Enzyme Replacement Therapy and Fabry Nephropathy

Abstract

Involvement of the kidneys in Fabry disease ("nephropathy") occurs in male and female individuals. The majority of patients with progressive nephropathy will have significant proteinuria and develop progressive loss of kidney function, leading to ESRD. All too often, treating physicians may ignore "normal" serum creatinine levels or "minimal" proteinuria and fail to assess properly the severity of kidney involvement and institute appropriate management. Fabry nephropathy is treatable, even in patients with fairly advanced disease. Although the cornerstone of therapy remains enzyme replacement therapy with agalsidase, this treatment alone does not reduce urine protein excretion. Treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors must be added to enzyme replacement therapy to reduce urine protein excretion with the hope that this will stabilize kidney function. Kidney function, with at least estimated GFR based on serum creatinine and measurements of urinary protein, should be measured at every clinic visit, and the rate of change of the estimated GFR should be followed over time. Antiproteinuric therapy can be dosed to a prespecified urine protein target rather than a specific BP goal, with the proviso that successful therapy will usually lower the BP below the goal of 130/80 mmHg that is used for other forms of kidney disease. The overall goal for treating Fabry nephropathy is to reduce the rate of loss of GFR to ؊1 ml/min per 1.73 m 2 /yr, which is that seen in the normal adult population. A systematic approach is presented for reaching this goal in the individual patient.

Prognostic Indicators of Renal Disease Progression in Adults with Fabry Disease

“…Institution of ACEi/ARB therapy during ERT will not necessarily confer renal protection (22), unless doses are titrated to achieve sustained reduction in proteinuria to Ͻ0.5 g/24 h (11). Recent recommendations for patients with Fabry disease receiving ERT include ACEi/ARB treatment to reduce urinary protein excretion to Ͻ0.5 g/24 h (23)(24)(25), with the goal of reducing the rate of kidney function loss to less than Ϫ1 ml/ min per 1.73 m 2 per year. Sixty-four percent of men and 43% of women in this cohort had averaged UP/Cr values Ն0.5 (data not shown), and only 22% of men and 19% of women reported receiving ACEi/ARBs at any time during the observation period.…”

Blood Pressure, Proteinuria and Nephropathy in Fabry Disease

“…The limited prevalence of hypertension and relatively lower systemic blood pressures in Fabry disease compared to other proteinuric forms of CKD present challenges in using traditional antiproteinuric therapies, especially if standard goals for blood pressure targets are applied [30]. The alternative approach is to consider reduction in proteinuria as the primary goal of therapy, even if the blood pressure is ‘within normal limits’.…”

“…Two reports describe reduction in proteinuria and hypertension in Fabry patients treated with agalsidase-α [20,21], but careful reading of these reports shows that the reported effects were associated with concomitant treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). There is a growing awareness that control of proteinuria with ACEIs or ARBs is essential for achieving the most optimal responses to ERT [22]. …”

“…The most convincing studies have been conducted in diabetic nephropathy, though results have been extrapolated to most proteinuric nephropathies considering the potentially common pathophysiology of proteinuric kidney diseases. One of the major treatment goals in the treatment of Fabry patients is reduction of proteinuria, and ERT by itself has failed to achieve this goal [22]. In a recent trial demonstrating the feasibility of using ACEIs/ARBs in Fabry patients, sustained reduction in proteinuria was achieved accompanied by a reduction in the progression of the nephropathy [26].…”

“…In contrast, the reduction of urine protein to the target level of 0.5 g/day in the high-risk group was associated with a substantial fall in blood pressure, but the final blood pressure levels were not statistically different between the two groups. These results have been interpreted as showing that ACEI/ARB therapy can be safely used in Fabry patients receiving ERT, that the reduction of proteinuria to the target of 0.5 g/day could be achieved despite the relatively ‘normal’ baseline blood pressure in the treated groups, and that the combination of antiproteinuric therapy and ERT achieved the optimal treatment goal of slowing progression to less than –1 ml/min/1.73 m 2 /year [22,28]. These preliminary observations are in the process of being extended in a multicenter, multinational open-label study [29].…”