Clinical benefit of enzyme replacement therapy in Fabry disease
Authors: F. Breunig, F. Weidemann, J. Strotmann, A. Knoll, C. Wanner
Journal: Kidney International (2006)

Enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (r-hαGalA) enhances microvascular globotriaosylceramide clearance and improves clinical symptoms in patients with Fabry disease. We evaluated whether these effects are translated into a long-term benefit of kidney and heart function. We did a single center, prospective, open label study in 26 patients with Fabry disease (one early death, follow-up in 25 patients). r-α-GalA was administered in a dosage of 1 mg/kg body weight every second week. The effect of therapy on clinical end points (death, cardiac and cerebrovascular event, renal failure), cardiac and renal function monitored by Doppler echocardiography, 99Tc-GFR, and proteinuria was investigated. After a mean treatment time of 23±8 months, nine patients experienced 12 end points, including two deaths. All end points occurred in patients with impaired renal function (n=16; GFR 71±17 ml/min/1.73 m2). Despite ERT, renal function deteriorated to 60±23 ml/min/1.73 m2 (P=0.04) and left ventricular posterior wall thickness (PWT) did not change (14.0±2.1 vs 13.4±2.3 mm). In contrast, patients without impairment of renal function (n=9) had a more favorable outcome (no clinical events; GFR 115±18 vs 102±14 ml/min/1.73 m2, NS; PWT 11.7±1 and 10.7±0.7 mm, P=0.04). Proteinuria remained unchanged (1.34±0.94 vs 1.01±0.97 g/day, n=10). Patients with impaired renal function have a less favorable outcome and may develop cardiovascular and renal end points despite ERT. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (r-hαGalA) enhances microvascular globotriaosylceramide clearance and improves clinical symptoms in patients with Fabry disease. We evaluated whether these effects are translated into a long-term benefit of kidney and heart function. We did a single center, prospective, open label study in 26 patients with Fabry disease (one early death, follow-up in 25 patients). r-α-GalA was administered in a dosage of 1 mg/kg body weight every second week. The effect of therapy on clinical end points (death, cardiac and cerebrovascular event, renal failure), cardiac and renal function monitored by Doppler echocardiography, 99Tc-GFR, and proteinuria was investigated. After a mean treatment time of 23±8 months, nine patients experienced 12 end points, including two deaths. All end points occurred in patients with impaired renal function (n=16; GFR 71±17 ml/min/1.73 m2). Despite ERT, renal function deteriorated to 60±23 ml/min/1.73 m2 (P=0.04) and left ventricular posterior wall thickness (PWT) did not change (14.0±2.1 vs 13.4±2.3 mm). In contrast, patients without impairment of renal function (n=9) had a more favorable outcome (no clinical events; GFR 115±18 vs 102±14 ml/min/1.73 m2, NS; PWT 11.7±1 and 10.7±0.7 mm, P=0.04). Proteinuria remained unchanged (1.34±0.94 vs 1.01±0.97 g/day, n=10). Patients with impaired renal function have a less favorable outcome and may develop cardiovascular and renal end points despite ERT. Fabry disease is a life-threatening X-linked lysosomal storage disorder due to a variety of mutations in the gene encoding for the lysosomal enzyme α-Galactosidase A (α-GalA). The resulting deficiency of α-GalA causes progressive intracellular accumulation of glycosphingolipids, mainly globotriaosylceramides (GL3). In childhood, the disease presents with acroparaesthesia, angiokeratoma, and anhidrosis. Further accumulation of GL3 in cells of the kidney, heart, and nervous system culminates in progressive organ failure.1.Desnick R.J. Ioannou Y.A. Eng C.M. Alpha galactosidase deficiency: Fabry disease.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 8th edn. Mac Graw-Hill, New York2001: 3733-3774Crossref Google Scholar In affected males, severe morbidity is caused by heart failure, arrhythmias, stroke, or end-stage renal disease.1.Desnick R.J. Ioannou Y.A. Eng C.M. Alpha galactosidase deficiency: Fabry disease.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 8th edn. Mac Graw-Hill, New York2001: 3733-3774Crossref Google Scholar, 2.Branton M.H. Schiffmann R. Kopp J.B. Natural history and treatment of renal involvement in Fabry disease.J Am Soc Nephrol. 2002; 13: 139-143PubMed Google Scholar Enzyme replacement therapy (ERT) with recombinant human α-GalA (r-hαGalA) reduces lysosomal GL3 deposition. Phase I and II clinical trials demonstrated safety and efficacy.3.Eng C.M. Banikazemi M. Gordon R.E. et al.A phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies.Am J Hum Genet. 2001; 68: 711-722Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 4.Schiffmann R. Murray G.J. Treco D. et al.Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.Proc Natl Acad Sci USA. 2000; 97: 365-370Crossref PubMed Scopus (333) Google Scholar A randomised, double-blind and placebo-controlled multicenter study with 1 mg/kg r-hαGalA in 58 patients showed a nearly complete clearance of GL3 in vascular endothelium of kidneys, heart, and skin.5.Eng C.M. Guffon N. Wilcox W.R. et al.Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease.N Engl J Med. 2001; 345: 9-16Crossref PubMed Scopus (1390) Google Scholar, 6.Thurberg B.L. Rennke H. Colvin R.B. et al.Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy.Kidney Int. 2002; 62: 1933-1946Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar Subsequently patients were enrolled in an open label extension trial and continued safety and efficacy in respect to stabilization of serum creatinine and sustained GL3 clearance in capillary endothelium of skin specimens was demonstrated.7.Wilcox W.R. Banikazemi M. Guffon N. et al.Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.Am J Hum Genet. 2004; 75: 65-74Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar Another controlled study demonstrated a decline of neuropathic pain.8.Schiffmann R. Kopp J.B. Austin H.A. et al.Enzyme replacement therapy in Fabry disease: a randomized controlled trial.JAMA. 2001; 285: 2743-2749Crossref PubMed Scopus (1125) Google Scholar However, the clinical benefit of ERT in Fabry patients with multiple organ involvement, such as cardiomyopathy and chronic kidney disease over prolonged periods of time, is unknown. Aim of this study was to evaluate the impact of ERT on heart and kidney function in a group of 26 patients with different stages of Fabry disease. In total, 26 patients with Fabry disease were found eligible for ERT because of severe symptoms and organ manifestation after diagnosis had been confirmed by measurement of α-GalA activity in serum and by mutational analysis. Results of enzyme activity and mutational analysis have previously been described in a subgroup of 16 patients.9.Weidemann F. Breunig F. Beer M. et al.Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease.Circulation. 2003; 108: 1299-1309Crossref PubMed Scopus (344) Google Scholar Two sisters (patients no. 10 and 24, see Table 1b) with proteinuria and clinical symptoms underwent renal biopsy and widespread GL3 deposition within the glomeruli justified inclusion into this study. One patient died after 10 months of ERT prior to follow-up evaluation. Baseline data of this patient are not included in this study. A history of acroparesthesia was reported in 23 patients, hypohidrosis was documented in 18 patients and angiokeratoma were found in 23 patients. At presentation, eight patients had chronic kidney disease stages 4 or 5, five patients were on renal replacement therapy; two on hemodialysis treatment since 5 and 7 years respectively, and three patients had received a kidney graft 2, 3, and 12 years ago. Mean age of the nine patients with a GFR>90 ml/min2 was 39±7.7 years. Those with GFR<90 ml/min2 were 43±9.5 years old (n=16). There was no significant correlation between age and GFR. Concomitant drug therapy at baseline consisted of diuretics (n=7), aspirin (n=7), ACE inhibitors and Angiotensin-I blocker (n=6), β blocker (n=4), non-dihydropyridine calcium channel blocker (n=2), and statins (n=1) and was continued throughout the study (see Tables 1a and b). Among the 12 patients who were classified as hypertensive, five were well controlled and achieved target blood pressure below 130/80 mmHg, seven had values above 130/80 mmHg (mean blood pressure 110±24/74±11 and 147±10/91±9 mmHg respectively). Blood pressure was normal in the remaining patients (119±17/80±11 mmHg). Serum concentration of total cholesterol and low-density lipoprotein cholesterol at baseline was 194±38 and 114±30 mg/dl, respectively. There was no significant change at follow-up (185±33 and 103±44 mg/dl). Statins were taken by one patient. Antihypertensive and antiproteinuric medication and baseline characteristics of the patients as well as major manifestation of the disease are presented in Tables 1a and b.Table 1aPatient demographic and clinical data at baselinePat./Sex/FamilyFollow-up in monthsAge at diagnosis/onset of therapyMajor organ manifestation1/m/I2543/43P, LVH, AH2/m/II3444/53P, LVH, VP, AH, CAD, CVS3/m/III3739/41P, LVH, AH, CVS4/m/IV2949/50P, LVH, AH, CAD, CABG, CVS5/m/V1831/33P, LVH, AH, CVS6/m/VI1236/41P, VP, PAD7/m/VII2433/34P, LVH, VP, CVS8/m/VI3342/46P, LVH, VP, AF9/m/V1329/29P, LVH, VP10/f/VII2342/43P11/m/VII2633/34P, LVH, VP12/m/VIII2430/30P, LVH, AH, CVS13/f/II1354/54P, LVH, VP14/m/XI1137/37P15/m/II2824/32KTX, LVH, VP, AH16/m/II3641/50KTX, LVH, VP, Stroke17/m/IX2328/55KTX, LVH, VP, PM, CAD, CABG, Stroke18/m/X2524/34ESRD, LVH, VP, AH19/m/XII1536/37ESRD20/f/V1456/57LVH, VP21/f/X3355/55LVH, AH22/m/VIII2427/31LVH23/f/XIII1224/39AH, CVS24/f/VII2339/40—25/m/XIV1331/38—m, male; f, female; P, 24 h proteinuria>30 mg; LVH, left ventricular hypertrophy; AH, arterial hypertension; VP, valvulopathy; CAD, coronary artery disease; CVS, cerebrovascular symptoms; CABG, coronary artery bypass graft; PAD, peripheral arterial disease; AF, atrial fibrillation; KTX, kidney transplantation; PM, pace maker; ESRD, end-stage renal disease. Open table in a new tab Table 1bPatient clinical data at baseline and follow-upGFR (ml/min/1.73 m2)Proteinuria (mg/day)Concomitant therapyBlood pressure (systolic/diastolic in mmHg)Pat./Sex/FamilyBsFuBsFuBsFuBsFu1/m/I7aGFR calculated by the MDRD equation.ESRDb0.5 month after initiation of enzyme replacement therapy.3402NAACE—130/80130/802/m/II48263020333BBACE, BB, D120/6080/603/m/III41aGFR calculated by the MDRD equation.3623003122BB, DACE, CCB125/88160/814/m/IV11aGFR calculated by the MDRD equation.ESRDc3 month after initiation of enzyme replacement therapy.2132NAACE, CCBACE, BB, D142/82105/705/m/V24ESRDd6 month after initiation of enzyme replacement therapy.2030NAACE, DACE153/101140/706/m/VI817117521060——108/7690/507/m/VII978715502263——134/79133/878/m/VI82651293321D, CCBARB, BB, D122/83125/969/m/V113101500<30——167/82128/8510/f/VII126104302338—ACE130/80116/8311/m/VII106110169359D—128/91130/7312/m/VIII878866<30——161/88153/9913/f/II951136371180—ACE101/70124/9714/m/XI1231211914862—ACE132/92144/7915/m/II56KTX46KTX60KTX<30KTXARBARB103/77160/8516/m/II81KTX118KTX<30KTX<30KTXDARB, A, D104/79110/6017/m/IX50KTX43KTX<30KTX<30KTXACE, DACE, D108/77140/7018/m/XESRD49KTXESRD<30—ACE, BB120/90120/7019/m/XIIESRDNAESRDNA——115/5394/5720/f/V7882<30287BBBB133/92159/8421/f/X7339<30<30DACE, D153/105116/8522/m/VIII8073<30<30BB—120/85124/8523/f/XIII14278<30<30ARBARB150/90120/7024/f/VII135114<30<30——105/98114/9025/m/XIV9393<30<30——108/73127/96GFR, glomerular filtration rate; Bs, baseline; Fu, follow-up; m, male; f, female; ESRD, end-stage renal disease CKD V; ESRD, developed; KTX; kidney transplantation; NA, not analyzed; ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin-II receptor blocker; BB, beta blocker; A, amiodarone (active agent); CCB, calcium channel blocker; D, diuretic.a GFR calculated by the MDRD equation.b 0.5 month after initiation of enzyme replacement therapy.c 3 month after initiation of enzyme replacement therapy.d 6 month after initiation of enzyme replacement therapy. Open table in a new tab m, male; f, female; P, 24 h proteinuria>30 mg; LVH, left ventricular hypertrophy; AH, arterial hypertension; VP, valvulopathy; CAD, coronary artery disease; CVS, cerebrovascular symptoms; CABG, coronary artery bypass graft; PAD, peripheral arterial disease; AF, atrial fibrillation; KTX, kidney transplantation; PM, pace maker; ESRD, end-stage renal disease. GFR, glomerular filtration rate; Bs, baseline; Fu, follow-up; m, male; f, female; ESRD, end-stage renal disease CKD V; ESRD, developed; KTX; kidney transplantation; NA, not analyzed; ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin-II receptor blocker; BB, beta blocker; A, amiodarone (active agent); CCB, calcium channel blocker; D, diuretic. Twenty-five patients were evaluated after a mean observation time of 23±8 months (range 12–37 months) during ERT. In general, ERT was well tolerated. No serious side effects occurred. Most patients reported fatigue like symptoms up to 12 h after infusion. Chills and shivering during enzyme administration were observed occasionally in six patients, one was temporarily treated with oral steroids. No patient had to stop or discontinue the treatment. During treatment gastrointestinal symptoms, such as abdominal pain and diarrhea, improved markedly. Increases of sweat production in specific areas such as axillas or feet, together with a decrease of neuropathic pain, were reported. Patients also reported weight gain. Body mass index (kg/m2) increased from 25.3±6.5 to 27.3±6.9 (P=0.02) in patients with normal kidney function, whereas there was no change in patients with impaired kidney function (22.7±3.2 vs 23.3±3.7). Overall NYHA classes did not change significantly (Table 2).Table 2Baseline and follow-up data of 25 patients with a GFR>90 ml/min/1.73 m2 and a GFR<90 ml/min/1.73 m2GFR>90 ml/min/1.73 m2 (n=16)GFR<90 ml/min/1.73 m2 (n=16)BaselineFollow-upPBaselineFollow-upPProteinuriaaProteinuria>100 mg/day. (mg/day)845±714bn=6.834±8160.962091±743cn=4.1024±12160.3SCrea (mg/dl)0.79±0.130.80±0.120.721.2±0.42dn=8.1.44±0.80.09GFR (ml/min/1.73 m2)115±18102±140.1571±17dn=8.60±230.039PWT (mm)11.7±1.010.7±0.70.01714.0±2.113.4±2.30.22FS (%)35±1041±40.0934±837±70.48WTF (%)30±1443±160.0742±1736±200.26NYHA class1.2±0.51.6±0.50.191.5±0.61.8±0.80.2BMI (kg/m2)25.3±6.527.3±6.90.03922.7±3.223.3±3.70.24GFR, glomerular filtration rate; SCrea, serum creatinine; PWT, posterior wall thickness; FS, fraction of shortening; WTF, wall thickening fraction; NYHA, New York Heart Association; BMI, body mass index.Patients with end-stage renal disease (n=8) were excluded for proteinuria, SCrea, and GFR measurements.a Proteinuria>100 mg/day.b n=6.c n=4.d n=8. Open table in a new tab GFR, glomerular filtration rate; SCrea, serum creatinine; PWT, posterior wall thickness; FS, fraction of shortening; WTF, wall thickening fraction; NYHA, New York Heart Association; BMI, body mass index. Patients with end-stage renal disease (n=8) were excluded for proteinuria, SCrea, and GFR measurements. A total number of 12 events were detected in nine patients during ERT. All events were exclusively observed in patients with impaired kidney function. Two deaths occurred, one at 10 months after enrolment due to heart failure (heart weight 820 g) while on hemodialysis treatment since 12 months and another at 14 months due to mesenteric infarction with extensive bowel necrosis. Causes of death were confirmed by autopsy. Initiation of hemodialysis treatment was required in two male patients who presented initially with chronic kidney disease stage 4. Episodes of vertigo and ataxia, followed by a transitory ischemic attack, were observed in one patient. Cardiac events consisted of myocardial infarction with subsequent coronary intervention (one patient), coronary artery bypass grafting (one patient), cardiac pacemaker implantation (two patients), and new onset of atrial fibrillation in two females (see Tables 1a and b). Echocardiography showed that LV end-diastolic posterior wall thickness (PWT) averaged 11.7±1.0 at baseline and decreased significantly to 10.7±0.7 mm after treatment in patients with preserved kidney function (P=0.017). A reduction of PWT from 14.0±2.1 to 13.4±2.3 mm was also observed in patients with impaired kidney function but did not reach significance (see Table 2). Patients with impaired baseline kidney function had a significant more pronounced LV hypertrophy (14.0±2.1 vs 11.7±1.0 mm, P=0.005). Left ventricular fractional shortening and wall thickening-fraction (WTF), as a parameter for regional myocardial function of the posterior wall, were within normal range at baseline and remained stable during the study period in all patients (see Table 2 for details). The 6 female patients showed a reduction of PWT from 13.2 to 11.7 mm and WTF was unchanged (27±12 vs 28±12%). GFR measurements and 24 h urinary protein excretion at baseline and follow-up were carried out in 20 patients, three of them with a functioning kidney graft. Two patients who were on hemodialysis treatment at baseline and three patients who progressed to end-stage renal disease 0.5, 3, and 6 months after the onset of ERT were excluded from the GFR measurements. Since it is believed that α-GalA production by the grafted kidney is sufficient to prevent local GL3 accumulation, we did not expect functional impairment and a change in proteinuria in transplanted patients due to Fabry disease. Among the remaining 17 patients, nine had a baseline GFR above 90 ml/min/1.73 m2 and eight below 90 ml/min/1.73 m2. In patients with normal kidney function, GFR was measured with a mean of 115±18 ml/min/1.73 m2, which declined to 102±14 ml/min/1.73 m2 (NS). In the remaining patients, mean GFR at presentation was 71±17 ml/min/1.73 m2 and deteriorated significantly to 60±23 ml/min/1.73 m2 (P=0.04). Accordingly, serum creatinine remained stable (0.79±0.13 vs 0.80±0.12 mg/dl) in the first group and tended to increase in the latter group without reaching significance (1.2±0.4 vs 1.4±0.7 mg/dl, P=0.09). In female patients (n=6), GFR declined from 108±30 to 94±30 ml/min/1.73 m2 mainly due to deterioration of GFR in two patients (73–39 and 143–78 ml/min/1.73 m2, respectively). On biopsy, both showed an involvement of podocytes and mesangial cells but no endothelial GL3 deposition. The amount of chronic damage in tubulo-interstitial tissue was 15–20% in the first patient. The latter patient showed no glomerulosclerosis but immune staining was positive for IgA suggesting additional IgA nephritis. At baseline, proteinuria was present in 12 of 19 patients not on renal replacement therapy (mean 1.57±1.05 g/day). There was a significant difference at baseline for patients with normal and impaired kidney function (0.85±0.72, n=6 and 2.3±0.79 g/day, n=6; P=0.007). Two patients with heavy baseline proteinuria and CKD stage 4 progressed to end-stage renal disease and could not be included in follow-up evaluation. For the remaining 10 patients, proteinuria did not change significantly during treatment period (1.34±0.94 vs 1.01±0.97 g/day). There was no significant change in proteinuria during treatment period in either group (Table 2). Table 1a and b outlines single 24 h urinary protein excretion of patients. Seven patients had biopsies in our center (three male and four female patients) before the start of ERT. The male patients had glomerulosclerosis of less than 5, 15–20, and 35–40% and showed, apart from podocyte and mesangial involvement, GL3 deposits in the vascular endothelium. There was only one female patient who showed glomerulosclerosis (15–20%), all had podocyte and mesangial GL3 deposits but no endothelial involvement. A correlation in respect to glomerulosclerosis and the course of kidney function under ERT could not be detected. The patient who died after 14 months of ERT due to mesenteric infarction had no GL3 depositions in his vascular endothelium of the mesenteric vessels, coronary, and glomerular arteries. However, there was significant GL3 detection in the lamina muscularis of the mesenteric artery and in the podocytes of the kidney. The patient who died after 10 months of ERT, due to sudden cardiac death, had only a slight general arteriosclerosis but a high-grade stenosis of the right coronary artery. No endothelial GL3 deposits could be detected. There was a massive LV hypertrophy (PWT of 19 mm) and a markedly dilated left and right ventricle of the heart. Treatment of Fabry disease with r-hαGalA can reverse substrate storage in the lysosome. Prospective clinical trials in patients with mild to moderate disease have demonstrated GL3 clearance from different cells of skin, heart, and the kidney as surrogate end points in parallel with an improvement of symptoms. This study enrolled a cohort of 26 patients with moderate to very advanced Fabry disease and investigated whether cellular GL3 clearance is followed by a long-term benefit. One might anticipate that response to ERT may differ depending on the stage of organ involvement at initiation of treatment. The main findings of the present study were that patients with renal dysfunction at study entry also displayed more severe cardiac hypertrophy as assessed by left ventricular wall thickness. It was striking to see that only patients with impaired renal function developed devastating end points. There were clear differences in the response to ERT depending on the baseline characteristics of the patients. GFR as well as myocardial hypertrophy was not stabilized in those patients with impaired kidney function at baseline. In accordance with published data, we observed a reduction of posterior left ventricular wall thickness during ERT in patients with normal kidney function.7.Wilcox W.R. Banikazemi M. Guffon N. et al.Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.Am J Hum Genet. 2004; 75: 65-74Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar, 9.Weidemann F. Breunig F. Beer M. et al.Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease.Circulation. 2003; 108: 1299-1309Crossref PubMed Scopus (344) Google Scholar How should these data be interpreted in respect to the positive results from the Fabrazyme® phase 3 and phase 3 open label extension study?5.Eng C.M. Guffon N. Wilcox W.R. et al.Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease.N Engl J Med. 2001; 345: 9-16Crossref PubMed Scopus (1390) Google Scholar, 7.Wilcox W.R. Banikazemi M. Guffon N. et al.Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.Am J Hum Genet. 2004; 75: 65-74Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar Of note is the comparatively young age of the patients (on average 30 years) in these studies, whereas the average age of our patients was 41 years. According to natural history data, most Fabry patients have already developed chronic kidney disease by the age of 40 years.10.Colombi A. Kostyal A. Bracher R. et al.Angiokeratoma corporis diffusum—Fabry's disease.Helv Med Acta. 1967; 34: 67-83PubMed Google Scholar, 11.Branton M.H. Schiffmann R. Sabnis S.G. et al.Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course.Medicine. 2002; 81: 122-138Crossref PubMed Scopus (376) Google Scholar, 12.Thadani R. Wolf M. West M.L. et al.Patients with Fabry disease on dialysis in the United States.Kidney Int. 2002; 61: 249-259Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar In our group, eight of the 26 patients required renal replacement therapy and five others had severe renal involvement, documented by pronounced proteinuria. Baseline kidney function in the phase 3 and phase 3 extension study was entirely normal.5.Eng C.M. Guffon N. Wilcox W.R. et al.Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease.N Engl J Med. 2001; 345: 9-16Crossref PubMed Scopus (1390) Google Scholar, 7.Wilcox W.R. Banikazemi M. Guffon N. et al.Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.Am J Hum Genet. 2004; 75: 65-74Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar Subgroup analysis of the study by Wilcox et al.7.Wilcox W.R. Banikazemi M. Guffon N. et al.Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.Am J Hum Genet. 2004; 75: 65-74Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar revealed that three of 58 patients had an increase of more than 50% in their serum creatinine levels during follow-up over 36 months. Common clinical characteristics of the three patients were renal scarring and sclerosis of more than 50% of their glomeruli, an age above 40, and a urinary protein/urinary creatinine ratio greater than or equal to 2. Thus, we can assume that the patients displaying renal impairment in our cohort would also represent advanced and/or irreversible histological kidney damage. The anticipation that rapid lysosomal clearance of GL3 from the glomerulus or the interstitium will translate into regression or remission of kidney disease may hold true in early stages of the disease. Advanced stages with remodelling of organ architecture, matrix accumulation, and deposition, may not respond to ERT, if at all during prolonged treatment. Certainly, the design of the phase 2 and 3 trials did not allow detecting improvements of kidney function during treatment, since function was normal at baseline and proteinuria was absent. Branton et al. followed the natural history of a series of patients demonstrating a progression from the onset of chronic renal insufficiency to end-stage renal disease during 4 years.11.Branton M.H. Schiffmann R. Sabnis S.G. et al.Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course.Medicine. 2002; 81: 122-138Crossref PubMed Scopus (376) Google Scholar Fourteen patients had an average loss of mean GFR of 12.2 ml/min/year. This loss of renal function over time is comparable with that seen in patients with diabetic nephropathy not receiving angiotensin antagonist therapy and faster than a number of other renal diseases, including many forms of glomerulonephritis.13.Ruggenenti P. Perna A. Gherardi G. et al.Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury.Am J Kidney Dis. 2000; 35: 1155-1165Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar Given that, we suggest that the GFR loss of 5.8 ml/min/year in the severely affected patients of the cohort studied here might represent a slowing of disease progression. On the other hand, excluding two nonprogressors with a borderline baseline GFR (Pat. 12, GFR 87 ml/min/1.73 m2 and Pat. 20, GFR 78 ml/min/1.73 m2), GFR decline of the remaining patients was 9 ml/min/year. However, the small number of patients studied and the limited observation time does not allow firm conclusions from this comparison. The results observed in our patients with mildly impaired or normal renal function are encouraging and are in agreement with the data reported by Eng et al.5.Eng C.M. Guffon N. Wilcox W.R. et al.Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease.N Engl J Med. 2001; 345: 9-16Crossref PubMed Scopus (1390) Google Scholar and Wilcox et al.7.Wilcox W.R. Banikazemi M. Guffon N. et al.Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.Am J Hum Genet. 2004; 75: 65-74Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar as well as registry data recently published by Beck and co-workers.14.Beck M. Ricci R. Widmer U. et al.Fabry disease: overall effects of agalsidase alfa treatment.Eur J Clin Invest. 2004; 34: 838-844Crossref PubMed Scopus (202) Google Scholar Proteinuria was present in overall 12 patients and was significantly higher in patients with impaired kidney function indicating a more advanced stage of kidney disease. Notably, among the five patients with the highest levels of proteinuria, three progressed to end-stage renal disease within the observation period. However, there was no significant change in proteinuria during treatment period regardless of kidney function. Recently, consensus has been achieved to combine enzyme replacement with cardiovascular and renoprotective co-medications, where needed.15.Desnick R.J. 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. 2003; 138: 338-346Crossref PubMed Scopus (605) Google Scholar This recommendation is based on good clinical care or treatment guidelines for cardiologists and nephrologists in general. However, standard treatment of proteinuria with angiotensin antagonist therapy in Fabry patients has not yet been attempted systematically and should be subject to further studies. Development of cardiomyopathy without renal damage has led to the discovery of a so-called cardiac variant and vice versa renal variants have been described recently.16.von Scheidt W. Eng C.M. Fitzmaurice T.F. et al.An atypical variant of Fabry's disease with manifestations confined to the myocardium.N Engl J Med. 1991; 324: 395-399Crossref PubMed Scopus (346) Google Scholar, 17.Nakao S. Kodama C. Takenaka T. et al.Fabry disease: detection of undiagnosed hemodialysis patients and identification of a 'renal variant' phenotype.Kidney Int. 2003; 64: 801-807Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar However, a combination of kidney and heart disease, demonstrated by left ventricular hypertrophy, was present in most of the patients, which is in accordance with existing literature.18.Pieroni M. Chimenti C. Ricci R. et al.Early detection of Fabry cardiomyopathy by tissue Doppler imaging.Circulation. 2003; 107: 978-984Crossref PubMed Scopus (217) Google Scholar, 19.Linhart A. Palecek T. Bultas J. et al.New insights in cardiac structural changes in patients with Fabry's disease.Am Heart J. 2000; 139: 1101-1108Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar Echocardiography demonstrated a significant decrease in left ventricular wall thickness during therapy only in the patients with less severe kidney involvement. Routine parameters of global LV-function failed to show any impairment of global systolic left ventricular function at baseline and follow-up regardless of baseline kidney function. This leads to the hypothesis, parallel to the observation in renal disease, that cardiac involvement cannot be reversed once cardiomyocyte infiltration exceeds certain limits. This is supported by biopsy studies showing cardiomyocytes with perinuclear GL3 deposits and interstitial widening due to intercellular fibrosis, which was more pronounced in patients with LVH.20.Sachdev B. Takenaka T. Teraguchi H. et al.Prevalence of Anderson–Fabry disease in male patients with late onset hypertrophic cardiomyopathy.Circulation. 2002; 105: 1407-1411Crossref PubMed Scopus (484) Google Scholar Another question is the relation between the occurrence of clinical end points and the extent of renal dysfunction or cardiac hypertrophy as surrogate parameters of disease severity at baseline. In this study, a striking distinction between those with renal impairment and cardiac hypertrophy and those with less severe disease affection was found. Not a single patient with normal kidney function reached a clinical end point. In contrast, nine of 16 patients with a GFR below 90 ml/min experienced 12 end points during treatment. This supports the assumption that ERT cannot profoundly influence disease progression and clinical outcome once the damage from the underlying disease is far advanced.21.Kampmann C. Baehner F. Whybra C. et al.Cardiac manifestations of Anderson–Fabry disease in heterozygous females.J Am Coll Cardiol. 2002; 40: 1668-1674Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar The definite answer can be given by a randomized controlled trail in this subgroup of patients. First clinical data from a controlled trial indicate that ERT may slow the progression of kidney disease significantly (S Waldek, personal communication). Vice versa, patients with normal renal function experienced considerable weight gain during treatment, a sensitive parameter of well being. The subgroup of six female patients participating in this study showed a good response to ERT in respect to reduction of LV mass. Kidney function was normal at baseline and remained stable over the study period except of two patients, one with renal sclerosis about 20% and another one with concomitant IgA nephritis. However, we also want to point out that recent data suggest that although X-linked, many women may be affected more severely than assumed in the past.22.Breunig F. Wanner C. Enzyme replacement therapy for Fabry disease: proving the clinical benefit.Nephrol Dial Transplant. 2003; 18: 7-9Crossref PubMed Scopus (16) Google Scholar One limitation of the present study is the lack of a control group. However, patients were referred for evaluation and initiation of treatment, shortly after publications of the phase 2/3 trials and approval of ERT in Europe,5.Eng C.M. Guffon N. Wilcox W.R. et al.Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease.N Engl J Med. 2001; 345: 9-16Crossref PubMed Scopus (1390) Google Scholar, 8.Schiffmann R. Kopp J.B. Austin H.A. et al.Enzyme replacement therapy in Fabry disease: a randomized controlled trial.JAMA. 2001; 285: 2743-2749Crossref PubMed Scopus (1125) Google Scholar and it was not in accordance with ethical considerations to enrol patients into a placebo treatment arm. Although the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers as a possible confounding factor cannot be excluded, a statistically significant impact between specific co-medication, blood pressure, and PWT could not be detected. As the present study has an explorative design, a composite primary end point was not specified a priori. A second limitation is the inclusion of patients on hemodialysis treatment in the evaluation of LV-hypertrophy regression. Additional risk factors for LVH may have been operative, such as anemia and hypertension, which may have counterbalanced some of the effects ERT has exerted on the left ventricle. However, hypertension was well controlled and average hemoglobin levels were normal throughout the study. In summary, patients with Fabry disease at the stage of severe organ involvement and impaired renal function may develop cardiovascular and renal end points despite ERT. There are potential benefits of ERT in patients with less advanced disease manifestation. Due to high costs of ERT, physicians hesitate to start treatment early during the course of the disease. Although lacking a control group, the present results of this study suggest that ERT should be started best before proteinuria, LVH, or any other organ involvement has developed in order to preserve kidney and cardiac function prior to irreversible organ damage. Twenty six patients (six females), mean age 41.4±8.9 years (range 29–57), with known Fabry disease were consecutively referred to the outpatient clinic of the University Hospital, Würzburg between June 2001 and August 2003. Diagnosis was made at a mean age of 37.3±9.4 years by kidney (n=7) or cardiac biopsy (n=1), through family screening (n=11), by diagnosis of angiokeratoma (n=3), by neurological examination (n=2), cornea verticillata (n=1), or blood spot screening and measurement of α-GalA activity (n=3). Patients received baseline and follow-up evaluation using a standardized protocol as described previously.23.Breunig F. Weidemann F. Beer M. et al.Fabry disease: diagnosis and treatment.Kidney Int. 2003; 63: 181-185Abstract Full Text Full Text PDF Scopus (40) Google Scholar Nine patients had normal kidney function with a GFR above 90 ml/min/1.73 m2 whereas GFR was impaired in 16 patients (<90 ml/min/1.73 m2), including those necessitating renal replacement therapy. End-diastolic (WTed) and end-systolic (WTes) wall thickness of the posterior wall as well as fractional shortening was measured using standard M-mode echocardiographical methods from parasternal long axis views (GE Vingmed System V, Horten, Norway; 2.5 MHz). WTF, as a parameter for regional myocardial function of the posterior wall, was calculated by WTF=[(Wtes–WTed)/WTed] × 100. All examinations were carried out on the same device by the same investigator. Measurements were recorded and analyzed by one physician blinded to patients and time of examination. Renal function testing consisted of glomerular filtration rate assessment by clearance of Technetium-99 m labelled DTPA (99Tc DTPA). A complete urine analysis was carried out and 24 h urine was collected to determine urinary protein excretion. The MDRD equation was used to estimate the GFR in three patients where DTPA clearance was not available at baseline. r-hαGalA (agalsidase β; Fabrazyme®, Genzyme, Cambridge, MA, USA) was administered intravenously at a dose of 1 mg/kg of body weight. Infusions were given every second week and started at an initial rate of 0.3 mg/min, which was gradually raised to 0.6 mg/min. Medical history, physical examination, and routine blood tests were performed at each visit. Blood pressure, heart rate, and body temperature were taken before and after every infusion. All patients were restudied every 12 months. The study was carried out according to 'The Declaration of Helsinki Principles' of 1964, as last revised in Edinburgh in October 2000, and was approved by the local Ethics Committee. Informed consent was given by all participating patients. Clinical end points consisted of death, implementation of renal replacement therapy, cerebrovascular event (defined as transitory ischemic attack and stroke), and cardiac event (defined as myocardial infarction, percutaneous coronary intervention, coronary bypass grafting, and any arrhythmia or pace maker implantation). Data are presented as mean±standard deviation of mean. Differences between baseline and follow-up (mean of 22.7±8.2 months) were tested using two tailed, paired Student's t-test. A P-value<0.05 was considered to indicate significance. Univariate regression analysis was carried out for blood pressure, medication with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to detect possible influence on PWT.