A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population.

BACKGROUND: Fabry disease (FD) is a genetic disorder characterized by accumulation of trihexosylceramide in lysosomes of various tissues leading to multiorgan manifestations, including progressive renal disease. Previous screening studies have shown that a non-neglectable proportion of haemodialysis(HD) patients have unsuspected FD. An extensive FD screening study, the largest to date, has been conducted in HD patients in Czech Republic. We aimed to uncover previously undiagnosed FD patients, to enable them to benefit from cause-specific therapeutic intervention with enzyme replacement therapy (ERT). METHODS: Large-scale screening was executed using a convenient automated enzymatic (alpha-galactosidose A, alpha-Gal A) dried blood spot on filter paper fluorescence method. RESULTS: In total, 3370 (45.1% males, 54.9% females) out of 4058 HD patients (83%) in Czech Republic participated in this blood spot screening (BSS) study. Abnormal low fluorescence readings were obtained in 117 patients (3.5%). Subsequent determination of plasma alpha-Gal A activity identified four males and three females with deficient plasma enzyme activity. Determination of alpha-Gal A activity in peripheral blood leucocytes and confirmatory molecular analysis resulted in four newly diagnosed Fabry males and one female. Subsequent family screening identified 10 family members with genotypically proven FD. Based on these screening results, ERT could be offered to five male FD patients. CONCLUSIONS: BSS represents a promising screening tool that has proven to be convenient and effective in uncovering unrecognized FD patients among the chronic HD population in Czech Republic.     

Enzyme replacement therapy in Fabry's disease: recent advances and clinical applications

Fabry's disease is a rare X-linked recessive disorder resulting from deficient lysosomal enzyme, alpha-galactosidase A (alpha-Gal A) activity. The deficiency leads to progressive glycosphingolipid globotriaosylceramide (Gb3) accumulation in fluids and tissues, including vascular endothelium, connective tissue, kidney, heart, brain and peripheral nerves. Classic Fabry's disease in hemizygous males has high morbidity and mortality due to end-stage renal disease (ESRD) requiring hemodialysis (HD) or kidney transplantation, myocardial involvement and central nervous system (CNS) complications. Most heterozygous females can also suffer from this severe disease deterioration. Until recently, Fabry's disease management consisted of symptomatic and palliative treatment, but this has changed with the availability of the recombinant human alpha-Gal A enzyme, agalsidase. Two different agalsidase formulations have been obtained: one from human fibroblast (agalsidase alpha), and one from Chinese hamster ovary (CHO) cells (agalsidase beta). Both preparations underwent clinical trials that documented the feasibility, efficacy and safety of the treatment. In addition, several clinical observations have proved that agalsidase reduces the storage of the substrate from several organs and tissues and, consequently, improves signs and symptoms of Fabry's disease. Additional clinical experiences have confirmed the initial clinical trial results, but further studies are needed to evaluate the long-term outcome of enzyme replacement therapy (ERT). We reviewed the clinical trial observations, as well as subsequent clinical experiences with ERT in patients with Fabry's disease.     

Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype

BACKGROUND: Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient alpha-galactosidase A (alpha-Gal A) activity. Renal failure is a major debilitating complication in classically affected males. To determine if this disorder is underdiagnosed in patients with end-stage renal disease (ESRD), the frequency of unrecognized males with Fabry disease on chronic hemodialysis was determined. METHODS: Plasma alpha-Gal A activity was measured in 514 consecutive males with ESRD on hemodialysis. Patients with low alpha-Gal A activity were evaluated clinically and their alpha-Gal A mutations were determined. RESULTS: Six (1.2%) of 514 hemodialysis patients had low plasma alpha-Gal A activities and a previously identified (E66Q, A97V, M296I) or novel (G373D) missense mutation. At ages 30 to 68 years, five patients lacked the classic manifestations of angiokeratoma, acroparesthesias, hypohidrosis, and ocular opacities, while the sixth lacked angiokeratoma and ocular changes. Five had left ventricular hypertrophy (LVH). CONCLUSION: The clinical spectrum of Fabry disease includes a "renal variant" phenotype in patients without classic symptoms who develop ESRD. Affected males undergoing hemodialysis or renal transplantation can be readily diagnosed by plasma alpha-Gal A assays. These patients and their family members may benefit from enzyme replacement therapy for the later, life-threatening cardiovascular and cerebrovascular complications of Fabry disease.     

A case of Fabry's disease with chronic renal failure]

Fabry's disease is a genetic disorder caused by the absence of alpha-galactosidase (alpha-Gal), the gene of which is carried on the long arm of the X chromosome. This enzymatic defect leads to an accumulation of glycosphingolipids in the plasma and lysosomes of endothelial, perithelial, and smooth muscle cells, especially involving those of the cardiovascular, renal and cerebrovascular systems. We report one male case of Fabry's disease with renal deterioration. A 36-year-old man who was a classic case with acroparesthesia, angiokeratoma, and hypohidrosis from 10 years of age, was diagnosed to be a hemizygote of Fabry's disease at 27 years as a result of severe decreased alpha-Gal activity of his peripheral white blood cells. This patient was found to have a point mutation of a G to A transition in exon 1. In May, 1989, he was reported to have proteinuria with normal renal function and admitted to our hospital due to renal deterioration in September, 1993. Laboratory examinations revealed a serum urea nitrogen of 65 mg/dl and creatinine value of 6.9 mg/dl. Urinary protein excretion was 3.9 g/day and urinary sugar was negative. On the renal biopsy specimens, light microscopic examinations revealed multiple sclerosing and collaptic lesions in glomeruli without severe tubulo-interstitial damage, but with stenotic change of the small arteries and arterioles. Electron microscopic examinations revealed a large number of electron dense deposits in the tubules. We diagnosed this case as Fabry's disease with chronic renal failure, however the pathogenesis of this renal progressive deterioration remained obscure. In this case, degenerative changes in the renal vessels due to Fabry's disease may be associated with rapid deterioration in renal function.     

alpha-Galactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease.

INTRODUCTION: Fabry disease or alpha-galactosidase A (alpha-Gal A) deficiency is an X-linked lysosomal storage disorder that often leads to renal insufficiency in males and occasionally in females. The disease is rare, but its prevalence may be underestimated due to its variable clinical picture. Enzyme supplementation therapy with rHu-alphaGal A is currently available. Limited experience has so far shown that therapy may at best stabilize renal function. Despite these preliminary findings, much effort is being put into screening high-risk groups for undiagnosed alpha-Gal A deficiency. We studied the prevalence of alpha-Gal A deficiency in a Dutch dialysis cohort to establish possible underdiagnosis. We discuss the benefits of screening for Fabry disease. METHODS: Activity of alpha-Gal A in whole blood was measured in a group of 508 male Dutch dialysis patients. RESULTS: Of the 508 patients studied only one patient, already known with Fabry disease, had a alpha-Gal A deficiency, a prevalence of 0.22% (95 CI 0-1.1%). CONCLUSIONS: No undiagnosed Fabry patients were found, indicating that in our studied cohort there is no large-scale underestimation of its prevalence. Even though screening of dialysis patients for Fabry disease might identify patients who remain otherwise unrecognized, screening of high-risk populations for alpha-Gal A deficiency should be carried out with caution since long-term efficacy of treatment is currently unknown.     

Two-tier approach for the detection of alpha-galactosidase A deficiency in a predominantly female haemodialysis population.

INTRODUCTION: Fabry's disease (AFD) is an X-linked lysosomal storage disease, resulting from a deficiency in alpha-galactosidase A (AGALA). Untreated, this leads to precocious failure of vital organ function and death. As enzyme replacement therapy is available, it is of vital importance that affected individuals can be traced. MATERIALS AND METHODS: We set up a screening in the Flemish haemodialysis population using a two-tier approach. The first tier was a determination of alpha-galactosidase A activity using a dried blood spot on filter paper, in the second tier, patients with the lowest alpha-galactosidase levels were further subjected to mutation analysis of the GLA gene. RESULTS: 1284 patients (1047 women, 237 men) were evaluated for inclusion, eliminating patients with definite renal diagnoses. Total 922 patients (71.8 %) were screened (742 women, 180 men). Fifty seven patients were subjected to further genetic analysis. Three GLA mutation carriers were identified: two apparently nonrelated female patients carry the missense mutation p.Ala143Thr (c.427G > A), a missense mutation p.Trp236Arg (c.706T > C) was identified in a man. While the male patient had been clinically diagnosed with AFD, the female patients had remained unrecognized. Additional family based screening resulted in the identification of nine mutation carriers (four males and five females). DISCUSSION: We demonstrated that the prevalence of GLA mutation carriers in our haemodialysis population is 0.3%. Our results show that the proposed approach accurately detects AFD patients. We conclude that screening for AFD in high risk populations is a cost-effective, technically feasible and clinically valuable objective.     

A case of focal segmental glomerulosclerosis with myeloid bodies

The presence of myeloid bodies in electron microscopy is a characteristic finding of Fabry's disease. Here, we present a male patient, whose renal biopsy findings suggested the coexistence of focal segmental glomerulosclerosis and Fabry's disease, because of the presence of segmental hyalinosis and/or sclerosis in glomeruli and myeloid bodies in electron microscopy. But finally, Fabry's disease was excluded as a diagnosis because the α-galactosidase A activity in leukocyte and plasma in this patient was within normal limits. After renal biopsy, although he received medication including steroid therapy, his renal function gradually decreased to end-stage renal failure and hemodialysis was initiated. Until now, he does not exhibit any specific symptoms. In conclusion, our case suggests that occasional myeloid bodies in renal biopsy specimens should be interpreted with caution.     

A nonsense mutation (R220X) in the alpha-galactosidase A gene causes typical Fabry disease in both genders

BACKGROUND: Fabry disease is an X-linked recessive disorder resulting from a deficiency of lysosomal alpha-galactosidase A (alpha-Gal A). Chronic renal failure is an important cause of death in patients with Fabry disease. We report on patients with Fabry disease (a hemizygous male and his mother) due to a nonsense mutation (R220X) in the alpha-Gal A gene. METHODS: The proband, a 41-year-old man, and his 71-year-old mother presented with renal and cardiac manifestations of Fabry disease. Histological examination and molecular analysis of the alpha-Gal A gene were performed. RESULTS: Typical histological findings of Fabry disease were observed in a renal biopsy specimen from the proband and in renal and myocardial necropsy specimens from the mother. Sequencing of a full-length alpha-Gal A cDNA from the proband indicated a C-T transition at codon 220, resulting in substitution of the predictable termination for arginine (R220X). Examination of genomic alpha-Gal A DNA revealed that the proband was a hemizygote and the mother was a heterozygous carrier for the mutation. CONCLUSION: This is the first detailed report of family members with Fabry disease due to a nonsense mutation (R220X) in the alpha-Gal A gene. Our study indicates that this mutation causes the typical disease in both genders.     

Clinical features and genetic analysis of a Chinese kindred with Fabry's disease.

BACKGROUND: Fabry's disease is an X-linked recessive inborn error of glycosphingolipid catabolism resulting from deficient activity of lysosomal enzyme alpha-galactosidase A causing occlusive microvascular diseases affecting the kidney, heart, peripheral nerves and brain. It is an uncommon disease in the Oriental population. METHODS AND RESULTS: We report a Chinese kindred of Fabry's disease and the relevant clinical features are discussed. The diagnosis of Fabry's disease was based on serum alpha-galactosidase A activity and typical histological features from renal biopsy in the index patient. Genetic analysis of two hemizygous male patients revealed a missense mutation predicting a leucine to proline substitution (L14P) in the alpha-galactosidase gene causing classical Fabry's disease in this family. This is a novel point mutation not described previously in the literature and the second report describing novel genetic mutations for Fabry's disease in Chinese patients. CONCLUSIONS: Fabry's disease is rare in Chinese patients but this diagnosis should be considered in patients with positive family history of kidney disease and relevant clinical features.     

Identification of a novel mutation and prevalence study for fabry disease in Japanese dialysis patients

Fabry disease--a genetic disorder characterized by the accumulation of globotriaosylceramide in cell lysosomes resulting from an X-linked deficiency of α-galactosidase A activity--presents with multiorgan manifestations, including progressive renal disease. Recently, its prevalence has been reported to be higher in hemodialysis (HD) patients than in the general population. We, therefore, examined patients on maintenance dialysis living in the Nagasaki Prefecture, Japan, to clarify the prevalence of Fabry disease. We screened 933 patients on maintenance dialysis, who were residents of Nagasaki Prefecture in Japan, for α-galactosidase A activity using a dried blood spot on filter paper. Patients with low α-galactosidase A activity were clinically assessed; subsequently, genetic analysis of the α-Galactosidase A gene (MIM:30064) was performed in these patients. Of the 933 patients, 55 had low α-galactosidase A activity; of these, one male and two females had α-Galactosidase A mutations. The prevalence of Fabry disease was thus 0.32%, which was similar to that reported previously. However, one mutation was newly identified, while the E66Q mutation observed in two patients was as previously identified. These two patients with the E66Q mutation were excluded because of the possibility of polymorphism; the prevalence of Fabry disease in the HD population was finally calculated to be 0.11%. The prevalence of Fabry disease in patients on maintenance dialysis living in Nagasaki Prefecture was 0.32%. Dried blood spot screening was considered as a simple and effective method for screening patients on maintenance dialysis for Fabry disease.     

Early renal failure in Fabry's disease

Two young males were observed with renal failure from Fabry's disease. These two patients had progressive decrease of renal function and required hemodialysis at ages 16 and 24. Diagnosis was confirmed by low plasma galactosidase levels and by skin and kidney biopsy. Each has had a successful kidney transplant with good graft function, the 16-year-old patient for five years and the 24-year-old for two years. Although the renal impairment usually does not appear until the fourth or fifth decade of life. Fabry's disease should be considered in the differential diagnosis of renal failure in young males.     

Being an elderly woman: is it a risk factor for morbidity after coronary artery bypass surgery?

OBJECTIVE: Despite the refinements in surgical techniques and postoperative care, elderly women still have a higher prevalence of postoperative morbidity. METHODS: The outcomes of 112 elderly women (>80 years) who underwent an elective CABG procedure were compared with those of males operated during the same time interval (n, 164). RESULTS: Median age of female and male patients were 82 and 83 years, respectively. Mean number of grafts did not differ significantly (3.7+/-0.8 vs 3.9+/-0.3, p=0.4) between groups. Overall early operative mortality rate was 8.6% (24 of 276 patients); 8.9% (10 of 112 patients) for female and 8.5% (14 of 164 patients) for male patients (p=0.1). Postoperative complications including prolonged ventilation time (13.4% in females vs 8.5% in male, p<0.01), atrial fibrillation (40% in females vs 33% in males, p=0.01), sternal reclosure (8% in females vs 4.2% in males, p=0.01), pneumonia (5.3% in females vs 3% in males, p=0.03), leg wound infection (11.7% in females vs 2.4% in males, p<0.001), renal dysfunction (10.7% in females vs 7.3% in young patients, p=0.02) have been found to be significantly higher in elderly women. Mean intensive care unit (3.2+/-1.1 days in females vs 1.6+/-0.4 in males, p=0.03), and hospital stays (13.6+/-2.1 days in females vs 9.1+/-1.2 in males, p=0.02) were also longer in female patients. Five-year survivals including all deaths for female and male patients were 57% and 62%, respectively. CONCLUSIONS: In elderly women, revascularization procedures can be done with acceptable mortality rates; but these patients are still associated with a higher prevalence of postoperative morbidity when compared with the male counterparts. Therefore, these patients have to be very carefully evaluated preoperatively and their postoperative care should be more comprehensive to reduce the incidence of postoperative complications.     

Crescentic glomerulonephritis in a patient with heterozygous Fabry's disease

A 58-year-old woman who suffered from a heterozygous Fabry's disease and immune complex crescentic glomerulonephritis (GN) is reviewed. The diagnosis was made on the basis of the pathologic findings and peripheral leukocyte alpha-galactosidase activity. Light microscopy revealed a vacuolization of epithelial cells and electron microscopy showed myelin figures in the cytoplasm of visceral epithelial cells typical of Fabry's disease at the first renal biopsy. During the following 4 months she developed progressive renal failure and a second renal biopsy disclosed the formation of cellular crescents in 7 of 11 glomeruli observed. A rare case of combined Fabry's disease and crescentic glomerulonephritis is discussed.     

Allograft loss in renal transplant recipients with Fabry's disease and activated protein C resistance

INTRODUCTION: Fabry's disease is associated with an increased incidence of thrombotic events and rejection. Spontaneous thrombosis of a functioning cadaveric renal allograft in a recipient with Fabry's disease prompted prospective evaluation of all transplant candidates with Fabry's disease for hypercoagulability. MATERIALS AND METHODS: Transplant candidates with Fabry's disease were tested for hypercoagulability, analyzed for HLA-type and ABO group, and comorbid conditions suggestive of hypercoagulability. RESULTS: A unique association of Fabry's disease with activated protein C Resistance was documented in a cohort of Caucasian male renal transplant recipients with Fabry's disease. Four of five patients were blood group A and had no significant comorbid conditions suggestive of hypercoagulability. The resistance to activation of protein C (APCR)(+) patients shared HLA loci-B8 and Dr3, although the APCR(-) patients shared HLA loci-B27 and -B38. CONCLUSIONS: Due to the observed increase in the incidence of APCR in our Fabry's cohort, we suggest screening all patients with Fabry's disease for APCR. Because factor V and factor Va receptors are found on vascular endothelium and peripheral blood monocytes, APCR in the presence of Fabry's disease may be a nonimmunological stimulus for rejection. Analysis of HLA typing in patients with Fabry's disease may further elucidate HLA-based association of Fabry's disease and resistance to activated protein C with the risk of thrombosis and rejection.     

Progression of coronary artery calcification after kidney transplantation

Abstract

Calcification of coronary vessels progresses rapidly in hemodialysis (HD) patients and comprises a strong predictor of cardiovascular events. The aim of this prospective study was to evaluate the coronary artery calcification (CAC) in patients with end stage renal disease undergoing regular HD and to determine the effect of renal transplantation (RT) in the progression of CAC, using the Agatston technique for calcium scoring. The study included 20 patients with end-stage renal disease undergoing a regular HD treatment (16 males, 4 females) 54.1?±?9.5 years old who had just received a renal transplant and 16 more HD patients (11 males, 5 females) 54.4?±?13.8 years old as control group. The baseline evaluation showed a very high prevalence of CAC in both groups, which was positively correlated with age (p?<?0.001) and CRP (p?=?0.03). The second (follow-up) evaluation showed a significant slower progression of calcification after RT. In both groups, high calcium score values in the follow-up evaluation had a strong positive correlation with baseline calcium score (p?<?0.001).     

Excellent outcome of renal transplantation in patients with Fabry's disease

INTRODUCTION: Fabry's disease is an X-linked error of glycosphingolipid metabolism. Clinical manifestations of the disease are secondary to accumulation of glycosphingolipids in various tissues. Renal failure and vascular complications are common. There are conflicting reports regarding the outcomes of patients with Fabry's disease after renal transplantation. METHODS: We reviewed the United States Renal Data System Registry database from 1988 and 1998, and found 93 patients with Fabry's disease who had received a renal transplant. Case-matched patients were identified to serve as controls. RESULTS: Patients with Fabry's disease demonstrated equivalent 5-year patient and graft survival, compared with controls (83% and 75%, respectively, for those with Fabry's disease vs. 82% and 67% for controls). CONCLUSION: Despite their high risk for cardiovascular complications, patients with Fabry's disease have excellent outcomes after renal transplantation.     

Polyomavirus BK Infection in End-stage Renal Disease: Analysis of Viral Replication in Patients on Hemodialysis or Peritoneal Dialysis

Patients in end-stage renal disease undergoing renal replacement treatment (ESRD-RRT) are considered immunocompromised. The hemodialysis (HD) or peritoneal dialysis (PD) procedures seem to produce alterations of the immune status. Interest in immunosuppression has increased due to the poliomavirus BK (BKV) infection. Our study evaluated the prevalence of BKV infection in ESRD-RRT patients and viral replication on HD or PD. From 2006 to 2011 we selected 58 patients (34 males) in ESRD-RRT for inclusion in our study. BKV replication was evaluated by qualitative real-time polymerase chain reaction. In ESRD-RRT patients, the prevalence of BKV replication on plasma was 21%. We identified two groups of patients according to the dialysis procedure: 36 patients on HD (HD group) and 22 on PD (PD group). BKV replication in the HD group was 33% (12 of 36) versus 0% (0 of 22) in the PD group. Different age, number of months on RRT, and preserved diuresis was observed in the HD versus PD groups. With our results we can speculate that BKV infection in ESRD-RRT patients is linked to factors involved in the uremia-related immune dysfunction but also to specific mechanisms related to the different RRTs. PD is an option that could be associated with a better transplant outcome for patients undergoing kidney transplantation.     

Sexual dimorphism in the aging kidney: Effects on injury and nitric oxide system

BACKGROUND: Male gender confers enhanced susceptibility to development of age-dependent kidney damage. In other models of progressive renal disease, development of injury is linked to declines in renal nitric oxide synthase (NOS) capacity. METHODS: We investigated the in vitro characteristics of the renal NOS system in young (3 to 5 months), middle-aged (11 to 13 months) and old (18 to 22 months) male and female Sprague-Dawley rats. RESULTS: NOS activity (pmol [3H]-arginine converted to [3H]-citrulline/mg protein/minute) is reduced in the soluble fraction of renal cortex from old versus young males but not females. In contrast, NOS activity in the soluble fraction of cerebellum is not altered by age or gender. The abundance of endothelial NOS (eNOS) and neuronal (nNOS) is reduced in renal cortex of old versus young males but is unchanged in female cortex. In renal medulla, eNOS protein is reduced with age in both males and females. We found no difference in abundance of either eNOS or nNOS protein in the cortex of young male and female rats. The incidence and severity of glomerular damage increases markedly with age in the male and only slightly in the female. CONCLUSION: These findings indicate that a relative reduction occurs in renal NOS in the male kidney with advancing age, whereas NOS protein and activity is maintained during aging in females. This, together with the marked age-dependent kidney damage seen in the male, suggests that the renal NO deficiency in the aging male rat may contribute to the age-dependent kidney damage.     

Erectile dysfunction in chronic renal failure patients undergoing hemodialysis in Egypt

In clinical practice, the attention given to sexual problems in patients with end-stage renal disease is low. In order to evaluate the erectile function in chronic renal failure patients undergoing hemodialysis (HD) as a renal replacement therapy in upper Egypt, we used the abridged version of the International Index of Erectile Function (IIEF-5). In all, 75 HD patients were subjected to clinical and laboratory investigations. The controls were 948 healthy males representing the general Egyptian population. The prevalence of erectile dysfunction (ED) among the HD patients was 82.5% compared to 30% among controls. The prevalence of ED in HD group was significantly higher than in controls. The prevalence of ED in HD patients <50 y was 80% and it was 88% in those > or =50 y, while the prevalence of ED among controls was 28 and 69.8%, respectively. The prevalence of severe degree of ED was significantly higher in both groups compared to controls, while moderate degree of ED showed a statistical significance compared to controls in age groups <50 y and mild degree of ED showed a statistical significance compared to controls in age groups > or =50 y. [corrected] Age (r=-0.3368, P<0.01), serum urea (r=-0.5974, P<0.001), and creatinine level (r=-0.5804, P<0.001) have a significant negative correlation with the presence of ED among HD patients, while serum hemoglobin (r=0.3396, P<0.001) and years of HD age (r=0.3147, P<0.01) have a significant positive correlation with the presence of ED among the HD patients. In view of the observed high prevalence of ED among the HD patients, we believe that a complete health evaluation of male HD patients should include a discussion about erectile function in the standard clinical care program of patients with renal disease.