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• W2012140802 abstract "A 37-year-old male was referred in 1999 for evaluation of proteinuria and a serum creatinine of 1.8 mg−1. He was asymptomatic. Apart from hyperlipidemia, there was no history of diabetes, hypertension, macroscopic hematuria, or family history of renal disease or any inheritable disorder. On evaluation the patient was in good heath and a review of systems was unremarkable. His weight was 70 kg, blood pressure was 115/75 mm Hg, pulse rate was 78, and temperature was 36°C. The physical examination was remarkable because of two reddish angiectasias of about 3 mm of diameter in the trunk, which blanched under pressure and was compatible with the diagnosis of angiokeratomas. Urinalysis showed a pH of 5.4, osmolality 478 mosm kg−1, protein 116 mg dl−1, negative ketones, and normal microscopic findings. Twenty-four-hour urine collection showed protein excretion of 2.4 g, with a creatinine clearance of 41 ml 17:41 ml min−1 1.73 m−2. Serum and urine protein electrophoresis were negative for a monoclonal protein. His serum albumin level was normal at 4 g dl−1. Other test results were normal or negative, including complement, antineutrophil cytoplasmic antibody, anti-DNA antibody, and hepatitis serology results. Renal ultrasound showed normal size kidneys, bilaterally. To ascertain the cause of his proteinuria, a renal biopsy was performed. Light-microscopy examination showed focal and segmental glomerulosclerosis (5/10 glomeruli totally sclerosed), as well as patchy interstitial fibrosis and tubular atrophy. Glomerular visceral epithelial cells showed cytoplasmic vacuolization, which was also present focally within tubular epithelial cells. No immune deposits were detected by immunofluorescence microscopy. Electron microscopy showed laminated myelin figures (zebra bodies) in glomerular visceral epithelial cells, and no immune deposits were identified. Leukocyte levels of α-galactosidase (α-Gal) were significantly reduced at 5.4%, establishing the diagnosis of Fabry disease. Because of his unique presentation, genetic diagnosis was performed by using polymerase chain reaction sequencing.1.Rodriguez-Mari A. Coll M.J. Chabas A. Molecular analysis in Fabry disease in Spain: fifteen novel GLA mutations and identification of a homozygous female.Hum Mutat. 2003; 22: 258Crossref PubMed Scopus (58) Google Scholar We identified a complex mutation (insertion and deletion) A368gsX24 (1102delGinsTTATAC), which has been previously described.1.Rodriguez-Mari A. Coll M.J. Chabas A. Molecular analysis in Fabry disease in Spain: fifteen novel GLA mutations and identification of a homozygous female.Hum Mutat. 2003; 22: 258Crossref PubMed Scopus (58) Google Scholar After his diagnosis, screening for Fabry disease was offered to his only child. The father's parents were deceased at the time of diagnosis. His 17-year-old daughter was found to have the same mutation, but leukocyte α-Gal levels were 50% of normal. Cardiac echocardiogram showed no evidence of left ventricular hypertrophy. Cranial magnetic resonance imaging disclosed two small areas suggestive of ischemic stroke. Slit-lamp examination of the eyes disclosed cornea verticillata. He was treated initially with angiotensin-converting inhibitor (enalapril 5 mg b.i.d.). Attempts to increase the dose further resulted in the development of symptomatic hypotension. Proteinuria persisted and he was started on enzyme replacement therapy (ERT) with agalsidase-beta (1 mg kg−1 every 2 weeks). Despite combined angiotensin-converting inhibitor and ERT, proteinuria (Figure 1) and renal disease progressed, with the patient reaching end-stage renal disease (ESRD) three and a half years after starting ERT (Figure 2). He never developed symptomatic peripheral neuropathy, vertigo, or lymphedema, and apart from angiotensin-converting inhibitor therapy he was on no other medication until late into the progression of his renal failure when erythropoietin and phosphate binder treatment was started.Figure 2Serum creatinine values before and after start of ERT.View Large Image Figure ViewerDownload (PPT) Fabry disease was first described in 1898 by Johaness Fabry and William Anderson, two physicians working independently of each other, in Bonn and London, respectively. They described patients with ‘angiokeratoma corporis diffusum’, the red-purple maculopapular skin lesions characteristic of the disorder (Figure 3). After these initial cases, other associated symptoms were described and eventually the lysosome was identified as the key organelle responsible for the pathology of the disease. We now know that the disease is due to an X-linked recessive inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal enzyme, α-Gal A.2.Clarke J.T. Narrative review: Fabry disease.Ann Intern Med. 2007; 146: 425-433Crossref PubMed Scopus (162) Google Scholar The enzymatic defect results in the progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide, GL-3), particularly in the vascular endothelial cells of the kidney and heart. A limited number of studies have investigated the incidence of lysosomal storage diseases (defined as the total number of cases diagnosed within a certain period of time, divided by the total number of live births in the same period). For Fabry disease, the incidence/prevalence oscillates from 1 in 40 000 to 1:117 000 in United States and Australia to 1:833 000 in Northern Portugal, the majority of them being Caucasians.3.Meikle P.J. Hopwood J.J. Clague A.E. Carey W.F. Prevalence of lysosomal storage disorders.JAMA. 1999; 281: 249-254Crossref PubMed Scopus (1711) Google Scholar,4.Thadhani R. Wolf M. West M.L. et al.Patients with Fabry disease on dialysis in the United States.Kidney Int. 2002; 61: 249-255Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar These figures are likely to underestimate the real prevalence of the disease as many patients with Fabry disease go undiagnosed due to the complexity of the diagnosis. Affected males have little, if any, α-Gal A activity, and the deposition of GL-3 occurs primarily in the lysosomes of vascular endothelial cells as well as in epithelial and smooth muscle cells throughout the body. Early clinical manifestations of the disease include angiokeratoma, acroparesthesias, episodic pain ‘crises’, hypohydrosis, and gastrointestinal complains. With time, progressive GL-3 accumulation in the microvasculature leads to renal, cardiovascular, and cerebrovascular manifestations such as proteinuria, renal failure, cardiac arrhythmias, and strokes leading to early death during the fourth and fifth decade of life, in affected men4.Thadhani R. Wolf M. West M.L. et al.Patients with Fabry disease on dialysis in the United States.Kidney Int. 2002; 61: 249-255Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar (Table 1).Table 1Potential disease manifestations by average age of onsetChildhood Episodic pain crises, acroparesthesia Hypohidrosis Corneal and lenticular opacities Recurrent fever Heat and cold intoleranceAdolescence Angiokeratomas FatigueAdulthood Renal dysfunction Isosthenuria, proteinuria, progressive renal insufficiency Cerebrovascular/neurological complications Early stroke, diplopia, dysarthria, nystagmus, nausea, vomiting, ataxia, vertigo, dizziness, hearing loss and tinnitus Cardiac dysfunction Left ventricular hypertrophy, coronary artery disease, arrhythmias, mitral insufficiency, congestive heart failureOther signs/symptoms Cornea verticillata, tortuous retinal vessels Growth retardation, delay puberty Impaired fertility Episodic diarrhea, weight loss Changes in joints and bones Impaired social functioning Depression Decreased quality of life Open table in a new tab Renal manifestations of Fabry disease are more evident in hemizygous males than in heterozygous females. However, due to non-random X inactivation, some females have a significant burden of disease, including renal failure. On gross description, the kidney may be enlarged due to accumulation of storage material. In some cases, cortical or parapelvic cysts have been demonstrated by radiographic imaging. On light microscopy, the glomerular tuft shows vacuolated glomerular cells, especially podocytes (Figure 4). Similar changes are present in the endothelial and mesangial cells, and in parietal epithelial cells of the Bowman's capsule. The vacuolated appearance is due to removal of the glycolipids during clearing and paraffin embedding of the tissue, but can be easily demonstrated in semithin sections of tissue embedded in epoxy resin and stained with toluidine blue (Figure 5). Similar cytoplasmic vacuolation can also be seen in the renal tubules, particularly in the epithelium of Henle's loop and the distal tubule. Cytoplasmic vacuolization can also be seen in endothelial cells of small arteries and arterioles, smooth muscle cells, and in interstitial cells, producing an early concentrating defect.5.Alroy J. Sabnis S. Kopp J.B. Renal pathology in Fabry disease.J Am Soc Nephrol. 2002; 13: S134-S138PubMed Google Scholar Later, progressive glomerulosclerosis manifested by proteinuria and ischemic changes in renal microvasculature result in capillary wall thickening, tubular atrophy, interstitial fibrosis, and arterial and arteriolar sclerosis. Immunofluorescence is negative. Electron microscopy shows enlarged podocytes filled with osmiophilic, granular to lamellated membrane structures (zebra bodies) (Figure 6). Accumulation of GL-3 leads to microvascular obstruction and ischemia, and ultimately renal function deteriorates with ESRD developing in the third to fifth decades of life, although cases of ESRD developing in the second decade have been reported.6.Sheth K.J. Roth D.A. Adams M.B. Early renal failure in Fabry's disease.Am J Kidney Dis. 1983; 2: 651-654Abstract Full Text PDF PubMed Scopus (48) Google ScholarFigure 5Glomerulus showing enlarged podocytes containing cytoplasmic lamellated inclusion bodies (arrows) (toluidine blue, × 600).View Large Image Figure ViewerDownload (PPT)Figure 6Electron micrograph showing electron-dense laminated myelin figures in glomerular epithelial cells (× 5000).View Large Image Figure ViewerDownload (PPT) The case reported hereby is a patient who presented with proteinuria with no other symptoms. A renal biopsy and genetic analysis disclosed that the patient was affected by Fabry disease with preferential kidney involvement. Fabry disease presenting solely with renal involvement is rare, and only a few cases have been reported in the literature.7.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, 8.Rosenthal D. Lien Y.H. Lager D. et al.A novel alpha-galactosidase a mutant (M42L) identified in a renal variant of Fabry disease.Am J Kidney Dis. 2004; 44: e85-e89Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 9.Sawada K. Mizoguchi K. Hishida A. et al.Point mutation in the alpha-galactosidase A gene of atypical Fabry disease with only nephropathy.Clin Nephrol. 1996; 45: 289-294PubMed Google Scholar Nakao et al.7.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 screened 514 unselected Japanese male patients with ESRD treated with chronic hemodialysis patients and identified six patients with Fabry disease (occurrence rate 1.2%). Among the cases reported by Nakao and co-workers, one had classic Fabry disease that was misdiagnosed, four had left ventricular hypertrophy, and only one had a normal echocardiogram. It appears that the kidney and heart are frequently involved in non-classic Fabry disease and that there are overlapping symptoms between cardiac and renal variants.10.Meehan S.M. Junsanto T. Rydel J.J. Desnick R.J. Fabry disease: renal involvement limited to podocyte pathology and proteinuria in a septuagenarian cardiac variant. Pathologic and therapeutic implications.Am J Kidney Dis. 2004; 43: 164-171Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar,11.Nakao S. Takenaka T. Maeda M. et al.An atypical variant of Fabry's disease in men with left ventricular hypertrophy.N Engl J Med. 1995; 333: 288-293Crossref PubMed Scopus (662) Google Scholar These data show that undiagnosed Fabry patients on dialysis may account from 0.25 to 1.2% of the total amount of male patients on dialysis. Until now, all reported cases of the renal variant, including those reported by Nakao and co-workers above, are caused by missense mutations, while patients with the classical phenotype have nonsense, severe missense, frameshift, and splicing mutations that result in no enzyme protein or mutant enzymes with very low activity. The case reported herein is produced by a frameshift mutation, with the most outstanding fact being that such a severe mutation (1102delG/insTTATAC) gives rise to a ‘renal variant’ of Fabry disease. Attempting to correlate the genotype to phenotypic variations is not straightforward. Many heterozygous and some hemizygous patients show no symptoms of the disease during most of their life. Residual α-Gal A activity as well as other genetic factors may affect the phenotype. Modifying genes may include those involved in glycolipid metabolism, which may increase α-Gal substrates, thus altering the disease severity. Also, differences in intracellular factors in different cell, tissues and organs may affect the transcription rate of the α-Gal gene, which may explain why the same kind of mutation accounts for such different phenotypes. The patient reported here shows mostly renal involvement (cornea verticillata and two small angiokeratomas were the only extra-renal feature), with the diagnosis made by renal biopsy. Why having some degree of α-Gal activity can protect one organ but not the other remains to be explained. In female patients, a non-random X-inactivation limited to the kidney (skewed towards inactivation of the wild type allele) could be the reason for the outstanding phenotype. In addition to the classical Fabry disease phenotype, and to the ‘renal’ variant, a ‘cardiac’ variant has also been identified.11.Nakao S. Takenaka T. Maeda M. et al.An atypical variant of Fabry's disease in men with left ventricular hypertrophy.N Engl J Med. 1995; 333: 288-293Crossref PubMed Scopus (662) Google Scholar,12.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 (347) Google Scholar These patients have residual α-Gal A activity, with GL-3 deposition confined to myocytes, and do not manifest the whole spectrum of symptoms present in classical Fabry disease.12.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 (347) Google Scholar Clinical presentation is usually in the fifth to the eighth decade with left ventricular hypertrophy, mitral insufficiency, and cardiomyopathy. Later in life, however, many of these patients will manifest renal involvement characterized by proteinuria without progression to ESRD.11.Nakao S. Takenaka T. Maeda M. et al.An atypical variant of Fabry's disease in men with left ventricular hypertrophy.N Engl J Med. 1995; 333: 288-293Crossref PubMed Scopus (662) Google Scholar,12.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 (347) Google Scholar Interestingly, the case reported by Sawada et al.9.Sawada K. Mizoguchi K. Hishida A. et al.Point mutation in the alpha-galactosidase A gene of atypical Fabry disease with only nephropathy.Clin Nephrol. 1996; 45: 289-294PubMed Google Scholar of a ‘renal variant’ showed the same mutation (G to A transition) as the patient reported by Sakuraba et al.13.Sakuraba H. Oshima A. Fukuhara Y. et al.Identification of point mutations in the alpha-galactosidase A gene in classical and atypical hemizygotes with Fabry disease.Am J Hum Genet. 1990; 47: 784-789PubMed Google Scholar who had a cardiac variant, reinforcing the impression of idiosyncratic transcriptional rate in different organs. Although it seems reasonable to use the terms ‘renal and cardiac variants’ to describe these cases, we believe that the term ‘extreme phenotypes’ would be more precise to explain the existence of such different phenotypes. In fact, most of the reported patients with the ‘renal variant’ have some kind of systemic involvement, such as cornea verticillata, left ventricular hypertrophy, or neurological involvement. In all cases the involvement of other organs was minor in relation to the kidney. However, it is very important to know these cases exist in order not to miss the diagnosis in these patients. Since Fabry disease is a potentially treatable condition, it is imperative to consider it in the differential diagnosis of any patient presenting with chronic progressive renal failure and proteinuria that cannot be readily explained by history or routine laboratory evaluation. This is of special importance in cases where there is unexplained family history of renal disease. The determination of α-Gal activity is easy and the renal biopsy shows typical changes, as described above. Screening for Fabry disease may be carried out by determining α-Gal levels in males with suggestive clinical features and/or compatible renal biopsy findings. The α-Gal A activity can easily be measured in plasma and leukocytes using the 4-methylumbelliferyl-α-D-galactopyranoside method.14.Desnick R.J. Allen K.Y. Desnick S.J. et al.Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygotes. Alpha-galactosidase activities in plasma, serum, urine, and leukocytes.J Lab Clin Med. 1973; 81: 157-171PubMed Google Scholar There are fewer pitfalls in the leukocyte assay than in the plasma assay. Classically affected hemizygotes have very low or undetectable enzyme activity, but some hemizygotes may have higher residual activity in plasma and/or leukocytes. It is therefore important to confirm the mutation in these individuals. The α-Gal A activity in females can range from the low level found in affected males to the normal range, possibly due to skewed X-inactivation. Therefore, heterozygotes cannot be reliably defined by enzymatic analysis, and mutation detection is mandatory if Fabry disease is suspected. The GLA gene, located at Xq22.1, is 12 kb in length and contains seven exons. To date, close to 400 mutations have been described in the GLA gene, most of which are private missense or nonsense mutations.15.Winchester B. Young E. Biochemical and genetic diagnosis of Fabry disease.in: Mehta A. Beck M. Sunder-Plassmann G. Fabry Disease: Perspectives from 5 Years of FOS. Oxford PharmaGenesis Ltd, Oxford2006: 169-181Google Scholar Therefore, the whole gene must be sequenced when looking for mutation in the GLA gene. Until recently, recognition of Fabry disease did not impact on the patient's prognosis, since no treatment was available. However, the availability of ERT with recombinant α-Gal has offered the promise of altering the natural history of this rare form proteinuric renal disease.16.Warnock D.G. Enzyme replacement therapy and Fabry kidney disease: quo vadis?.J Am Soc Nephrol. 2007; 18: 1368-1370Crossref PubMed Scopus (14) Google Scholar Currently, there are two forms of ERT available for the treatment of Fabry disease: (1) Replagal (agalsidase-alpha; Shire Human Genetic Therapies Inc., Cambridge, MA, USA) and (2) Fabrazyme (agalsidase-beta; Genzyme Corporation Inc., Cambridge, MA, USA). With the exception of the structures of the oligosaccharide side chains, the primary amino-acid sequences of the gene products are the same.17.Linthorst G.E. Hollak C.E. Donker-Koopman W.E. et al.Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta.Kidney Int. 2004; 66: 1589-1595Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar The approved doses of agalsidase-alpha and agalsidase-beta are 0.2 and 1.0 mg kg−1, intravenously, biweekly, respectively. In the US, only agalsidase-beta has been approved for the treatment of Fabry disease by the Food and Drug Administration, although both agents are available for clinical use in other countries.18.Desnick R.J. Enzyme replacement therapy for Fabry disease: lessons from two alpha-galactosidase A orphan products and one FDA approval.Expert Opin Biol Ther. 2004; 4: 1167-1176Crossref PubMed Scopus (99) Google Scholar Randomized, placebo-controlled trials, and long-term, open-label extension studies of both products have consistently demonstrated that ERT reduces GL-3 levels in plasma and urine as well as glycosphingolipids accumulation in capillary endothelial cells, renal glomerular cells, and tubular epithelial cells.19.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,20.Schiffmann R. Kopp J.B. Austin III, H.A. et al.Enzyme replacement therapy in Fabry disease: a randomized controlled trial.JAMA. 2001; 285: 2743-2749Crossref PubMed Scopus (1130) Google Scholar In patients with relatively mild disease, the use of ERT has been able to decrease neuropathic pain, stabilize renal function, decrease left ventricular mass, and relieve gastrointestinal symptoms.20.Schiffmann R. Kopp J.B. Austin III, H.A. et al.Enzyme replacement therapy in Fabry disease: a randomized controlled trial.JAMA. 2001; 285: 2743-2749Crossref PubMed Scopus (1130) Google Scholar,21.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 (362) Google Scholar However, strokes continue to occur in some patients despite ERT.21.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 (362) Google Scholar Similarly, the coronary microvascular dysfunction appears not to be completely reversed by ERT.22.Elliott P.M. Kindler H. Shah J.S. et al.Coronary microvascular dysfunction in male patients with Anderson–Fabry disease and the effect of treatment with alpha galactosidase A.Heart. 2006; 92: 357-360Crossref PubMed Scopus (140) Google Scholar Results of a multicenter phase IV trial in which 82 patients with initial glomerular filtration rate (GFR) values <80 ml min−1 1.73 m−2 who were prospectively randomized (2:1) to treatment with agalsidase-beta or placebo have recently been published.23.Banikazemi M. Bultas J. Waldek S. et al.Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.Ann Intern Med. 2007; 146: 77-86Crossref PubMed Scopus (494) Google Scholar The median time in treatment was 18.5 months and the study ended when approximately one-third of the patients had experienced a total of 27 clinical events (renal, cardiac, and cerebrovascular complications or death), 17 (63%) of which were renal events. Clinical events occurred less in the agalsidase-beta group, but the differences were not statistically significant. There was, however, an imbalance in the degree of baseline proteinuria, with patients allocated to the ERT arm having significantly higher degrees of proteinuria than those on the placebo arm, a fact that complicates the interpretation of the outcome of the study.24.Schiffmann R. Enzyme replacement in Fabry disease: the essence is in the kidney.Ann Intern Med. 2007; 146: 142-144Crossref PubMed Scopus (18) Google Scholar After adjustment for baseline proteinuria, the intention-to-treat analysis showed that ERT was associated with a 53% risk reduction of an event, although due to the small number of patients in the trial, the results were still not statistically significant (P=0.058). When the analysis was limited to the 74 patients who had no protocol violation, the 61% reduction in risk for a clinical event with ERT was statistically significant (P=0.034). Secondary analysis of this study showed that the benefit of ERT was greater in those patients with GFR values >55 ml min−1 per 1.73 m2, but those patients with more severe renal disease did not exhibit the same benefits.23.Banikazemi M. Bultas J. Waldek S. et al.Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.Ann Intern Med. 2007; 146: 77-86Crossref PubMed Scopus (494) Google Scholar In this study, 12% of the patients were affected women, but the authors do not report on the outcomes on these patients. Most treatment-related events were mild or moderate infusion-associated reactions (rigors and fever), occurred in 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group, and were most common during the first 6 months of treatment. One patient in the agalsidase-beta group experienced severe hypotension and had a positive serum IgE test result. Two others who had developed urticaria and rigors during infusions subsequently developed a positive skin test. Both were subsequently re-challenged and continue to receive treatment without anaphylaxis. Forty-three patients (68%) developed IgG antibodies against recombinant agalsidase-beta.23.Banikazemi M. Bultas J. Waldek S. et al.Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.Ann Intern Med. 2007; 146: 77-86Crossref PubMed Scopus (494) Google Scholar These antibodies tended to fall over time and do not appear to affect therapeutic efficacy.21.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 (362) Google Scholar Data collected from a European post-marketing follow-up survey has confirmed that ERT is safe and well tolerated in adults and children when used in a wide range of patients and in daily clinical practice, including home therapy. Proteinuria has emerged as a major player in the development of progressive tubular injury, interstitial fibrosis, and GFR loss, including Fabry disease.21.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 (362) Google Scholar The higher the sustained levels of proteinuria, the faster the decline in renal function. Two studies that underscore the importance of proteinuria in Fabry patients as well as the limitations of EFR in addressing this issue have recently been published.16.Warnock D.G. Enzyme replacement therapy and Fabry kidney disease: quo vadis?.J Am Soc Nephrol. 2007; 18: 1368-1370Crossref PubMed Scopus (14) Google Scholar Germain et al.25.Germain D.P. Waldek S. Banikazemi M. et al.Sustained, long-term renal stabilization after 54 months of agalsidase Beta therapy in patients with Fabry disease.J Am Soc Nephrol. 2007; 18: 1547-1557Crossref PubMed Scopus (366) Google Scholar provide the data on 58 patients who completed a 20-week, double-blind, randomized, placebo-controlled, phase III study of agalsidase-beta, and were transitioned to an extension trial to receive biweekly 1 mg kg−1 agalsidase-beta for up to an additional 54 months. Median serum creatinine and estimated glomerular filtration rate (eGFR) remained normal in the 41 patients with renal data at month 54. Six patients had renal disease progression; most (four of six) were older than 40 years and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment.25.Germain D.P. Waldek S. Banikazemi M. et al.Sustained, long-term renal stabilization after 54 months of agalsidase Beta therapy in patients with Fabry disease.J Am Soc Nephrol. 2007; 18: 1547-1557Crossref PubMed Scopus (366) Google Scholar In the second study, Schiffmann et al.26.Schiffmann R. Askari H. Timmons M. et al.Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing.J Am Soc Nephrol. 2007; 18: 1576-1583Crossref PubMed Scopus (118) Google Scholar evaluated whether adult male patients with Fabry disease who had demonstrated a continuing decline in GFR despite 2–4 years of conventionally dosed agalsidase-alpha therapy (0.2 mg kg−1 biweekly) would benefit from increasing ERT to a weekly dosing. Before switching to weekly dosing, the 11 patients who participated in the study had a mean rate of change in eGFR of -8.0±0.8 ml min−1 1.73 m−2 per year. After switching to weekly dosing, three patients demonstrated an improvement in eGFR and six patients demonstrated a slowing in the rate of eGFR decline; only two patients failed to improve their eGFR slope.26.Schiffmann R. Askari H. Timmons M. et al.Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing.J Am Soc Nephrol. 2007; 18: 1576-1583Crossref PubMed Scopus (118) Google Scholar Although derived from a limited" @default.
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• W2012140802 title "Fabry disease: An underrecognized cause of proteinuria" @default.
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