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.

Total or partial deficiency of the human lysosomal hydrolase a-galactosidase A is responsible for Fabry disease, the X-linked inborn error of glycosphingolipid metabolism. Together with the predominant a-galactosidase A gene mRNA product encoding the lysosomal enzyme, a weakly regulated alternatively spliced a-galactosidase A transcript is expressed in normal tissues, but its overexpression, due to the intronic g.9331G4A mutation, leads to the cardiac variant. We report the molecular characterization of five Fabry patients including two siblings. Sequencing analysis of the a-galactosidase A gene coding region and intron/exon boundaries identified the new c.124A4G (p.M42V) genetic lesion as well as a known deletion in three patients, whereas in the two remaining patients, no mutations were identified. To evaluate possible a-galactosidase A gene transcription alterations, both predominant and alternatively spliced mRNAs were quantified by absolute real-time PCR on total RNA preparations from the patients' fibroblasts. An impressive reduction in the predominant a-galactosidase A transcript was detected in the last patients (Pt 4 and Pt 5). However, the alternatively spliced mRNA was dramatically overexpressed in one of them, carrying a new intronic lesion (g.9273C4T). These findings strongly suggest a correlation between this new intronic mutation and the unbalanced a-galactosidase A mRNAs ratio, which could therefore be responsible for the reduced enzyme activity causing Fabry disease. The real-time assay developed here to investigate the two a-galactosidase A mRNAs might play a crucial role in revealing possible genetic lesions and in confirming the pathogenetic mechanisms underlying Fabry disease.

In nine chronic haemodialysis patients, treated alternately with acetate and bicarbonate, the main critical factors in oxygen supply to the tissues were evaluated: Hb values, blood gas parameters, red cell 2-3 diphosphoglycerate (2-3 DPG), phosphataemia and P50 in vivo. Predialytic P50 was higher than in normal controls. During dialysis, arterial pO2 and pCO2 significantly decreased in acetate dialysis, whereas they were stable in bicarbonate dialysis. Rising alkalinisation was accompanied, both in acetate dialysis and in bicarbonate dialysis, by reduction of P50, while 2-3 DPG did not change. The acute increase in Hb-O2 affinity adversely affected peripheral oxygen release. In acetate dialysis this mechanism might magnify the effects of dialysis-induced hypoxaemia, affecting the clinical tolerance.

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