Dialysis and Transplantation in Fabry Disease

Abstract

F abry disease results in kidney damage and leads to progressive impairment of renal function in almost all male patients and in a significant proportion of females (1-4). The life expectancy is reduced for both genders (5-7), and the major causes of death include cardiac death, stroke, or the consequences of ESRD (7,8).The availability of enzyme replacement therapy (ERT) since 2001 has led to major expectations with regard to improvement of clinical symptoms and disease burden in patients with Fabry disease (9,10). However, Fabry patients requiring renal replacement therapy (RRT) represent a group of patients with specific comorbidities possibly affecting the outcome and efficacy of ERT (11,12).This article summarizes the current knowledge about the effect of ERT in Fabry patients requiring dialysis therapy or who have received a kidney transplant. A second goal is to address important research questions in the field. What Do We Know? Progression of Fabry NephropathyProteinuria and progressive renal deterioration may develop rapidly in Fabry disease. Schiffmann et al. re-examined the natural history of Fabry nephropathy with a retrospective analysis of 279 men and 168 women. In men with an estimated GFR (eGFR) of more than 60 ml/min/1.73 m 2 , the slope of renal function was Ϫ3 and for women was Ϫ0.9 ml/min/1.73 m 2 per year; for men with eGFR Ͻ60 ml/min/1.73 m 2 , it was Ϫ6.8 and for women it was Ϫ2.1 ml/min/1.73m 2 per year. Patients with proteinuria Ͼ1 g/24 h had a worse prognosis (13). Therefore, clinical experiences addressed to evaluate the role of ERT (14 -17) should be compared with this study and not only with small-scale study results (2). Of interest, women who progress Published online ahead of print. Publication date available at www.cjasn.org.

The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: Data from individual patients and family studies

“…In contrast to those Spanish data, neither the p.(Arg118Cys) nor the p.(Asp313Tyr) GLA variants were identified in the 2688 men enrolled in the Portuguese screening of FD among non-selected dialysis patients [48]. Although the Portuguese investigators also used a DBS α-Gal assay for case finding, the <30% cut-off level of residual enzyme activity to proceed with further diagnostic tests (unpublished data) was more stringent than in the Spanish study, and patients showing high residual enzyme activities, in the range observed in hemizygous males for GLA p.(Arg118Cys) or p.(Asp313Tyr), would not be selected for genotyping.…”

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

“…Males who are hemizygous for this GLA p.Asn215Ser may present with renal dysfunction at advanced age, with the kidney biopsy showing predominant involvement of podocytes and minimal or absence of GSL deposits in other cell types [62], but only exceptionally [63] has the p.Asn215Ser mutation been identified in FD case-finding studies among HD patients. Indeed, the GLA p.Asn215Ser mutation was not detected in any of 13 large-scale studies screening for FD among patients on RRT that were carried out before 2010 (summarized at [64, 65]), nor in any of those that have been published subsequently [53, 66–70], adding up to more than 20,000 RRT patients screened and more than 30 newly diagnosed carriers of pathogenic GLA mutations. Mutation p.Asn215Ser was also not identified in any of the large stroke patient cohorts of the multinational European “Stroke in Young Fabry Patients study” (n =5023) [52], the “Belgian Fabry study” (n = 1000) [71], the “Stroke Prevention in Young Men Study” (n = 558) [72] and the “PORTYSTROKE study – Screening Genetic Conditions in Portuguese Young Stroke Patients” (n = 493) [45].…”

Fabry nephropathy: a review – how can we optimize the management of Fabry nephropathy?

“…Although this was better than 3-year survival in a diabetic control population (53%), it was significantly lower than in the non-diabetic control group (74%) [87]. This is almost certainly due to the added disease burden from the cardiovascular complications of Fabry disease [88]. Thus, ERT should be considered on an individual patient basis in an attempt to reduce the risk of cardiovascular events.…”

“…In fact, the results of renal transplantation are so encouraging that it should be considered as the first-line option to correct renal dysfunction in patients with Fabry disease and ESRD [91]. However, despite the positive data supporting renal transplantation, Fabry disease has been shown to confer a higher risk of death versus diabetic control patients (odds ratio 2.15) [88]. …”