Transplant 11(Suppl 7):4-20, 1996 Roy S, Gaudin K, Germain DP, et al: Optimisation of the separation of four major neutral glycosphingolipids: Application to a rapid and simple detection of urinary globotriaosylceramide in Fabry disease. J Chromatogr B Analyt Technol Biomed Life Sci 805: 331-337, 2004 Tsutsumi O, Sato M, Sato K, et al: Early prenatal diagnosis of inborn error of metabolism: A case report of a fetus affected with Fabry’s disease. Asia Oceania J Obstet Gynaecol 11:39-45, 1985 Farge D, Nadler S, Wolfe LS, et al: Diagnostic value of kidney biopsy in heterozygous Fabry’s disease. Arch Pathol Lab Med 109:85-88, 1985 Marguery MC, Giordano F, Parant M, et al: Fabry’s disease: Heterozygous form of different expression in two monozygous twin sisters. Dermatology 187:9-15, 1993 Rodriguez FH Jr, Hoffmann EO, Ordinario AT Jr, et
Kidney Manifestations of Fabry Disease
al: Fabry’s disease in a heterozygous woman. Arch Pathol Lab Med 109:89-91, 1985 76. Grunfeld JP, Lidove O, Barbey F: Heterozygotes with Fabry’s disease. Contrib Nephrol 136:208-210, 2001 77. Kawamura O, Sakuraba H, Itoh K, et al: Subclinical Fabry’s disease occurring in the context of IgA nephropathy. Clin Nephrol 47:71-75, 1997 78. Meroni M, Spisni C, Tazzari S, et al: Isolated glomerular proteinuria as the only clinical manifestation of
147
Fabry’s disease in an adult male. Nephrol Dial Transplant 12:221-223, 1997 79. Frustaci A, Chimenti C, Ricci R, et al: Improvement in cardiac function in the cardiac variant of Fabry’s disease with galactose-infusion therapy. N Engl J Med 345:25-32, 2001 80. Siatskas C, Medin JA: Gene therapy for Fabry disease. J Inherit Metab Dis 24(Suppl 2):25-41, 2001;discussion 11-22