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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.

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About one third of patients with type 1 diabetes develop diabetic nephropathy long-term (usually not before at least 10 years of diabetes), though this proportion is falling as standards of care have risen. Nephropathy is strongly associated with other microvascular complications of diabetes, so that some degree of retinopathy is to be expected, and evidence of neuropathy is common. Patients with type 2 diabetes are equally susceptible, but this is an older group in which vascular disease and other pathologies are also more likely. The rise in type 2 diabetes accounts for diabetes being the most common recorded cause of end stage renal disease (ESRD) in the developed world.Diabetic nephropathy is characterized by a progression through hyperfiltration, microalbuminuria, hypertension, overt proteinuria, nephrotic syndrome, loss of GFR, to ESRD. Risk factors for developing it include genetic factors (though no major single gene effects have been identified), and quality of glycaemic control.The risk of progression can at early stages be reduced by improved glycaemic control, and control of hypertension also slows progression. However angiotensin converting enzyme inhibitors or receptor blockers (ACEi, ARB) are the standard of care for patients with microalbuminuria or overt proteinuria, as they have been shown to reduce the risk of renal endpoints. Combination therapy with both ACEi and ARB together has been associated with a high risk of AKI, hyperkalaemia and other adverse effects so is not generally recommended. Other promising agents in combination are under investigation but none adequately proven at this stage.Patients who reach ESRD have reduced survival on all modalities compared to age-matched patients with other diagnoses. Best rehabilitation and survival for those who are suitable is through renal transplantation, though combined pancreas-renal transplantation may offer still better outcomes for selected patients.

To examine whether enhanced in vivo proteolysis of von Willebrand factor (vWF) would account for the reported loss of larger multimers in acute thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), we studied eight patients with acute TTP/HUS whose blood samples were collected into an anticoagulant containing a cocktail of protease inhibitors to impede in vitro proteolysis. In all, enhanced proteolytic degradation of vWF was expressed as a relative decrease in the intact 225-Kd subunit of vWF and a relative increase in the 176-Kd fragment. However, instead of the loss of larger forms of normal multimers reported by other investigators, the plasma of all but one of our patients (whether they had TTP or HUS) contained a set of larger than normal (supranormal) multimers. Hence, although proteolytic fragmentation of vWF was enhanced during acute TTP/HUS, this phenomenon was not associated with the loss of larger multimers. In the five patients who survived the acute disease and underwent plasma exchange (three with HUS and two with chronic relapsing TTP), subunits and fragments returned to normal values, and supranormal multimers were no longer detected in plasma. In conclusion, even though vWF proteolysis is enhanced in acute TTP/HUS, it does not lead to loss of larger multimers.