Reducing agalsidase beta infusion time in Fabry patients: low incidence of antibody formation and infusion-associated reactions in an Italian multicenter study.

BACKGROUND: Fabry disease is a rare progressive X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A. Agalsidase beta is a recombinant enzyme replacement therapy authorized in Europe at a standard dose of 1.0 mg/kg intravenously every other week at an initial infusion rate of ≤ 0.25 mg/min until patient tolerance is established, after which the infusion rate may be increased gradually. However, specific practical guidance regarding the progressive reduction in infusion time is lacking. This study investigated a new and specific protocol for reducing agalsidase beta infusion time in which a stable dosage of 15 mg/h is infused for the first four months, and the infusion rate is increased progressively from 15 to 35 mg/h for the subsequent four infusions. The shortest infusion time is reached after six months and maintained thereafter. The incidence of infusion-associated reactions (IARs) and the development of anti-drug antibodies were analyzed, and the disease burden and the clinical evolution of the disease at 12 months were evaluated. RESULTS: Twenty-five of the 31 patients were naïve to enzyme or chaperone treatment at baseline and six patients had been switched from agalsidase alfa. The reduced infusion time protocol was well tolerated. Only one patient exhibited an IAR, with mild symptoms that resolved with low-dose steroids. Six patients globally seroconverted during treatment (4 with a classic phenotype and 2 with late-onset disease). All but three patients were seronegative at month 12. All patients were stable at the study's end (FAbry STabilization indEX value < 20%); reducing infusion time did not negatively impact clinical outcomes in any patient. The perceived medical assessment showed that the quality of life of all patients improved. CONCLUSIONS: The study demonstrates that reducing agalsidase beta infusion time is possible and safe from both an immunogenic and clinical point of view. The use of a low infusion rate in the first months when the probability of onset of the development of antibodies is higher contributed to very limited seroconversion to antibody-positive status.

Comorbid conditions and gender impact the primary survival of distal radio-cephalic arteriovenous fistula inpatients on long-term hemodialysis.

BACKGROUND: Vascular access failure complicates the clinical picture of patients on long-term hemodialysis, increasing the number of hospitalizations and the respective costs. In these patients we analyzed the possible meaningful relationship between comorbidities and primary survival of the autologous distal radio-cephalic arteriovenous fistula (dAVF), pointing out the influence of other variables on that relationship. METHODS: We evaluated the dAVF placed in our unit between January 1, 1995, and December 31, 2003, on 105 patients (55 males) 63.8 +/- 14.1 (average +/- SD) years old. The dAVF creation date was the starting point while the dAVF failures due to either thrombosis or malfunction (KT/V < 1.2) were the study end-point. Death, conversion to peritoneal dialysis, transfer to other units and renal transplantation were assumed as censure criteria. ICED score, single comorbidities, use of temporary catheter at the hemodialysis initiation, serum lipids and CRP levels, hematocrit, blood platelet count and coagulative parameters (at the time of the dAVF creation) were considered as covariates. The Kaplan-Meier method and Cox's proportional hazards regression were used in the dAVF survival analysis. RESULTS: During the study we recorded 38 dAVF failures (median primary survival of the dAVF 487.3 days, with a failure rate of 0.645 per patient-year). Age, lab variables, single comorbidities, and use of temporary catheters did not impact the dAVF primary survival. Conversely ICED score > 1 (P = 0.014; hazard ratio = 1.648; 95% CI = 1.106-2.454) as well as feminine gender (P = 0.018; hazard ratio = 1.640; 95% CI = 1.024-2.256) increased the risk of dAVF failure. CONCLUSIONS: In our cohort of patients on long-term hemodialysis neither the single comorbidities nor the temporary catheterization influence the lifespan of the vascular access. However our data demonstrated the meaningful inverse relationship between dAVF primary survival and a composite comorbidity index reflecting not only the type of the diseases but also their associations and severities. This relationship was not influenced by other covariates although the feminine gender was significantly associated with worse survival of the vascular access.