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.     

Enzyme replacement therapy with agalsidase beta in kidney transplant patients with Fabry disease: a pilot study

BACKGROUND: We sought to assess the safety and efficacy of enzyme replacement therapy (ERT) with recombinant human-alpha-galactosidase A (rh-alpha-Gal A) in kidney transplant recipients with Fabry disease, a previously unstudied population. METHODS: Three male kidney transplant recipients with biochemically, genetically, and histologically confirmed Fabry disease and documented Fabry myocardiopathy received the rh-alpha-Gal A, agalsidase beta, 1 mg/kg of body weight every 2 weeks by intravenous infusion and were monitored biochemically, clinically, and electrocardiographically and echocardiographically for 18 months. RESULTS: Patients showed biochemical, clinical/functional, and morphologic response to ERT. Plasma globotriaosylceramide decreased 23% to 50%. Extremity pain resolved within 2 months in the patient with this manifestation. On echocardiography, left ventricular mass, end diastolic diameter (EDD), and cardiac contractility, shown by ejection fraction (EF), improved in 2 of the 3 patients receiving essentially all planned infusions. EDD and EF remained basically stable, but cardiac morphologic abnormalities progressed in the other patient, who had a 5-month interruption in ERT after the initial month. Mild mitral insufficiency persisted in all patients, as did atrial fibrillation in the affected individual. After a combined total of 116 infusions, no treatment-related adverse event, intolerance, or seroconversion was seen. Renal function remained stable and the immunosuppression regimen unchanged in all patients. CONCLUSION: Our pilot study provides preliminary evidence that ERT with agalsidase beta, 1 mg/kg every 2 weeks, is safe and often effective against extra-renal manifestations in kidney transplant patients with Fabry disease. Studies with longer courses of this and higher doses of ERT are merited in this population.     

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.     

Gastric emptying in patients on renal replacement therapy

In addition to gastrointestinal tract symptoms such as nausea, vomiting, and loss of appetite, impaired gastric emptying time (GET) may be related to nutritional parameters and nutritional status of patients on renal replacement therapy (RRT). Patients on RRT are affected by several factors such as uremic toxins, the presence of dialysate in the peritoneal cavity, and the drugs used against renal allograft rejection. In this study, we investigated the gastric emptying time and its relationship with biochemical and nutritional parameters in patients on RRT: those on hemodialysis and peritoneal dialysis, and renal transplantation patients. Seventy-five patients, 44 on hemodialysis, 16 on peritoneal dialysis, and 15 renal transplant patients, were included in the study. They were examined for gastric emptying time using a radioisotopic method. The results were compared with the GET of healthy subjects. Each group of patients was evaluated in terms of hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, blood glucose, total protein, albumin, serum lipids, parathyroid hormone (PTH) and body mass index and biceps and triceps skinfold. The mean GET of patients on RRT was significantly longer than the mean GET of healthy subjects (87.8 +/- 23.4 vs. 55 +/- 18 min, p<0.05). The mean GET of each therapy subgroups was significantly longer than the healthy subjects (the mean GET was 85.1 +/- 22.4 min for hemodialysis, 87.7+/-31.8 min for peritoneal dialysis, and 94.6+/-16.7 min for renal transplant patients, respectively, p<0.05). On the other hand, the differences in the mean GET between the three therapy subgroups were not statistically significant (p>0.05). In addition, time on replacement therapy inversely and blood glucose positively correlated with GET in renal transplant patients. In conclusion, GET was longer in patients on all three RRT modalities than in healthy subjects. GET was not significantly different in dialysis patients and renal transplant patients.     

Current incidence, treatment patterns and outcome of end-stage renal disease among indigenous groups in Australia and New Zealand

SUMMARY: The changes in rates of treated end-stage renal disease (ESRD) among indigenous populations have profound consequences for those individuals affected and for health-care providers. By using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, we examined the current incidence, treatment and outcomes of ESRD among indigenous groups in Australia and New Zealand. All patients who began renal replacement therapy (RRT) in Australia or New Zealand between October 1991 and September 2000 were included. Rates of ESRD, RRT modalities, renal transplantation and mortality were the outcomes examined. End-stage renal disease rates among indigenous groups in Australia and New Zealand exceeded non-indigenous rates up to eightfold. The median age of indigenous ESRD patients was younger (51 vs 60 years, P  < 0.0001), and there was an excess of comorbidities, particularly diabetes. For Australian Aboriginal and Torres Strait Islanders, and New Zealand Maori patients, mortality rates across all modalities of RRT were 70% higher than non-indigenous rates. Indigenous people were less likely to receive a renal transplant prior to dialysis treatment, less likely to be accepted onto the cadaveric transplant waiting list, and less likely to receive a well-matched transplant. The poorer outcomes among Australian Aboriginal and Torres Strait Islanders, and New Zealand Maori patients did not appear to be explained by the different comorbid conditions or age. Whether the outcomes reflect unmeasured differences in disease burden or treatment differences is not known. Tackling this problem will involve a spectrum of people and approaches, from tertiary care providers and RRT to local staff and preventative programs.     

Renal replacement therapy options from an Indian perspective: dialysis versus transplantation

In developing countries such as India, the management of end-stage renal disease (ESRD) is largely guided by economic considerations. In the absence of health insurance plans, fewer than 10% of all patients receive renal replacement therapy (RRT). Hemodialysis (HD) is mainly a short-term measure to support ESRD patients prior to transplant. Infections are common in dialysis patients. The majority of patients starting HD die or are forced to abandon treatment because of cost constraints within the first 3 months. The cost of peritoneal dialysis (PD) is two times higher than that of HD, fewer than 2% of patients are started on PD. Among the three RRT options available, renal transplant is the preferred mode, as it is most cost-effective and provides a better quality of life. But due to financial constraints and nonavailability of organs, only about 5% of ESRD patients undergo transplant surgery. Though the removal of organs from brain-dead patients has been legalized, the concept of donation of organs from deceased donors has not received adequate social sanction. Only 2% of all transplants are performed from deceased donors. Due to limited access to RRT, the ideal approach should be to reduce the incidence of ESRD and attempt preventive measures. Preemptive transplant, reducing the duration of dialysis prior to transplant, use of immunosuppression for only up to 1 year, and availability of more deceased donor organs may be helpful to make RRT options within the reach of the common man.     

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.     

The impact of major perioperative renal insult on long-term renal function and survival after cardiac surgery

Temporary renal replacement therapy (RRT) facilitates recovery from a major perioperative renal injury and, although RRT can improve the hospital outcome, it is not known as to whether it mitigates long-term renal sequelae. Therefore, we investigated the risk of long-term dialysis after RRT post-cardiac surgery. We analysed prospectively the data collected for all hospital survivors who received RRT following cardiac surgery between March 1996 and July 2010, excluding those on dialysis preoperatively or with a functioning renal transplant. The follow-up data were obtained for all surviving patients. The mean age of the 82 patients was 68.6 ± 9.9 years, and 60 (73%) were male. Severe pre-existing renal dysfunction with a serum creatinine level of >200 μmol/l was present in 15 (18%) patients and diabetes in 31 (38%) patients. Operative procedures included redo surgery (n = 11, 13%) and thoracic aortic surgery (n = 9, 11%). During a 13.4-year follow-up, there were 38 late deaths. Only three patients with severe preoperative renal dysfunction received dialysis. The Kaplan-Meier 5- and 7-year survival rates for this patient cohort were 54% and 38%, respectively. In conclusion, a major renal insult requiring temporary RRT after cardiac surgery does not increase the risk for renal dialysis in the long term for patients with normal renal function preoperatively.     

Gastric Emptying in Patients on Renal Replacement Therapy

In addition to gastrointestinal tract symptoms such as nausea, vomiting, and loss of appetite, impaired gastric emptying time (GET) may be related to nutritional parameters and nutritional status of patients on renal replacement therapy (RRT). Patients on RRT are affected by several factors such as uremic toxins, the presence of dialysate in the peritoneal cavity, and the drugs used against renal allograft rejection. In this study, we investigated the gastric emptying time and its relationship with biochemical and nutritional parameters in patients on RRT: those on hemodialysis and peritoneal dialysis, and renal transplantation patients. Seventy‐five patients, 44 on hemodialysis, 16 on peritoneal dialysis, and 15 renal transplant patients, were included in the study. They were examined for gastric emptying time using a radioisotopic method. The results were compared with the GET of healthy subjects. Each group of patients was evaluated in terms of hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, blood glucose, total protein, albumin, serum lipids, parathyroid hormone (PTH) and body mass index and biceps and triceps skinfold. The mean GET of patients on RRT was significantly longer than the mean GET of healthy subjects (87.8 ± 23.4 vs. 55 ± 18 min, p < 0.05). The mean GET of each therapy subgroups was significantly longer than the healthy subjects (the mean GET was 85.1 ± 22.4 min for hemodialysis, 87.7 ± 31.8 min for peritoneal dialysis, and 94.6 ± 16.7 min for renal transplant patients, respectively, p < 0.05). On the other hand, the differences in the mean GET between the three therapy subgroups were not statistically significant (p > 0.05). In addition, time on replacement therapy inversely and blood glucose positively correlated with GET in renal transplant patients. In conclusion, GET was longer in patients on all three RRT modalities than in healthy subjects. GET was not significantly different in dialysis patients and renal transplant patients.     

Survival and transplantation outcomes of children less than 2 years of age with end-stage renal disease

Background

Young children with end-stage renal disease (ESRD) requiring renal replacement therapy (RRT) have traditionally experienced high rates of morbidity and mortality; however, detailed long-term follow-up data is limited.

Methods

Using a population-based retrospective cohort with data from a national organ failure registry and administrative data from Canada’s universal health care system, we analysed the outcomes of 87 children starting RRT (before age 2 years) and followed them until death or date of last contact [median follow-up 4.7 years, interquartile range (IQR) 1.4–9.8). We assessed secular trends in survival and the influence of: (1) age at start of RRT and (2) etiology of ESRD with survival and time to transplantation.

Results

Patients were mostly male (69.0 %) with ESRD predominantly due to renal malformations (54.0 %). Peritoneal dialysis was the most common initial RRT (83.9 %). Fifty-seven (65.5 %) children received a renal transplant (median age at first transplant: 2.7 years, IQR 2.0–3.3). During 490 patient-years of follow-up, there were 23 (26.4 %) deaths, of which 22 occurred in patients who had not received a transplant. Mortality was greater for patients commencing dialysis between 1992 and 1999 and among the youngest children starting RRT (0–3 months). Children with ESRD secondary to renal malformations had better survival than those with ESRD due to other causes. Among the transplanted patients, all but one survived to the end of the observation period.

Conclusion

Children who start RRT before 3 months of age have a high risk of mortality. Among our paediatric patient cohort, mortality rates were much lower among children who had received a renal transplant.     

Pediatric dialysis and renal transplantation in Kuwait over the past 11 years

Data on end-stage renal disease (ESRD) patients and their renal replacement therapy (RRT) were collected retrospectively from the three dialysis centers, the pediatric urology unit, and the organ transplant center of Kuwait. The study period was from 1 January 1986 to 31 December 1996. A total of 61 children, 50 of whom were Kuwaiti nationals, required RRT for ESRD during those 11 years. This gave an average annual incidence rate of 18 per million Kuwaiti children. Glomerulonephritis was the most-frequent underlying disease and accounted for 44% of total cases, while pyelonephritis (including urinary tract anomalies and dysplastic kidneys) was responsible for 30%. Multisystem disease was responsible for ESRD in 7 patients (14%), 2 of whom had lupus nephritis, 2 vasculitis, 2 Henoch-Schönlein purpura, and 1 hemolytic uremic syndrome. Continuous ambulatory peritoneal dialysis and home intermittent peritoneal dialysis, using cycler machines, were not favored dialysis techniques by most parents, especially for those <6 years old. The actuarial survival on dialysis was 75%±7% at 12 months. Of the 8 patients who died, 7 were <6 years old. Thirty-eight patients received 46 kidney transplants, 13 of which were performed on a pre-emptive basis. The actuarial patient survivals at 12 months for those receiving first live and cadaveric kidney transplants were 90%±5% and 85%±2%, respectively, while those for grafts were 76%±8% and 66%±2%, respectively. This is the first nationwide long-term study of the incidence and etiology of pediatric ESRD in our area and the RRT in a country with adequate treatment facilities.     

Improved outcome of young children on nightly automated peritoneal dialysis

We reviewed our center’s experience with nightly automated peritoneal dialysis (APD) as maintenance renal replacement therapy (RRT) for infants and children under the age of 5 years and compared it with national dialysis and transplant data. A retrospective chart review of 19 consecutive patients with the onset of end-stage renal disease (ESRD) before 5 years of age (mean = 1.8 years) between June 1988 and June 1994 was performed. All patients received nightly APD, supplemental feedings, calcitriol, erythropoietin, and 10 of 19 were on growth hormone (rhGH) therapy. The growth of our patients was maintained or improved during the study period, with the 10 of 19 on rhGH gaining a mean of one standard deviation in height when followed for 2 years. Our school-age children were all in age-appropriate classes. There were no deaths in our group; the incidence of peritonitis was lower than in national data. We conclude that APD is a realistic option for the treatment of ESRD in the 0- to 5-year-old child. Because of the improved graft and patient survival in older children, APD in a specialized center might be the RRT of choice in this age group, allowing good growth and development while maximizing the chances of an eventual and successful renal transplant. Received August 21, 1996; received in revised form and accepted March 26, 1997     

Surgical Interventions for Renal Replacement Therapy from the View of Nephrologists

Summary BACKGROUND: The number of patients with end-stage renal disease (ESRD) is increasing worldwide at a rate of approximately 5 % per year. In Austria, 6049 patients were suffering from ESRD in the year 2001, an annual rate of 1093 patients. Higher age of patients and co-morbidities are forcing nephrologists to find the optimal renal replacement therapy (RRT) and access modality for the individual patient. METHODS: For patients with ESRD needing RRT, both nephrologist and surgeon should be consulted to ensure optimal management and treatment including vascular access surgery. Patients planned for peritoneal dialysis (PD) are treated with the cooperation of a visceral surgeon. A catheter is inserted into the pelvic area to enable solution exchange. In patients who are to undergo hemodialysis (HD), nephrologists have to decide whether the cardiac condition is suitable for surgical access creation such as fistula or graft. Otherwise alternative hemodialysis devices such as a central venous catheter (CVC), or subcutaneously implantable ports (Dialock^®), have to be discussed. Access function is routinely monitored during dialysis treatment, but still remains the weak component of extracorporeal RRT responsible for 40 % of hospitalization of HD patients. RESULTS: At the dialysis unit of the University Hospital of Graz, 107 patients were under RRT (70 HD and 37 PD), and 235 patients were hemodialyzed in private units in Graz in 2001. 81 ESRD patients were newly enrolled in the chronic HD program. 131 HD accesses were created in new HD patients and patients under treatment for chronic HD. 36 patients developed HD access complications and in these patients, 181 surgical and/or radiological interventions were performed. CONCLUSIONS: In 12 % of the HD patients in Graz, access problems occurred. These patients have a high frequency of surgical and radiological interventions. Access monitoring and measurement of recirculation may help to reduce the complication rate by 38 %. Before onset of RRT, patients need special management to ensure the best dialysis modality. ESRD patients who are suffering from cardiac diseases, diabetes mellitus, or bad peripheral vascular status need a multidisciplinary approach with nephrologists, cardiologists, surgeons and radiologists working together to find the optimal access for dialysis treatment.     

Outcome of renal replacement therapy in the very elderly.

BACKGROUND: In a retrospective case-note and computer database analysis we assessed the outcome of very elderly patients (> or = 75 years old) with end-stage renal disease (ESRD) on renal replacement therapy (RRT). METHODS: Fifty-eight individuals aged 75 or over (group 1) commenced RRT between 1 January 1991 and 31 December 1995. Comparisons were made with other patients commencing RRT who were divided into two groups: group 2 (201 individuals 65-74 years old) and group 3 (379 patients <65 years old). All subjects were followed up until the point of assessment (30 June 1998), the time of death, or withdrawal from dialysis. Survival rates in the three groups were compared using Kaplan-Meier method. The number of hospital admissions, length of in-patient stay, and complications rate on RRT were assessed for group 1. RESULTS: One-year survival rates in groups 1, 2 and 3 were 53.5, 72.6, and 90.6% respectively and the 5-year survival rates were 2.4, 18.8, and 61.4% respectively. The very elderly spent 20% of their time in hospital, 46% had two co-morbid factors at the outset, and 26% developed multiple complications while on RRT. Withdrawal from dialysis remained the most common cause of death in this group of individuals (38%), followed by cardiovascular causes (24%) and infections (22%). CONCLUSION: Very elderly ESRD patients on RRT have a very poor outcome and, since they are the largest growing group of RRT patients, this has important implications for future health policies.     

The epidemiology of end-stage renal disease in Iran in an international perspective.

INTRODUCTION: The epidemiology of end-stage renal disease (ESRD) and renal replacement therapy (RRT) is under continuous evolution all over the world. We report here the epidemiological analysis of ESRD and RRT in Iran and discuss it against the background of the international situation. METHODS: This epidemiological report is based on data from centre questionnaires which were collected in Iran from 1997 onwards, with a response rate of 100%. RESULTS: The prevalence/incidence of RRT patients were 238/49.9 p.m.p. in the year 2000. Haemodialysis and kidney transplantation were the most common RRT modalities, accounting for 53.7% and 45.5% of prevalent RRT patients, respectively. The proportion treated by peritoneal dialysis was very low (<1%). Home haemodialysis was not performed. The majority of haemodialysis centres used synthetic membranes (70%) and 100% of the sessions were performed using acetate as a buffer; 42.5% of haemodialysis patients were treated with a twice-weekly regimen, whilst 49.6% were on the standard thrice-weekly regimen. The majority of RRT patients in Iran were young to middle aged. The great majority of renal allografts came from living donors (mainly unrelated to recipients). The main renal diseases leading to ESRD were diabetes and hypertension. The third most common category was "cause unknown". CONCLUSION: The epidemiology of RRT in Iran is characterized by: (i) young patient age (younger than the international average); (ii) high proportion of patients receiving renal allograft; (iii) use of living-unrelated donors as the major source of renal allografts.     

Quality of life in children with end-stage renal disease undergoing renal replacement therapy: a cross-sectional survey

Objective To evaluate the quality of life (QOL) of children with uremia who underwent renal replacement therapy (RRT) and identify the influencing factors for QOL in order to improve the QOL of children with uremia. Methods Children with ESRD who underwent dialysis or kidney transplantation (KT) at Children's Hospital of Fudan University between November 2016 and October 2017 were enrolled. The children and/or their parents completed and returned the Pediatric QOL Inventory Measurement Models (PedsQLTM) 4.0 questionnaire. Moreover, the clinical data of these children were collected. According to the way of RRT, children were divided into dialysis group and KT group. The differences of scores between two groups were compared. Multiple linear regression analysis was used to analyze the factors affecting the QOL of children. Results A total of 79 children undergoing RRT were enrolled. Among them, 48 cases in the dialysis group and 31 cases in the KT group. For children in KT group, the total PedsQL scores of child-self and parent-proxy assessment were higher than those in dialysis group (P＜0.05). The total scores for the QOL of child-self and parent-proxy assessment were roughly the same for KT children (P＞0.05). The total scores for the QOL of child-self and parent-proxy assessment were different for dialysis children (P=0.05). Short stature (height＜3th percentile) and elevated left ventricular mass index (LVMI) were the independent influencing factors for the QOL of child-self and parent-proxy assessment in children undergoing KT, respectively (B=12.162, t=2.681, P＜0.05; B=-0.240, t=-4.276, P＜0.01). Conclusions QOL was higher in children undergoing KT than those on dialysis. Short stature and elevated LVMI were the independent influencing factors for QOL in children undergoing KT.     

Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting.

BACKGROUND: Fabry disease is an X-linked disorder of glycosphingolipid catabolism that is the result of an intracellular deficiency in the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). This enzymatic defect results in the accumulation of globotriaosylceramide (Gb(3)) within cells and causes progressive neurological, cardiovascular and renal dysfunction. Our objective is to describe the safety and renal effects of long-term enzyme replacement therapy. METHODS: This was a single centre, prospective open-label treatment trial in 25 adult male Fabry patients who had completed a 6-month randomized placebo-controlled study and subsequently enrolled in an open-label extension study. Patients were treated every other week with agalsidase alfa (0.2 mg/kg) infused intravenously over 40 min. The main outcome measures were safety, antibody response and renal glomerular filtration rate (GFR). RESULTS: During the 4-4.5 years of enzyme replacement therapy, all eligible subjects were able to transition to home therapy. Eight patients developed persistent IgG antibodies to agalsidase alfa, but IgE antibodies were not detected in any patient. The development of IgG antibodies appeared not to affect any clinical end points. Estimated GFR remained stable in subgroups of patients with Stage I (GFR >90 ml/min) or Stage II (GFR 60-89 ml/min) chronic kidney disease at baseline. In contrast, in the subgroup of patients with Stage III chronic kidney disease (GFR 30-59 ml/min), the slope of the decline in GFR was reduced compared with comparable historical controls, suggesting that enzyme replacement therapy was slowing the decline of renal function in this susceptible population. CONCLUSIONS: Long-term enzyme replacement therapy with agalsidase alfa is safe and may slow the progressive decline in renal function that was commonly observed in adult males with Fabry disease.     

Combined assessment of cardiac systolic dysfunction and coronary atherosclerosis used to predict future cardiac deaths after starting hemodialysis

BACKGROUND/AIMS: Identification of end-stage renal disease (ESRD) patients at high risk for cardiac events is important for clinical dialysis management. The present study determined whether the combination of cardiac function and coronary atherosclerosis could predict future cardiac events after starting renal replacement therapy (RRT). METHODS: We prospectively assessed left ventricle ejection fraction (EF) and Gensini score (GS) using angiographic severity of coronary atherosclerosis in 88 consecutive ESRD patients [mean age 62 years; 69 males (78%); 55 patients (64%) with diabetic nephropathy] at the initiation of RRT. EF was analyzed by echocardiogram, and GS was scored by coronary angiography within 3 months after starting RRT. The study end point was cardiac death. For analysis of the association between cardiac death and EF and GS measures, the univariate and multivariate Cox proportional hazards model was used. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value, and accuracy of event-free prediction were evaluated. RESULTS: Twenty-four patients (27%) had low cardiac function (EF <50%; low EF) and 44 patients (50%) had severe coronary atherosclerosis (GS >15; high GS). During a follow-up period of 3 years, cardiac death occurred in 21 patients (24%). The PPV of low EF and high GS was 42 and 39%, respectively; the highest PPV (53%) was obtained when low EF and high GS were combined. The cumulative survival rate at 5 years in patients with both low EF and high GS was significantly lower than those with high EF and low GS (91 vs. 22%, p < 0.0005). CONCLUSION: The combined assessment of cardiac function and coronary atherosclerosis at the initiation of RRT strongly predicts future cardiac events.     

Renal replacement therapy in Europe: the results of a collaborative effort by the ERA-EDTA registry and six national or regional registries.

BACKGROUND: In June 2000 a new ERA-EDTA Registry Office was opened in Amsterdam. This Registry will only collect core data on renal replacement therapy (RRT) through national and regional registries. This paper reports the technical and epidemiological results of a pilot study combining the data from six registries. METHODS: Data from the national renal registries of Austria, Finland, French-Belgium, The Netherlands, Norway, and Scotland were combined. Patients starting RRT between 1980 and 1999 (n=57371) were included in the analyses. Cox proportional hazards regression was used to predict survival. RESULTS: The use of different coding systems for ESRD treatment by the registries made it difficult to merge the data. Incidence and prevalence of RRT showed a continuous increase with a marked variation in rates between countries. The 2-, 5- and 10-year patient survival was 67, 35 and 11% in dialysis patients and 90, 81 and 64% after a first renal allograft. Multivariate analysis showed a slightly better survival on dialysis in the 1990-1994 (RR 0.94, 95% CI 0.90-0.98) and the 1995-1999 cohort (RR 0.88, 95% CI 0.84-0.92) compared to the 1980-1984 cohort. In contrast, there was a much greater improvement in transplant-patient survival, resulting in a 56% reduction in the risk of death within the 1995-1999 cohort (RR 0.44, 95% CI 0.39-0.50) compared to the 1980-1984 cohort. CONCLUSIONS: This study provides support for the feasibility of a "new style" ERA-EDTA registry and the collection of data is now being extended to other countries. The improvement in patient survival over the last two decades has been much greater in transplant recipients than in dialysis patients.     

Clinical benefit of enzyme replacement therapy in Fabry disease

Enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A (r-halphaGalA) enhances microvascular globotriaosylceramide clearance and improves clinical symptoms in patients with Fabry disease. We evaluated whether these effects are translated into a long-term benefit of kidney and heart function. We did a single center, prospective, open label study in 26 patients with Fabry disease (one early death, follow-up in 25 patients). r-Alpha-GalA was administered in a dosage of 1 mg/kg body weight every second week. The effect of therapy on clinical end points (death, cardiac and cerebrovascular event, renal failure), cardiac and renal function monitored by Doppler echocardiography, 99Tc-GFR, and proteinuria was investigated. After a mean treatment time of 23 +/- 8 months, nine patients experienced 12 end points, including two deaths. All end points occurred in patients with impaired renal function (n = 16; GFR 71 +/- 17 ml/min/1.73 m2). Despite ERT, renal function deteriorated to 60 +/- 23 ml/min/1.73 m2 (P = 0.04) and left ventricular posterior wall thickness (PWT) did not change (14.0 +/- 2.1 vs 13.4 +/- 2.3 mm). In contrast, patients without impairment of renal function (n = 9) had a more favorable outcome (no clinical events; GFR 115 +/- 18 vs 102 +/- 14 ml/min/1.73 m2, NS; PWT 11.7 +/- 1 and 10.7+/-0.7 mm, P = 0.04). Proteinuria remained unchanged (1.34 +/- 0.94 vs 1.01 +/- 0.97 g/day, n = 10). Patients with impaired renal function have a less favorable outcome and may develop cardiovascular and renal end points despite ERT.