Dialysis and Transplantation in Fabry Disease: Indications

for Enzyme Replacement Therapy

Renzo Mignani,* Sandro Feriozzi,† Roland M. Schaefer,‡ Frank Breunig,§
João Paulo Oliveira,储 Piero Ruggenenti,¶ and Gere Sunder-Plassmann**
*Department of Nephrology and Dialysis, Infermi Hospital, Rimini, Italy; †Department of Nephrology and Dialysis,
Belcolle Hospital, Viterbo, Italy; ‡Department of Internal Medicine D, University of Muenster, Muenster, Germany;
§
Department of Internal Medicine I, University of Würzburg, Würzburg, Germany; 储Departments of Nephrology and of
Human Genetics, Hospital São João and University of Porto, Porto, Portugal; ¶Department of Renal Medicine, Clinical
Research Center for Rare Diseases “Aldo & Cele Daccò,” Mario Negri Institute, Bergamo, Italy and Unit of
Nephrology, Azienda Ospedaliera “Ospedali Riuniti di Bergamo,” Bergamo, Italy; and **Division of Nephrology and
Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria

ESRD is a major cause of morbidity and premature mortality in Fabry disease, particularly in classically affected males. The
decline of renal function in Fabry nephropathy is adversely affected by male gender, advanced chronic kidney disease (CKD),
and severe proteinuria. The diagnosis of Fabry nephropathy may be missed if not specifically addressed in progressive CKD
and patients have been first identified in screening programs of dialysis patients. Fabry patients have worse 3-year survival
rates on dialysis as compared with nondiabetic controls. The 5-year survival rate of transplanted Fabry patients is also lower
than that of controls. However, because Fabry nephropathy does not recur in the allograft and transplanted Fabry patients
appear to have better overall outcomes than those maintained on dialysis, kidney transplantation should be recommended as
a first choice in renal replacement therapy (RRT) for Fabry disease. Appropriately designed and powered studies are not
available to answer the question whether enzyme replacement therapy (ERT) influences outcomes, the course of cardiomy-
opathy, events, or survival in Fabry patients on RRT. The authors are not aware of compelling indications for ERT in RRT
patients because progression of cardiomyopathy was documented during ERT. Whether the excess mortality risk of Fabry
patients on RRT can be prevented by ERT is unknown. Despite observational reports of symptomatic improvement, the
available evidence supporting ERT for such patients is not compelling enough. To clarify this issue, studies are needed to test
the effectiveness of agalsidases in preventing cardiac and cerebrovascular complications in Fabry patients with ESRD.
Clin J Am Soc Nephrol 5: 379 –385, 2010. doi: 10.2215/CJN.05570809

F
abry disease results in kidney damage and leads to
progressive impairment of renal function in almost all
male patients and in a significant proportion of females
(1– 4). The life expectancy is reduced for both genders (5–7), and
the major causes of death include cardiac death, stroke, or the
consequences of ESRD (7,8).
The availability of enzyme replacement therapy (ERT) since
2001 has led to major expectations with regard to improvement
of clinical symptoms and disease burden in patients with Fabry
disease (9,10). However, Fabry patients requiring renal replace-
ment therapy (RRT) represent a group of patients with specific
comorbidities possibly affecting the outcome and efficacy of
ERT (11,12).
Published online ahead of print. Publication date available at www.cjasn.org.
Correspondence: Dr. Gere Sunder-Plassmann, Division of Nephrology and Dial-
ysis, Department of Medicine III, Medical University Vienna, Währinger Gürtel
18 –20, A-1090 Vienna, Austria. Phone: ⫹43-1-40400-4217; Fax: ⫹43-1-40400-4392;
E-mail: gere.sunder-plassmann@meduniwien.ac.at
This article summarizes the current knowledge about the
effect of ERT in Fabry patients requiring dialysis therapy or
who have received a kidney transplant. A second goal is to
address important research questions in the field.
What Do We Know?
Progression of Fabry Nephropathy
Proteinuria and progressive renal deterioration may develop
rapidly in Fabry disease. Schiffmann et al. re-examined the
natural history of Fabry nephropathy with a retrospective anal-
ysis of 279 men and 168 women. In men with an estimated GFR
(eGFR) of more than 60 ml/min/1.73 m2, the slope of renal
function was ⫺3 and for women was ⫺0.9 ml/min/1.73 m2 per
year; for men with eGFR ⬍60 ml/min/1.73 m2, it was ⫺6.8 and
for women it was ⫺2.1 ml/min/1.73m2 per year. Patients with
proteinuria ⬎1 g/24 h had a worse prognosis (13). Therefore,
clinical experiences addressed to evaluate the role of ERT (14 –
17) should be compared with this study and not only with
small-scale study results (2). Of interest, women who progress

Copyright © 2010 by the American Society of Nephrology ISSN: 1555-9041/502–0379

380 Clinical Journal of the American Society of Nephrology
to ESRD do so at the same mean age as men (18). Another
recent analysis of the Fabry registry showed that 14% of male
and 2% of female patients included in this survey had a history
of RRT (19).
Since the availability of ERT, its long-term protective effect
on the progressive deterioration of kidney dysfunction has not
been fully established. Open-label extension studies of the piv-
otal clinical trials have demonstrated that renal function re-
mained stable in the long-term in most patients with Fabry
disease who were treated with agalsidase alfa or beta for more
than 4 years (15,20). However, baseline renal function was
normal in most of these patients. In contrast, patients with
impaired renal function presented with a continuous decline of
renal function despite conventionally dosed ERT (14,15,20,21).
Epidemiology, Case-Finding Studies, and Outcomes in
Patients on RRT
Four reports described the prevalence and outcomes of Fabry
disease among ESRD patients. In Europe (22) and in the United
States (11), the prevalence of Fabry disease among patients on
RRT was 0.0188 (83/440,665 patients) and 0.0167 (42/250,352
patients), respectively. Importantly, 12% of ESRD patients with
Fabry disease were female in both registries. In the meantime,
several case-finding studies among ESRD populations have
shown a more than 10 times higher prevalence of Fabry disease
as compared with the U.S. Renal Data System or European
Renal Association-European Dialysis and Transplant Associa-
tion registries (Table 1) (23,24).
Some of these patients did not present with the typical der-
matologic, neuropathic, and ocular features of classical Fabry
disease and have a more limited renal phenotype, which may
be difficult to recognize clinically (25), particularly in the ab-
sence of a known family history of Fabry disease or if a diag-
nostic kidney biopsy has not been done.
Three-year survival of dialysis patients with Fabry disease
was worse as compared with nondiabetic dialysis patients in
Europe (60%) and in the United States (63%) (11,22). Among
kidney transplant recipients, 3-, 5-, and 10-year graft and pa-
tient survival was similar in patients with Fabry disease and
matched patients without Fabry disease in Europe (22) and the
United States (26). Most recently, Shah et al. examined out-
comes of 197 (0.085%) patients with Fabry disease among
233,280 U.S. kidney transplant recipients (12). Although 5-year
graft survival was similar in patients with or without Fabry
disease, Fabry disease conferred a higher risk of death as com-
pared with a matched control population (hazard ratio, 2.15;
95% confidence interval, 1.52 to 3.02).
Pharmacokinetics of ERT in Dialysis and Transplant
Patients
Pastores et al. (27) determined pharmacokinetics in 22 Fabry
patients (two women) receiving either hemodialysis (n ⫽ 9) or
who had a functioning renal transplant (n ⫽ 13; eGFR 64.5 ⫾ 6.0
ml/min/1.73 m2). Agalsidase alfa was infused biweekly at a
dose of 0.2 mg/kg. A typical biphasic plasma elimination pro-
file was seen in dialysis and transplant patients, similar to that
observed in 18 Fabry patients with normal GFR. The serum
Clin J Am Soc Nephrol 5: 379 –385, 2010
clearance profiles for dialysis and transplant patients were
comparable with 18 Fabry patients with normal renal function.
In a study of 10 Fabry patients receiving agalsidase beta at a
dose of 1 mg/kg infused biweekly over 4 hours during and off
dialysis, Kosch et al. investigated the effect of the dialysis pro-
cedure on enzyme activity (28). The rise in plasma activity of
␣-galactosidase A during infusion and steady-state levels were
comparable for enzyme administrations with (high-flux and
low-flux) or without dialysis.
These results confirmed the theoretical assumption that the
recombinant agalsidases are not cleared by hemodialysis filters.
ERT in Dialysis Patients
To date, only limited data are available on Fabry patients
receiving ERT and undergoing dialysis therapy at the same
time. The efficacy of ERT, which has been shown in patients
with preserved renal function or at early stages of renal disease
(9,10,21), could be hampered by the multiple pathogenic factors
and comorbidities in patients on maintenance hemodialysis
therapy.
The clinical outcome of nine patients with Fabry disease after
2 years of treatment with agalsidase beta undergoing dialysis
treatment (six hemodialysis, three peritoneal dialysis) was first
reported in an open-label, nonrandomized Italian study (29).
Six of nine patients enrolled underwent clinical and Doppler
echocardiography assessment at baseline and after 24 months
by means of physical examination, a questionnaire on typical
Fabry manifestations, and two-dimensional echocardiography.
Echocardiography parameters were also available for 2 years
before study entry. An overall amelioration of clinical symp-
toms was noted; in particular gastrointestinal pain improved in
all patients and the use of analgesic medication could be re-
duced. No patient experienced cardiovascular or cerebrovascu-
lar events during follow-up. Notably Fabry patients had a
significant higher left ventricular (LV) mass at baseline com-
pared with control groups of healthy subjects and dialysis
patients (healthy: 40 ⫾ 5.7 g/height2.7; ESRD: 63 ⫾ 9.7; ESRD
and Fabry: 73 ⫾ 29*; P ⬍ 0.5* versus healthy subjects). During
follow-up echocardiography data were available in all six pa-
tients and showed an increase in LV mass index of 6% in the 2
years before study entry and of 3% after the 2 years of ERT.
Indeed, the mean slope of LV mass index decreased from
0.98 ⫾ 0.01 in the pretreatment period to 0.46 ⫾ 0.96 in the ERT
period (P ⫽ 0.06) (29).
Mignani and colleagues conducted a nationwide survey in
Italy to elucidate the cardiac status in patients on RRT receiving
ERT (30). A total of 33 patients could be included, 16 (one
female) receiving dialysis treatment. Patients were followed
over a mean of 61 months and ERT duration was 45 months. At
3 years of ERT, the mean LV mass index had increased by 19%
(from 210.9 to 251.0 g/m2, P ⫽ NS) in the 7 patients with
available two-dimensional Doppler echocardiography data.
Strikingly, 6 years after the start of the survey, 6 of 16 patients
had died (all receiving dialysis treatment) and 6 had received a
renal transplant with only 4 survivors remaining on dialysis
and on ERT. Nine severe cardiac and cerebrovascular events
were recorded during follow-up in dialysis patients (10.8
Table 1. Overview of 18 case-finding studies among patients with CKD
Study Agalsidase Percent Percent Percent
Author and Citation Country n (all) n (male) n (female)
Population Test (all) (male) (female)

Utsumi, Clin Exp Nephrol, 2000 (37) HD, PD Japan P 2/722 0.277 2/440 0.455 0/282 0.000
Clin J Am Soc Nephrol 5: 379 –385, 2010

Desnick, Abstract, 2002 (38) HD, PD, male USA P, L 9/1903 0.473
Spada, Abstract, 2002 (39) HD, PD, male Italy DBS 4/1765 0.227
Pagliardini, Abstract, 2002 (40) ESRD, male Europe DBS 12/4671 0.257
Linthorst, Nephrol Dial Transplant, HD, PD male Netherlands WB 1/508 0.197
2003 (41)
Nakao, Kidney Int, 2003 (25) HD, male Japan P 6/514 1.167
Kotanko, J Am Soc Nephrol, HD, PD Austria DBS 4/2480 0.161 4/1516 0.264 0/964 0.000
2004 (23)
Rocha, Abstract, 2004 (42) HD Portugal DBS 4/4000 0.100 – –
Ichinose, Clin Exp Nephrol, 2005 (43) HD, male Japan P 1/450 0.222
Bekri, Nephron Clin Pract, 2005 (44) HD France L 1/106 0.943 1/59 1.695 0/47 0.000
Tanaka, Clin Nephrol, 2005 (45) HD Japan P 5/696 0.718 4/401 0.998 1/295 0.339
Merta, Nephrol Dial Tranplant, HD Czech DBS 5/3370 0.148 4/1521 0.263 1/1849 0.054
2007 (24) Republic
Maslauskiene, Medicina, 2007 (46) HD, male Lithuania DBS 0/536 0,000
Terryn, Nephrol Dial Tranplant, HD Belgium DBS 3/922 0.325 1/180 0.556 2/742 0.270
2008 (47)
Andrade, Clin J Am Soc Nephrol, CKD, HD, PD, Canada P 0/499 0.000
2008 (48) KTR, male
Porsch, Renal Failure, 2008 (49) HD, male Brazil DBS 2/558 0.358
Rasaiah, Nephrol Dial Transplant HD, PD Canada DBS 0/147 0.000 – –
Plus, 2008 (50)
Kleinert, Transpl Int, 2009 (51) KTR, male Austria DBS, L 5/1306 0.383
HD, hemodialysis; PD, peritoneal dialysis; KTR, kidney transplant recipients; P, plasma; L, leukocyte; WB, whole blood; DBS, dried blood spot.
Therapy for Fabry Disease in ESRD Patients
381
382 Clinical Journal of the American Society of Nephrology
events per 100 person years). For instance, stroke alone ac-
counted for 4.9 per 100 person years among incident dialysis
patients as recently reported by Sozio and colleagues (31).
In conclusion, Fabry patients on hemodialysis therapy suffer
from the primary Fabry-related cardiomyopathy and an addi-
tional cardiovascular risk related to uremia. ERT in this cohort
of high-risk patients has the potential to alleviate typical man-
ifestations of Fabry disease (e.g., recurrent pain crises and ab-
dominal pain) and may therefore be indicated in many patients.
The increase in LV mass is a key feature of patients with Fabry
disease and patients undergoing chronic dialysis therapy. Sup-
posing a progressive worsening of LV mass in untreated pa-
tients, it can be speculated that the increase in LV mass in
dialyzed Fabry patients may be slowed down but not reduced
by ERT, as shown for Fabry patients not on dialysis therapy
(32,33). Whether ERT is efficacious in reducing the cardiac and
cerebrovascular mortality in patients with ESRD undergoing
dialysis therapy has not been shown to date. This remains to be
elucidated in prospective end-point studies in larger patient
cohorts or by analyzing available registry data.
ERT in Kidney Transplant Recipients
Several studies have described the effects of ERT in patients
with normal renal function or with mild-to-moderate chronic
renal failure, but limited data are available on the effect of ERT
after kidney transplantation. In a pilot clinical trial, Mignani et
al. examined the safety and efficacy of ERT (agalsidase beta 1
mg/kg every other week for 18 months) in three kidney trans-
plant patients with Fabry disease and severe cardiac involve-
ment (34). In all patients, the extrarenal symptoms disappeared
within 2 months after commencing ERT. Renal function was
preserved until the end of the study without any variation of
the immunosuppressive regimens.
To further explore renal function and cardiac disease after
transplantation, a nationwide collaborative study was con-
ducted in Italy (30). Thus far, one patient of this largest study
received agalsidase alfa and 16 received agalsidase beta at the
standard dose. After 48 months of ERT, no change in renal
function was observed. Mean serum creatinine increased from
1.78 mg/dl at baseline to 1.92 mg/dl (⫹8%, P ⫽ NS) after 4
years of ERT, and mean creatinine clearance decreased from
52.9 to 45.2 ml/min (⫺15%, P ⫽ NS). The rate of decline in renal
function from baseline to the last visit was ⫺1.92 ml/min per
year. Proteinuria was less than 200 mg/d after 4 years of ERT
and 14 of the 17 patients still had a functioning kidney allograft
6 years after the survey. Two patients suffered graft failure and
returned to dialysis treatment, and ERT was stopped in one
patient for reasons unrelated to the therapy. No significant
change in Fabry cardiomyopathy was noted at study conclu-
sion. The mean LV mass index varied by 6% (from 234.6 to
220.8 g/m2, P ⫽ NS) after 3 years of ERT. However, cardiac
response to agalsidase beta treatment was not uniform; echo-
cardiography did not demonstrate an appreciable reduction in
LV mass in 2 of 11 patients that reached the 4th year follow-up.
Finally, only three cardiac or cerebrovascular events occurred
in the allograft recipients (3.12 events per 100 person years).
More recently, Cybulla et al. (35) explored the effects of
Clin J Am Soc Nephrol 5: 379 –385, 2010
agalsidase alfa in transplant patients with Fabry disease. Allo-
graft function of 20 patients from the Fabry Outcome Survey
registry was analyzed after approximately 3.5 years (median) of
agalsidase alfa therapy at the standard dose of 0.2 mg/kg every
other week. After 2 years of ERT, there was a slight but NS
increase in serum creatinine (1.4 mg/dl at baseline versus 1.6
mg/dl) and a decrease in eGFR (59.2 ml/min/1.73 m2 at base-
line versus 51.1 ml/min/1.73 m2 at 2 years). Similar to the
previously mentioned study, proteinuria remained stable dur-
ing this time period.
In summary, agalsidase alfa and beta seem to be safe and
well tolerated in renal transplant patients. However, the inabil-
ity to perform a randomized controlled study, limited longitu-
dinal follow-up given that ERT has been available for a rela-
tively short time period, and the lack of a control group
(nontreated Fabry patients or non-Fabry transplant patients)
limit the relevance of this statement; therefore, further studies
are needed to confirm these observations.
It may be tempting to hypothesize that a kidney graft in a
patient with Fabry disease undergoes accumulation of globotri-
aosylceramide related to recipient-derived cells (e.g., endothe-
lial progenitor cells), leading to some functional damage of the
transplant. However, the retrospective study by Shah et al. has
shown no worse graft survival in transplanted Fabry patients as
compared with patients with other causes of ESRD. Their find-
ings suggest that any theoretical compromise of the graft re-
lated to Fabry disease is not relevant in the context of clinical
transplantation (12).
Summary of What We Know
Patients on hemodialysis therapy are a high-risk group for
Fabry disease. Several case-finding studies using currently
available technology have revealed a considerably high preva-
lence of Fabry disease among this population (Table 1). In the
pre-ERT era, analyses of data from nontreated Fabry patients
receiving dialysis have shown that ESRD is associated with
significant morbidity and mortality as compared with diabetic
or nondiabetic dialysis patients. Studies available to date on the
effect of ERT in dialysis patients have suggested a possible
stabilization or lower progression of cardiomyopathy in treated
patients. However, the lack of a control group and the low
number of patients investigated limit the relevance of this
result.
By contrast, in non-ERT Fabry transplant patients, if com-
pared with matched controls, graft survival is similar but kid-
ney transplant recipients with Fabry disease share a higher risk
of death. However, in general transplant outcomes are more
favorable than dialysis outcomes.
Regarding specific therapy, ERT with agalsidase alfa or beta
is safe in dialysis and transplant patients, and differences in
pharmacokinetics or loss of enzyme activity have not been
observed. With regard to the effects of ERT in ESRD, several
confounding factors will have to be considered. In particular,
volume overload, arterial hypertension, and uremic toxins are
able to negatively influence the outcome of chronic kidney
disease (CKD) patients.
Clin J Am Soc Nephrol 5: 379 –385, 2010
What Do We Not Know?
The prevalence of Fabry disease among CKD stage I to IV
patients is currently not known. Furthermore, the clinical vari-
ability of Fabry disease and the current causes of death in
patients with various stages of CKD are enigmatic. No conclu-
sive histologic evidence that Fabry nephropathy recurs in allo-
grafts from non-Fabry donors has ever been presented. How-
ever, we should strengthen the use of allograft biopsies to gain
further knowledge on globotriaosylceramide deposits in trans-
planted Fabry patients.
We actually have a poor understanding of the course of the
Fabry cardiomyopathy in untreated CKD patients versus CKD
patients treated with ERT. Thus, it is largely unknown which
Fabry patients respond to ERT in terms of slowing or halting
progression of the systemic disease. Last but not least, we are
not aware of compelling indications for ERT in RRT patients
because progression of cardiomyopathy was documented dur-
ing ERT. Although patients may clinically respond to treat-
ment, we are currently not aware of a mechanism of improved
survival in RRT patients on ERT.
Patients with Fabry disease are at excess risk of developing
cardiovascular disease. Therefore, the use of angiotensin-con-
verting enzyme inhibitors or angiotensin II receptor blockers to
maximize cardioprotection is suggested to be prudent in this
patient population, particularly if patients are on RRT. These
treatments might also exert a renoprotective effect in kidney
transplant recipients.
What Can We Do with What We Do Know?
In general, we endorse case-finding studies within an orga-
nized frame among high-risk populations, such as male ESRD
patients. We should raise the awareness of this rare disease
among nephrologists and other specialists that are likely to
encounter unrecognized Fabry patients to improve early diag-
nosis. In ESRD patients, other typical clinical manifestations of
Fabry disease may be useful diagnostic clues to specifically
screen for ␣-galactosidase deficiency (36).
Regarding ERT and progression of Fabry nephropathy, we
should focus our attention on some important points: ERT
should be started early in male patients, although the body of
evidence for prevention of ESRD by early initiation of ERT
needs to be improved. Other factors of progression of renal
diseases, including arterial hypertension and proteinuria,
should be taken into account. If treatment effects are examined
in clinical studies, patients should be stratified by the level of
proteinuria, renal function, and blood pressure. In ESRD, the
positive effects of ERT are blurred by the uremic state and
kidney transplantation is the standard of care. Preemptive
transplantation should be encouraged. In general, the indica-
tion for ERT can be considered on an individual basis (e.g.,
young patients versus patients with severe multiorgan manifes-
tations).
Key Research Questions
High priority on the research agenda is to be given to the
development of a reliable screening test for women and men to
enable more effective case-finding strategies. Current causes of
Therapy for Fabry Disease in ESRD Patients 383
death in predialysis, dialysis, and transplant patients should be
examined using Fabry registries to better understand the nat-
ural course of the disease in ESRD patients, including compar-
isons of morbidity and mortality of ERT-treated and ERT-naïve
patients on RRT. Finally, we have to improve the understand-
ing of ERT outcomes in dialysis and transplant patients by
conducting randomized controlled trials and using other de-
signs, including nested case-control studies.
Appendix
Participants in the Symposium Session “Dialysis and Trans-
plantation in Fabry Disease patients” at the Official Satellite of
the World Congress of Nephrology titled “Focus on Fabry
Nephropathy: Biomarkers, Progression, and Disease Severity”,
held in Bergamo, Italy, on May 28, 2009, included the following:
R. Mignani, Rimini, Italy; S. Feriozzi, Viterbo, Italy; R.M.
Schaefer, Muenster, Germany; F. Breunig, Würzburg, Germa-
ny; J.P. Oliveira, Porto, Portugal; P. Ruggenenti, Bergamo, Italy;
G. Sunder-Plassmann, Vienna, Austria; M. Beck, Mainz, Ger-
many; A. Levin, Vancouver, Canada; I. Maya, Birmingham,
Alabama; M. Banikazemi, New York; G. Biagini, Curitiba, Bra-
zil; A. Delgado, Rio de Janeiro, Brazil; and B. Vujkovac,
Ljubljana, Slovenia. In addition to the forenamed participants,
Genzyme Corporation (one) and Shire Human Genetic Thera-
pies (three) employees were present at the meeting but had no
role in the presentations and did not influence the outcome of
the discussions.
Acknowledgments
The authors wish thank Dr. Hans Ebels of Genzyme Corporation for
language editing of the final version of the manuscript. The authors
maintained full and independent responsibility for the content of this
manuscript.
Disclosures
R.M. received honoraria, research grants, and travel grants from
Genzyme Corporation. S.F., R.S., and G.S.-P. received honoraria, re-
search grants, and travel grants from Shire Human Genetic Therapies
and Genzyme Corporation. F.B. received honoraria and research grants
from Genzyme Corporation and Shire Human Genetic Therapies. J.P.O.
received speaker fees, research grants, and travel grants from Genzyme
Corporation. P.R. has nothing to declare.
References
1. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo
A, Kampmann C, Linhart A, Sunder-Plassmann G, Ries M,
Beck M: Fabry disease defined: Baseline clinical manifes-
tations of 366 patients in the Fabry Outcome Survey. Eur
J Clin Invest 34: 236 –242, 2004
2. Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk
JM, Altarescu G, Goldfarb L, Brady RO, Balow JE, Austin
HA III, Kopp JB: Natural history of Fabry renal disease:
Influence of alpha-galactosidase A activity and genetic
mutations on clinical course. Medicine (Baltimore) 81: 122–
138, 2002
3. Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi
M, Feldt-Rasmussen U, Sims K, Waldek S, Pastores GM,
Lee P, Eng CM, Marodi L, Stanford KE, Breunig F, Wanner
384 Clinical Journal of the American Society of Nephrology
C, Warnock DG, Lemay RM, Germain DP: Females with
Fabry disease frequently have major organ involvement:
Lessons from the Fabry registry. Mol Genet Metab 93: 112–
128, 2008
4. Whybra C, Kampmann C, Willers I, Davies J, Winchester B,
Kriegsmann J, Bruhl K, Gal A, Bunge S, Beck M: Anderson-
Fabry disease: Clinical manifestations of disease in female
heterozygotes. J Inherit Metab Dis 24: 715–724, 2001
5. MacDermot KD, Holmes A, Miners AH: Anderson-Fabry
disease: Clinical manifestations and impact of disease in a
cohort of 98 hemizygous males. J Med Genet 38: 750 –760,
2001
6. MacDermot KD, Holmes A, Miners AH: Anderson-Fabry
disease: Clinical manifestations and impact of disease in a
cohort of 60 obligate carrier females. J Med Genet 38: 769 –
775, 2001
7. Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P: Life
expectancy and cause of death in males and females with
Fabry disease: Findings from the Fabry registry. Genet Med
11: 790 –796, 2009
8. Mehta A, Clarke JTR, Giugliani R, Elliott P, Linhart A, Beck
M, Sunder-Plassmann G: Natural course of Fabry disease:
Changing pattern of causes of death in FOS-Fabry Out-
come Survey. J Med Genet 46: 548 –552, 2009
9. Schiffmann R, Kopp JB, Austin HA III, Sabnis S, Moore DF,
Weibel T, Balow JE, Brady RO: Enzyme replacement ther-
apy in Fabry disease: A randomized controlled trial. JAMA
285: 2743–2749, 2001
10. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P,
Waldek S, Caplan L, Linthorst GE, Desnick RJ: Safety and
efficacy of recombinant human alpha-galactosidase A re-
placement therapy in Fabry’s disease. N Engl J Med 345:
9 –16, 2001
11. Thadhani R, Wolf M, West ML, Tonelli M, Ruthazer R,
Pastores GM, Obrador GT: Patients with Fabry disease on
dialysis in the United States. Kidney Int 61: 249 –255, 2002
12. Shah T, Gill J, Malhotra N, Takemoto SK, Bunnapradist S:
Kidney transplant outcomes in patients with Fabry dis-
ease. Transplantation 87: 280 –285, 2009
13. Schiffmann R, Warnock DG, Banikazemi M, Bultas J,
Linthorst GE, Packman S, Sorensen SA, Wilcox WR,
Desnick RJ: Fabry disease: Progression of nephropathy,
and prevalence of cardiac and cerebrovascular events be-
fore enzyme replacement therapy. Nephrol Dial Transplant
24: 2102–2111, 2009
14. Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO:
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
15. Germain DP, Waldek S, Banikazemi M, Bushinsky DA,
Charrow J, Desnick RJ, Lee P, Loew T, Vedder AC,
Abichandani R, Wilcox WR, Guffon N: Sustained, long-
term renal stabilization after 54 months of agalsidase beta
therapy in patients with Fabry disease. J Am Soc Nephrol 18:
1547–1557, 2007
16. West M, Nicholls K, Mehta A, Clarke JT, Steiner R, Beck M,
Barshop BA, Rhead W, Mensah R, Ries M, Schiffmann R:
Agalsidase alfa and kidney dysfunction in Fabry disease.
J Am Soc Nephrol 20: 1132–1139, 2009
17. Feriozzi S, Schwarting A, Sunder-Plassmann G, West M,
Cybulla M: Agalsidase Alfa Slows the Decline in Renal
Clin J Am Soc Nephrol 5: 379 –385, 2010
Function in Patients with Fabry Disease. Am J Nephrol 29:
353–361, 2009
18. Ortiz A, Oliveira JP, Waldek S, Warnock DG, Cianciaruso
B, Wanner C: Nephropathy in males and females with
Fabry disease: Cross-sectional description of patients be-
fore treatment with enzyme replacement therapy. Nephrol
Dial Transplant 23: 1600 –1607, 2008
19. Ortiz A, Cianciaruso B, Cizmarik M, Germain DP, Mignani
R, Oliveira JP, Villalobos J, Vujkovac B, Waldek S, Wanner
C, Warnock DG: End-stage renal disease in patients with
Fabry disease: Natural history data from the Fabry regis-
try. Nephrol Dial Transplant 2009 [Epub ahead of print]
20. Schiffmann R, Askari H, Timmons M, Robinson C, Benko
W, Brady RO, Ries M: Weekly enzyme replacement ther-
apy may slow decline of renal function in patients with
Fabry disease who are on long-term biweekly dosing. J Am
Soc Nephrol 18: 1576 –1583, 2007
21. Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley
CB, McDonald M, Finkel R, Packman S, Bichet DG, War-
nock DG, Desnick RJ: Agalsidase-beta therapy for ad-
vanced Fabry disease: A randomized trial. Ann Intern Med
146: 77– 86, 2007
22. Tsakiris D, Simpson HK, Jones EH, Briggs JD, Elinder CG,
Mendel S, Piccoli G, dos Santos JP, Tognoni G, Van-
renterghem Y, Valderrabano F: Report on management of
renale failure in Europe, XXVI,: Rare diseases in renal
replacement therapy in the ERA-EDTA Registry. Nephrol
Dial Transplant 11[Suppl 7]: S4 –20, 1996
23. Kotanko P, Kramar R, Devrnja D, Paschke E, Voigtlander
T, Auinger M, Pagliardini S, Spada M, Demmelbauer K,
Lorenz M, Hauser AC, Kofler HJ, Lhotta K, Neyer U,
Pronai W, Wallner M, Wieser C, Wiesholzer M, Zodl H,
Födinger M, Sunder-Plassmann G: Results of a nationwide
screening for Anderson-Fabry disease among dialysis pa-
tients. J Am Soc Nephrol 15: 1323–1329, 2004
24. Merta M, Reiterova J, Ledvinova J, Poupetova H, Dobro-
volny R, Rysava R, Maixnerova D, Bultas J, Motan J,
Slivkova J, Sobotova D, Smrzova J, Tesar V: A nationwide
blood spot screening study for Fabry disease in the Czech
Republic haemodialysis patient population. Nephrol Dial
Transplant 22: 179 –186, 2007
25. Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y,
Yoshida A, Kanzaki T, Enriquez AL, Eng CM, Tanaka H,
Tei C, Desnick RJ: Fabry disease: Detection of undiagnosed
hemodialysis patients and identification of a “renal vari-
ant” phenotype. Kidney Int 64: 801– 807, 2003
26. Ojo A, Meier-Kriesche HU, Friedman G, Hanson J, Cibrik
D, Leichtman A, Kaplan B: Excellent outcome of renal
transplantation in patients with Fabry’s disease. Transplan-
tation 69: 2337–2339, 2000
27. Pastores GM, Boyd E, Crandall K, Whelan A, Piersall L,
Barnett N: Safety and pharmacokinetics of agalsidase alfa
in patients with Fabry disease and end-stage renal disease.
Nephrol Dial Transplant 22: 1920 –1925, 2007
28. Kosch M, Koch HG, Oliveira JP, Soares C, Bianco F, Breun-
ing F, Rasmussen AK, Schaefer RM: Enzyme replacement
therapy administered during hemodialysis in patients with
Fabry disease. Kidney Int 66: 1279 –1282, 2004
29. Pisani A, Spinelli L, Sabbatini M, Andreucci MV, Procac-
cini D, Abbaterusso C, Pasquali S, Savoldi S, Comotti C,
Cianciaruso B: Enzyme replacement therapy in Fabry dis-
Clin J Am Soc Nephrol 5: 379 –385, 2010
ease patients undergoing dialysis: Effects on quality of life
and organ involvement. Am J Kidney Dis 46: 120 –127, 2005
30. Mignani R, Feriozzi S, Pisani A, Cioni A, Comotti C, Cossu
M, Foschi A, Giudicissi A, Gotti E, Lozupone VA, Marchini
F, Martinelli F, Bianco F, Panichi V, Procaccini DA, Raga-
zzoni E, Serra A, Soliani F, Spinelli L, Torti G, Veroux M,
Cianciaruso B, Cagnoli L: Agalsidase therapy in patients
with Fabry disease on renal replacement therapy: A na-
tionwide study in Italy. Nephrol Dial Transplant 23: 1628 –
1635, 2008
31. Sozio SM, Armstrong PA, Coresh J, Jaar BG, Fink NE,
Plantinga LC, Powe NR, Parekh RS: Cerebrovascular dis-
ease incidence, characteristics, and outcomes in patients
initiating dialysis: The choices for healthy outcomes in
caring for ESRD (CHOICE) study. Am J Kidney Dis 54:
468 – 477, 2009
32. Weidemann F, Breunig F, Beer M, Sandstede J, Tur-
schner O, Voelker W, Ertl G, Knoll A, Wanner C, Strot-
mann JM: Improvement of cardiac function during en-
zyme replacement therapy in patients with Fabry
disease: A prospective strain rate imaging study. Circu-
lation 108: 1299 –1301, 2003
33. Widemann F, Niemann M, Breunig F, Herrmann S, Beer M,
Störk S, Voelker W, Ertl G, Wanner C, Strotmann J: Long-
term effects of enzyme replacement therapy on Fabry car-
diomyopathy: evidence for a better outcome with early
treatment. Circulation 119: 524 –529, 2009
34. Mignani R, Panichi V, Giudicissi A, Taccola D, Boscaro
F, Feletti C, Moneti G, Cagnoli L: Enzyme replacement
therapy with agalsidase beta in kidney transplant pa-
tients with Fabry disease: A pilot study. Kidney Int 65:
1381–1385, 2004
35. Cybulla M, Walter KN, Schwarting A, Divito R, Feriozzi S,
Sunder-Plassmann G: Kidney transplantation in patients
with Fabry disease. Transpl Int 22: 475– 481, 2009
36. Öqvist B, Brenner BM, Oliveira JP, Ortiz A, Schaefer R,
Svarstad E, Wanner C, Zhang K, Warnock DG: Nephrop-
athy in Fabry disease: The importance of early diagnosis
and testing in high-risk populations. Nephrol Dial Trans-
plant 24: 1736 –1743, 2009
37. Utsumi K, Kase R, Takata T, Sakuraba H, Matsui N, Saito
H, Nakamura T, Kawabe M, Lino Y, Katayama Y: Fabry
disease in patients receiving maintenance dialysis. Clin Exp
Nephrol 4: 49 –51, 2000
38. Desnick RJ: Fabry disease: unrecognized ESRD patients
and effectiveness of enzyme replacement on renal pathol-
ogy and function. Am J Hum Genet Suppl 71: 417, 2002
39. Spada M, Pagliardini S: Screening for Fabry disease in
endstage nephropathies. J Inher Metabol Dis 25 [Suppl I]:
113, 2002
40. Pagliardini S, Canavese C, Locatelli F, Spada M: Prevalence
of Fabry disease in male patients with end-stage nephrop-
athy [Abstract]. Abstract presented at The European Sym-
posium on Fabry Disease; November 8 to 9, 2002; Athens,
Greece
41. Linthorst GE, Hollak CE, Korevaar JC, Van Manen JG,
Therapy for Fabry Disease in ESRD Patients 385
Aerts JM, Boeschoten EW: alpha-Galactosidase A defi-
ciency in Dutch patients on dialysis: a critical appraisal of
screening for Fabry disease. Nephrol Dial Transplant 18:
1581–1584, 2003
42. Rocha S, Pinto R, Dickson J, Joao Pais M, Clara Sa Miranda
M: Screening of Fabry in individuals submitted to haemo-
dialysis [Abstract]. Abstract presented at Fabry 5th Round
Table Meeting; October 22 to 23, 2004; Warsaw, Poland
43. Ichinose M, Nakayama M, Ohashi T, Utsunomiya Y, Koba-
yashi M, Eto Y: Significance of screening for Fabry disease
among male dialysis patients. Clin Exp Nephrol 9: 228 –232,
2005
44. Bekri S, Enica A, Ghafari T, Plaza G, Champenois I, Chouk-
roun G, Unwin R, Jaeger P: Fabry disease in patients with
end-stage renal failure: the potential benefits of screening.
Nephron Clin Pract 101: c33– c38, 2005
45. Tanaka M, Ohashi T, Kobayashi M, Eto Y, Miyamura N,
Nishida K, Araki E, Itoh K, Matsushita K, Hara M, Kuwa-
hara K, Nakano T, Yasumoto N, Nonoguchi H, Tomita K:
Identification of Fabry’s disease by the screening of alpha-
galactosidase A activity in male and female hemodialysis
patients. Clin Nephrol 64: 281–287, 2005
46. Maslauskiene R, Bumblyte IA, Sileikiene E, Grazulis S,
Laurinavicius A, Pleckaitis M, Alekniene D, Dobrovol-
skiene R, Vainauskas V, Juodeikiene L, Steckis R, Saka-
lauskiene M, Macius K, Urbanaviciene J, Labutiene V,
Gaupsiene E, Ziaukiene G, Burbaickaja S, Gailiu៮ nas J: The
prevalence of Fabry’s disease among male patients on he-
modialysis in Lithuania (a screening study). Medicina (Kau-
nas) 43 Suppl 1: 77– 80, 2007
47. Terryn W, Poppe B, Wuyts B, Claes K, Maes B, Verbeelen
D, Vanholder R, De Boeck K, Lameire N, De Paepe A, De
Schoenmakere G: Two-tier approach for the detection of
alpha-galactosidase A deficiency in a predominantly fe-
male haemodialysis population. Nephrol Dial Transplant 23:
294 –300, 2008
48. Andrade J, Waters PJ, Singh RS, Levin A, Toh BC, Vallance
HD, Sirrs S: Screening for Fabry disease in patients with
chronic kidney disease: limitations of plasma alpha-galac-
tosidase assay as a screening test. Clin J Am Soc Nephrol 3:
139 –145, 2008
49. Porsch DB, Nunes AC, Milani V, Rossato LB, Mattos CB,
Tsao M, Netto C, Burin M, Pereira F, Matte U, Giugliani R,
Barros EJ: Fabry disease in hemodialysis patients in south-
ern Brazil: prevalence study and clinical report. Ren Fail 30:
825– 830, 2008
50. Rasaiah VI, Underwood JP, Oreopoulos DG, Medin JA:
Implementation of high-throughput screening for Fabry
disease in Toronto dialysis patients. Nephrol Dial Transplant
Plus 1: 129 –130, 2008
51. Kleinert J, Kotanko P, Spada M, Pagliardini S, Paschke E,
Paul K, Voigtländer T, Wallner M, Kramar R, Stummvoll
HK, Schwarz C, Horn S, Holzer H, Födinger M, Sunder-
Plassmann G: Anderson-Fabry disease: a case-finding
study among male kidney transplant recipients in Austria.
Transpl Int 22: 287–292, 2009