Cystatin C as a marker of early changes of renal function in Fabry nephropathy

BACKGROUND: A sensitive, feasible and reproducible marker for renal function is necessary to evaluate the clinical efficacy of enzyme replacement therapy (ERT) in Fabry nephropathy. Serum creatinine has some limitations and cystatin C has been proposed, in other nephropathies, as a useful marker of renal function. The use of cystatin C as a marker of glomerular filtration rate (GFR) was investigated in Fabry patients receiving ERT. METHODS: Renal function was evaluated with serum creatinine, serum cystatin C and estimated GFR (through Modification of Diet in Renal Disease [MDRD], Cockcroft-Gault [C&G] and Hoek formulae) in 21 Fabry patients receiving ERT with agalsidase alfa for 3 years and in 13 Fabry patients receiving agalsidase alfa for 4 years. RESULTS: During years of ERT while serum creatinine remained stable, cystatin C values showed a significant, increasing trend right from the first year of ERT. CONCLUSIONS: In Fabry disease, cystatin C is a sensitive and reliable marker of renal function, and it should be taken into account when evaluating GFR trends during ERT.     

Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing

This study was performed to determine whether adult male patients with Fabry disease who demonstrate a continuing decline in renal function despite 2 to 4 yr of conventionally dosed agalsidase alfa therapy (0.2 mg/kg every other week [EOW]) show an improved slope of decline with weekly administration using the same dosage. Eleven (27%) of 41 adult male patients with Fabry disease who participated in long-term agalsidase alfa clinical trials and who had demonstrated a slope of decline in estimated GFR (eGFR) of > or =5 ml/min per 1.73 m(2)/yr while receiving long-term treatment with agalsidase alfa at the currently recommended dosage of 0.2 mg/kg, infused EOW, were enrolled in this open-label, prospective study. Patients were switched from EOW to weekly infusions and followed for an additional 24 mo. Before switching to weekly dosing, eGFR was 53.7 +/- 6.3 ml/min per 1.73 m(2) (mean +/- SEM), and mean rate of change in eGFR was -8.0 +/- 0.8 ml/min per 1.73 m(2)/yr. During the 24-mo follow-up period after switching to weekly dosing, the mean rate of change in eGFR was observed to slow to -3.3 +/- 1.4 ml/min/1.73 m(2)/yr (P = 0.01 versus EOW). 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. A multiple regression model confirmed that the weekly infusion regimen was the strongest explanatory variable for the change in eGFR (P = 0.0008), with a weaker contribution from the concomitant use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (P = 0.02). These results suggest that weekly infusions of agalsidase alfa at a dosage of 0.2 mg/kg may be beneficial in the subgroup of patients who have Fabry disease and whose kidney function continues to decline after 2 to 4 yr or more of standard EOW dosing.     

Agalsidase therapy in patients with Fabry disease on renal replacement therapy: a nationwide study in Italy.

BACKGROUND: In Fabry disease, end-stage renal disease (ESRD) and severe neurologic and cardiac complications represent the leading causes of late morbidity and mortality. A comprehensive Italian nationwide survey study was conducted to explore changes in cardiac status and renal allograft function in Fabry patients on renal replacement therapy (RRT) and enzyme replacement therapy (ERT). METHODS: This study was designed as a cross-sectional survey study with prospective follow-up. Of the 34 patients identified via searches in registries, 31 males and 2 females who received RRT and ERT (agalsidase beta in 30 patients, agalsidase alpha in 3) were included. Left ventricular mass index (LVMI), interventricular septal thickness at end diastole (IVSD), left ventricular posterior wall thickness (LVPWT) and renal allograft function were assessed at ERT baseline and subsequently at yearly intervals. RESULTS: The patients in the dialysis and transplant groups had been started on dialysis at age 42.0 and 37.1 years (mean), respectively, and patients in the transplant group received their renal allograft at age 39.8 years (mean). The mean age at the start of ERT was similar, 44.1 and 44.6 years, respectively. The mean RRT follow-up was 61.1 and 110.6 months for dialysis and transplant patients, respectively, whereas the ERT duration was 45.1 and 48.4 months, respectively. Cardiac parameters increased in dialysis patients. In transplant patients, mean LVMI seemed to plateau during agalsidase therapy at a lower level as compared to baseline. Decline in renal allograft function was relatively mild (-1.92 ml/min/year). Agalsidase therapy was well tolerated. Serious ERT-unrelated events occurred more often in the dialysis group. CONCLUSIONS: Kidney transplantation should be the standard of care for Fabry patients progressing towards ESRD. Transplanted Fabry patients on ERT may do better than patients remaining on maintenance dialysis. Larger, controlled studies in Fabry patients with ESRD will have to demonstrate if ERT is able to change the trajectory of cardiac disease and can preserve graft renal function.     

Kidney transplantation in patients with Fabry disease

Little is known about the effects of enzyme replacement therapy (ERT) in kidney transplant recipients with Fabry disease. Clinical characteristics of transplant recipients in the Fabry Outcome Survey (FOS) were therefore examined in patients with Fabry disease with or without ERT. Of the 837 European patients in FOS (March 2006), 34 male patients and two female patients had received kidney transplants. Mean age at transplantation was 37.6 ± 10.9 years, mean time since transplantation was 7.7 ± 6.4 years, median estimated glomerular filtration rate (eGFR) was 44.4 ml/min/1.73 m², and median proteinuria was 296 mg/24 h. Of 27 patients with baseline data, 59% had hypertension, 74% had left ventricular hypertrophy, 22% had cardiac valve disease, 30% had arrhythmia, and 22% had transient ischaemic attacks and 15% stroke. Twenty patients (74%; two female patients, 18 male patients) were receiving ERT with agalsidase alfa. At enrolment or at the start of ERT, median eGFRs were 59 and 35 ml/min/1.73 m² ( P  = 0.05) and median proteinuria levels were 240 and 420 mg/24 h (not significant) in treated and untreated patients respectively. Renal function remained stable in patients receiving ERT. In conclusion, agalsidase alfa is well tolerated in patients with Fabry disease who have undergone renal transplantation.     

Progressive renal failure despite long-term biweekly enzyme replacement therapy in a patient with Fabry disease secondary to a new α-galactosidase mutation of Leu311Arg (L311R)

A 37-year-old Japanese man affected by Fabry disease secondary to a novel mutation of Leu311Arg (L311R) in α-galactosidase demonstrated progressive renal failure despite biweekly enzyme replacement therapy (ERT) for approximately 10 years. Kidney biopsy revealed foamy glomerular epithelial cells, compatible with the typical pathologic features of Fabry disease. The patient entered a phase III study of Replagal^® (agalsidase alfa) in 2001, allowing him to continue ERT with biweekly dosing for almost 10 years. During 2 years of that period, he was continued on Fabrazyme^® (agalsidase beta) biweekly dosing. His estimated GFR was calculated to decrease by 9.9 mL/min/1.73 m² per year. Patients with Fabry disease have been reported to have a mean decrease in GFR of 12.2 ± 8.1 mL/min/1.73 m² per year. This result suggests that biweekly ERT is only mildly effective at preventing loss of kidney function.     

Kidney Function and 24-Hour Proteinuria in Patients with Fabry Disease during 36 Months of Agalsidase Alfa Enzyme Replacement Therapy: A Brazilian Experience

Background. Prior to the introduction of enzyme replacement therapy (ERT), management of Fabry disease (FD) consisted of symptomatic and palliative measures. ERT has been available for several years using recombinant human agalsidase alfa, an analogue of alpha-galactosidase A (GALA). However, the limitations of ERT in improving kidney function have not been established. This study evaluates the safety and therapeutic effect of agalsidase alfa replacement in terms of kidney function and reduction in 24-hour proteinuria. Methods. During the period between January 1, 2002, and August 1, 2005, nine Fabry patients (7 male, 2 female) were treated according to protocol, receiving 0.2 mg/kg agalsidase alfa IV every two weeks. Kidney function was evaluated by measuring the glomerular filtration rate (GFR) using chromium ethylene diamine tetra-acetate clearance (⁵¹Cr-EDTA mL/min/ 1.73 m²) at baseline, 12, 24, and 36 months. 24-hour proteinuria was measured at baseline, 3, 6, 12, 18, 24, and 36 months of ERT. Kidney disease was classified according to National Kidney Foundation Disease Outcome Quality Initiative (NKF/DOQI) Advisory Board criteria, which define stage I chronic kidney disease (CKD) as GFR ≥ 90mL/min/1.73 m², stage II as 60–89 mL/min/1.73m², stage III as 30–59 mL/min/1.73 m², stage IV as 15–29 mL/min/1.73m², and stage V as < 15 mL/min/1.73m². Results. Six patients completed 36 months of therapy, 2 patients completed 18 months, and 1 patient completed 12 months. Mean patient age at baseline was 34.6 ± 11.3 years. During the study period, kidney function remained stable in patients with stages I, II, or III CKD. One patient, who entered the study with stage IV CKD, progressed to end-stage chronic kidney disease, beginning hemodialysis after 7 months and receiving a kidney transplant after 12 months of ERT. Proteinuria also remained stable in the group of patients with pathologic proteinuria. The use of agalsidase alfa was well tolerated in 99.5% of the infusions administered. Conclusion. Over the course of 36 months of ERT, there was no change in kidney function and 24-hour proteinuria. This suggests that agalsidase alfa may slow or halt the progression of kidney disease when used before extensive kidney damage occurs. No significant side effects were observed with ERT during the course of the study.     

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-α or -β). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about –30 ml/min per 1.73 m²; P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.     

Agalsidase Alfa and Kidney Dysfunction in Fabry Disease

In male patients with Fabry disease, an X-linked disorder of glycosphingolipid metabolism caused by deficient activity of the lysosomal enzyme α-galactosidase A, kidney dysfunction becomes apparent by the third decade of life and invariably progresses to ESRD without treatment. Here, we summarize the effects of agalsidase alfa on kidney function from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients. The mean baseline GFR among 54 nonhyperfiltrating patients (measured GFR <135 ml/min per 1.73 m²) treated with placebo was 85.4 ± 29.6 ml/min per 1.73 m²; during 6 mo of placebo, the mean annualized rate of change in GFR was −7.0 ± 32.9 ml/min per 1.73 m². Among 85 nonhyperfiltrating patients treated with agalsidase alfa, the annualized rate of change was −2.9 ± 8.7 ml/min per 1.73 m². Treatment with agalsidase alfa did not affect proteinuria. Multivariate analysis revealed that GFR and proteinuria category (<1 or ≥1 g/d) at baseline significantly predicted the rate of decline of GFR during treatment. This summary represents the largest group of male patients who had Fabry disease and for whom the effects of enzyme replacement therapy on kidney function have been studied. These data suggest that agalsidase alfa may stabilize kidney function in these patients.Fabry disease is an X-linked disorder of glycosphingolipid metabolism caused by deficiency of the activity of the lysosomal enzyme α-galactosidase A (α-Gal A),¹ resulting from one of many mutations of the gene GLA located at the Xq22.1.² The disease occurs with an incidence of approximately 1 in 117,000 live male births,³ although recent surveys suggest that the incidence may be much higher.⁴ Fabry disease primarily affects male individuals; female heterozygotes are reported to experience all of the signs and symptoms of Fabry disease but with a later onset and a more variable phenotype than is seen in men.^5,6 The signs and symptoms of Fabry disease are thought to be due to progressive accumulation of globotriaosylceramide (Gb₃) within tissues and organs. Among other signs and symptoms, progressive kidney dysfunction is nearly universal in male individuals with Fabry disease. The initial sign of decline in kidney function is proteinuria or microalbuminuria, which has been reported in affected male individuals as young as 16 yr⁷ and is present in half of male individuals by age 35 yr.⁸ Gb₃ accumulation within the glomeruli results in mesangial widening and glomerular sclerosis, with a resultant loss of filtering capacity.⁹ Chronic renal insufficiency (defined as serum creatinine levels ≥1.5 mg/dl) has an onset in the third decade of life and progresses rapidly to ESRD, with a reported average rate of decline in filtering capacity of 12.2 ml/min per yr (range 3.3 to 33.7 ml/min per yr) once chronic renal insufficiency has been reached.⁸ The average age at initiation of dialysis for ESRD in male patients with Fabry disease ranged between 36.7 and 42.0 yr.^5,10 Kidney dysfunction in female patients with Fabry disease is less prevalent than and usually not as severe as that in male patients but does progress to ESRD in some cases.^6,10Enzyme replacement therapy (ERT) with human α-Gal A was approved for treatment of Fabry disease in 2001 and has been reported to alleviate neuropathic pain,¹¹ result in regression of hypertrophic cardiomyopathy,¹² improve sweat function,¹³ reduce plasma and urine sediment Gb₃ levels,^11,14 and reduce microvascular endothelial Gb₃ deposits.^11,14 In one long-term (up to 4.5 yr) study of 25 male individuals with Fabry disease, agalsidase alfa, α-Gal A produced by gene activation in a human cell line, was reported to stabilize kidney function in patients with stage 1 or 2 chronic kidney disease¹⁵ at baseline and to slow the progression of renal dysfunction in adult male patients with stage 3 chronic kidney disease compared with historical control subjects.¹⁶ Observational studies of the patients enrolled in the Fabry Outcome Survey (FOS) suggested a similar renoprotective effect of agalsidase alfa.^17–19 The results of a recent, double-blind, placebo-controlled trial suggested that agalsidase beta, a recombinant form of α-Gal A produced in Chinese hamster ovary cells, slowed the progression of major clinical events in patients with Fabry disease and mild to moderate kidney disease, with the benefit being greater in patients with estimated GFR (eGFR) >55 ml/min per 1.73 m² at baseline than in those with baseline eGFR ≤55 ml/min per 1.73 m².²⁰ In this report, we present a summary of the effects of agalsidase alfa on kidney function in all of the adult male patients who were enrolled in prospective, randomized, placebo-controlled clinical studies of agalsidase alfa and their open-label extension studies and who were treated for at least 12 mo.     

Antiproteinuric therapy and fabry nephropathy: sustained reduction of proteinuria in patients receiving enzyme replacement therapy with agalsidase-beta

This report describes an open-label, nonrandomized, prospective evaluation of the effects of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy on patients who have Fabry disease and also received enzyme replacement therapy with agalsidase-beta, given at 1 mg/kg body wt every 2 wk. Previous placebo-controlled phase III and phase IV trials with agalsidase-beta demonstrated clearing of globotriaosylceramide from vascular endothelia but little effect on proteinuria or progressive loss of kidney function in patients with Fabry disease and severe chronic kidney disease marked by overt proteinuria and/or estimated GFR <60 ml/min per 1.73 m2. Angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker therapy is the standard of care for patients with proteinuric kidney diseases, but their use is challenging in patients with Fabry disease and low or low-normal baseline systemic BP. A group of patients with Fabry disease were treated with antiproteinuric therapy, in conjunction with agalsidase-beta; sustained reductions in proteinuria with stabilization of kidney function were achieved in a group of six patients who had severe Fabry nephropathy; the progression rate was -0.23 +/- 1.12 ml/min per 1.73 m2 per yr with 30 mo of follow-up.     

Safety and pharmacokinetics of agalsidase alfa in patients with Fabry disease and end-stage renal disease.

BACKGROUND: Fabry disease (FD) is caused by an X-linked deficiency in the activity of alpha-galactosidase A and the resultant accumulation of globotriaosylceramide (Gb3) in multiple tissues. Nearly all classically affected males with FD experience kidney dysfunction, with progression to end-stage renal disease (ESRD) in the third decade of life or shortly thereafter. METHODS: Twenty-two FD patients (20 men and 2 women) receiving dialysis or who had a history of kidney transplantation were treated with agalsidase alfa in an open label setting using the same dosing regimen given to patients without ESRD (0.2 mg/kg every other week). Pharmacokinetics (PK) were determined during and following the initial dose, and safety was evaluated during therapy. Change in plasma Gb3 level was used as a surrogate marker of enzyme activity in vivo. RESULTS: A typical biphasic plasma elimination profile was seen in both dialysis and transplant patients, similar to that observed in 18 non-ESRD FD patients. Calculated PK parameters were similar to the three patient groups. In the male patients, plasma Gb3 level declined by 43% after 6 months (P<0.001). Infusion reactions were experienced by 8 of 21 (38%) patients, but did not result in any infusions being stopped prematurely. Anti-agalsidase alfa IgG antibodies were detected in 15.8% of males and 0% female patients. No anti-agalsidase alfa IgE antibodies were detected. CONCLUSIONS: The same dosing regimen of agalsidase alfa may be safely administered to FD patients with ESRD as given to those without ESRD.     

Agalsidase alfa slows the decline in renal function in patients with Fabry disease

The aim of this study was to determine the effects of enzyme replacement therapy with agalsidase alpha on renal function in patients with Fabry nephropathy. Serum creatinine data were collected from 165 adult patients during 3 years of treatment. Serum creatinine increased in all men whereas it was stable in women, except in stage II renal disease (Kidney Disease Outcomes Quality Initiative). The estimated glomerular filtration rate (eGFR) declined in males with stage I and II (from 115.0 +/- 22.2 to 98.3 +/- 27.3 and from 76.5 +/- 8.1 to 66.3 +/-21.6 ml/min/1.73 m(2), respectively; both p < 0.01), whereas eGFR was stable in stage III. In females, eGFR was stable in stages I and III, and decreased in stage II (from 72.5 +/- 8.3 to 67.3 +/- 13.6 ml/min/1.73 m(2); p = 0.01). The 24-hour proteinuria was <1 g in all patients, and most patients (96%) were treated with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors. Agalsidase alpha in combination with ACE inhibitors/ARB may be effective in slowing the deterioration in renal function in Fabry nephropathy.     

Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease

Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.     

Enzyme replacement therapy and renal function in 201 patients with Fabry disease

AIM: Fabry disease is a rare lysosomal storage disorder caused by deficient activity of alpha-galactosidase A, resulting in progressive cellular accumulation of glycolipids, which may ultimately result in endstage renal disease. We examined the effects of enzyme replacement therapy (ERT) with Agalsidase-alpha on renal function using data from a large international database, the Fabry Outcome Survey (FOS). METHODS: This analysis was based on 1,040 serum creatinine measurements in 201 patients with Fabry disease, aged 20 - 60 years, with serum creatinine concentrations of less than 2 mg/dl and duration of ERT of up to 4.7 years. Both pretreatment and treatment data were used to examine independent predictors of changes in serum creatinine. In a second approach longitudinal serum creatinine measurements from 1 year before treatment, at baseline and 1 and 2 years after the start of treatment were analyzed in 20 patients with chronic kidney disease (CKD) Stage 2 and 3. RESULTS: We found an independent negative association between serum creatinine and time on Agalsidase-alpha treatment (p < 0.05). Renal function declined significantly (p < 0.05) in the year before treatment. After 1 year of treatment, however, the decline in estimated glomerular filtration rate had been halted, and renal function was preserved for up to 2 years. CONCLUSIONS: In conclusion, ERT with Agalsidase-alpha is associated with decrease of serum creatinine and may prevent the deterioration of renal function in patients with Fabry disease.     

Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta

BACKGROUND: Fabry disease is an X-linked inherited disorder that is caused by excessive lysosomal globotriaosylceramide (CTH) storage due to a deficiency in alpha-galactosidase A (alpha-Gal A). Two recombinant enzyme preparations have been approved as treatment modality. We studied emergence and properties of alpha-Gal A antibodies in treated patients. METHODS: During the first 6 to 12 months of intravenous administration of recombinant enzymes (rh-alpha-Gal A) formation of antibodies was studied in 18 adult Fabry patients (two females). RESULTS: The female patients did not develop detectable amounts of antibodies following enzyme therapy. After 6 months of treatment with either agalsidase alpha or beta, 11/16 male patients showed high titers of immunoglobulin G (IgG) antibodies that cross-react in vitro similarly with both recombinant enzymes. The anti-rh-alpha-Gal A IgG neutralizes rh-alpha-Gal A activity in vitro for 65% to 95%. During infusion with rh-alpha-Gal A, circulating enzyme-antibody complexes are formed and these complexes are taken up by leukocytes in the peripheral blood. After 6 months of treatment all IgG-negative patients showed a significant (P < 0.01) reduction of urinary CTH (1890 +/- 797 to 603 +/- 291 nmol CTH/24hr urine), compared to IgG-positive patients (mean increase from 2535 +/- 988 to 2723 +/- 1212), suggesting a negative effect of circulating antibodies on renal tubular CTH clearance. CONCLUSION: Emergence of antibodies with in vivo neutralizing capacities is frequently encountered in treated Fabry disease patients. Complete cross-reactivity of these antibodies suggests that it is unlikely that switching from one to the other recombinant protein prevents the immune response and related effects. Further studies on the clinical implications of alpha-Gal A antibodies are essential.     

Angiotensin I-converting enzyme gene polymorphism in non-diabetic renal disease.

BACKGROUND: The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene determines the concentration of ACE in serum and local tissues. The role of this polymorphism in progressive chronic renal disease is still not fully clear. METHODS: We analysed the impact of the D/D polymorphism on the rate of decline in renal function in patients with non-diabetic, chronic progressive renal insufficiency. Seventy non-diabetic patients, aged 21-69 years at baseline, with moderately advanced renal insufficiency due to primary chronic renal disease were followed for an average of 3 years with repeated measurements of their glomerular filtration rate (GFR). Their mean GFR at baseline was 41 ml/min/1.73 m(2) body surface area (BSA). The polymerase chain reaction (PCR) amplification method was used to detect the I/D polymorphism of the ACE gene. GFR was measured as the clearance of (51)Cr-EDTA and the individual rate of progression was calculated using linear regression. RESULTS: The distributions of the genotypes were: D/D 30%, I/D 49%, and I/I 21%. The rates of progression in the three ACE genotype groups were an annual decline in renal function of -4.2 (SD 4.6) ml/minx1.73 m(2) BSA in the D/D group, -2.7 (SD 3. 4) in the I/D group and -1.7 (SD 3.4) in the I/I group (ANOVA P=0. 12). In patients with proteinuria below 3.5 g/24 h, the D/D group had a significantly higher rate of progression than patients with the I allele. The same was found in a separate analysis when only patients with normal apoliprotein B (below 155 mg/dl) levels were analysed. Furthermore, the D/D genotype was a significant predictor of a more rapid decline in renal function in male, but not female, patients. CONCLUSION: The results in this study in non-diabetic patients with chronic renal disease indicate that the presence of the D allele in the ACE genotype may be of particular importance as a predictor of a high rate of progression in male patients who otherwise do not have a major burden of documented and important prognostic factors for progressive renal insufficiency.     

Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy

BACKGROUND: Fabry disease, a lysosomal storage disease caused by deficient lysosomal alpha-galactosidase A activity, is characterized by globotriaosylceramide (GL-3) accumulation in multiple cell types, particularly the vasculature, leading to end organ failure. Accumulation in the kidney is responsible for progressive decline in renal function in male patients with the classical phenotype, resulting in renal failure in their third to fifth decades of life. With the advent of recombinant protein synthesis technology, enzyme replacement therapy has become a viable alternative to dialysis or renal transplantation, previously the only available treatment options for end-stage renal disease. METHODS: The pre- and post-treatment renal biopsies were analyzed from fifty-eight Fabry patients enrolled in a Phase 3 double-blind, randomized, placebo-controlled trial followed by a six-month open label extension study of the recombinant human enzyme, alpha-galactosidase A (r-halphaGalA), administered IV at 1 mg/kg biweekly. The purpose of this investigation was to detail the pathologic changes in glycosphingolipid distribution and the pattern of post-treatment clearance in the kidney. RESULTS: Baseline evaluations revealed GL-3 accumulations in nearly all renal cell types including vascular endothelial cells, vascular smooth muscle cells, mesangial cells and interstitial cells, with particularly dense accumulations in podocytes and distal tubular epithelial cells. After 11 months of r-halphaGalA treatment there was complete clearance of glycolipid from the endothelium of all vasculature as well as from the mesangial cells of the glomerulus and interstitial cells of the cortex. Moderate clearance was noted from the smooth muscle cells of arterioles and small arteries. Podocytes and distal tubular epithelium also demonstrated evidence for decreased GL-3, although this clearance was more limited than that observed in other cell types. No evidence of immune complex disease was found by immunofluorescence despite circulating anti-r-halphaGalA IgG antibodies. CONCLUSIONS: These findings indicate a striking reversal of renal glycosphingolipid accumulation in the vasculature and in other renal cell types, and suggest that long-term treatment with r-halphaGalA may halt the progression of pathology and prevent renal failure in patients with Fabry disease.     

Combined Heart and Kidney Transplantation in a Patient with Fabry Disease in the Enzyme Replacement Therapy Era

Fabry disease (FD) is an X-linked genetic disease, resulting from the deficiency of alpha-galactosidase A, a lysosomal enzyme responsible for the cleavage of glycosphingolipids. In absence of enzyme replacement therapy (ERT), globotriaosylceramide (Gb3) accumulates in tissue, leading to progressive organ damage with severe renal, cardiac and central nervous system complications.
We herein describe the first case of successful combined and simultaneous heart and kidney transplantation in a young male patient with FD complicated by end-stage renal disease and severe heart failure not responding to late-onset ERT.
Combined heart and kidney transplantation can be recommended for Fabry patients with end-stage renal disease and overt hypertrophic cardiomyopathy, severe ischemic or valvular heart disease.     

Focal and segmental glomerular sclerosis (FSGS) in a man and a woman with Fabry's disease

We describe a man and a woman with Fabry's disease. Renal biopsies showed late and early stages respectively of focal and segmental glomerulosclerosis (FSGS) and vascular changes. Clinically the hemizygous patient had advanced renal disease with nephrotic range proteinuria and serum creatinine 122 micromol/l. The female carrier had minimal albuminuria, borderline GFR with a normal serum creatinine, acroparesthesias, moderate fatigue, tinnitus and headache accompanied by ischemic cerebral lesions. Enzyme replacement therapy (ERT) was initiated according to our Fabry protocol, partly due to the renal morphologic findings. We conclude that FSGS and vascular changes may be an early morphologic finding in Fabry's disease, even in patients with subtle albuminuria. The potential role of FSGS as a marker of progressive renal disease in some Fabry patients is discussed. As FSGS and vascular changes obviously may exist across a wide range of clinical presentations and have potential prognostic implications, we suggest that a renal biopsy should be performed prior to enzyme replacement therapy in all adult Fabry patients with proteinuria of various levels. Efforts should be made to develop a scoring system to evaluate potential histologic markers. Protocol biopsies may have therapeutic implications and may provide valuable information in the evaluation of start and dosing of ERT.     

Home treatment for Fabry disease: practice guidelines based on 3 years experience in The Netherlands.

INTRODUCTION: Recently, chronic supplementation with alpha-galactosidase A (alphaGal A) has been approved as a treatment modality for Fabry disease. The aim of the current study was to investigate the feasibility of home therapy for Fabry disease during a follow-up of >3 years and to make a proposal for practice guidelines. METHODS: Based on experience in previous clinical trials, an algorithm for home treatment eligibility was developed. The number of successful and uneventful infusions was recorded, as well as adverse and infusion-associated events. The presence and titre of recombinant human (rh)-alphaGal A antibodies were monitored every 3 months. RESULTS: Thirty of the 36 patients eligible for home treatment received a total of 1418 infusions at home (median 44 infusions, range 1-108), between March 2001 and July 2005. Mean age was 44.7 years (17-71). Seventeen patients receiving home treatment (57%) were male. The majority of patients (27 out of 30, 90%) undergoing home treatment received 0.2 mg/kg agalsidase alpha or beta. Six male patients developed an infusion-associated event, of which three developed these at home. All patients with an infusion-associated event were anti-rh-alphaGal A IgG positive at 3 months, but three patients with rh-alphaGal A antibodies did not develop side effects. Antibody titres between these patients did not differ. None of the events was life-threatening or necessitated urgent admission. CONCLUSION: Home treatment with rh-alphaGal A for Fabry disease with 0.2 mg/kg for males and both 1.0 and 2.0 mg/kg for females is feasible and safe, and reduces both the burden related to chronic intravenous therapy and health care costs. Whether this can also be applied for male patients treated with 1.0 mg/kg has not yet been determined.     

Decline in kidney function before and after nephrology referral and the effect on survival in moderate to advanced chronic kidney disease.

BACKGROUND: The burden of chronic kidney disease (CKD) is high, but its natural history and the benefit of routine nephrology care is unclear. This study investigated the decline in kidney function prior to and following nephrology referral and its association with mortality. METHODS: This study provides a retrospective review of the individual rates of glomerular filtration rate (GFR) decline (millilitre per minute per 1.73 m(2)/year) for the 5 years before and after referral in 726 new referrals with stages 3-5 CKD to one renal unit between 1997 and 2003. Blood pressures are averages at referral, 1 and 3 years post referral. Logistic regression and Cox's models tested factors predicting post-referral GFR decline and the impact on mortality. RESULTS: Mean (SD) age was 72 (14), and 389 (54%) patients had stages 4-5 CKD. GFR decline slowed significantly from -5.4 ml/min/1.73 m(2)/year (-13. to -2) before to -0.35 ml/min/1.73 m(2)/year (-3 to +3) after referral (P < 0.001). Blood pressure also reduced significantly (155/84 to 149/80, P < 0.05) with most changes occurring within 1 year of referral. Factors predicting a non-progressive post-referral decline included a lower systolic blood pressure at referral and 1 year after referral, a CKD diagnosis other than diabetic nephropathy, less baseline proteinuria and a non-progressive pre-referral GFR decline. A non-progressive post-referral GFR decline was independently associated with significantly better survival (hazard ratio 0.55, 95% CI 0.40-0.75, P 相似文献