Fabry disease: enzyme replacement therapy, sartans and ACE inhibitor
Enzyme replacement therapy ( ERT ) is the standard therapy for Fabry disease. Enzyme replacement therapy partially cleared microvascular deposits of GL-3 from the heart, kidney and skin of most Fabry patients. However, deposits in podocytes may persist for years in adults. GL-3 clearance from the myocardium and kidney concurs with a decrease of left ventricular mass and an improvement of regional myocardial function and stabilizes renal function if started early.
In contrast, ERT may be less effective in the presence of tissue fibrosis identified either by the presence of glomerulosclerosis in renal biopsy, by surrogate markers of kidney fibrosis such as proteinuria greater than 1g/d or an eGFR less than 45 ml/min or by evidence of replacement fibrosis in left ventricle ( LV ).
Thus even with ERT, the annual progression of LV replacement fibrosis is 0.7±0.7% in males and 0.2±0.3% in females, emphasizing the need to understand the molecular mechanism and optimize anti-fibrotic therapy.
This has two clinical implications: a) before starting with ERT a baseline staging of the extent of fibrosis should be obtained in all patients for adjusting outcome expectations. Disease stabilization is unlikely in the presence of fibrosis. b) add-on therapies targeting fibrosis may be beneficial in patients with evidence of fibrosis.
These add-on therapies are expected to be used in addition to enzyme replacement therapy or to any other treatments aimed at correcting the metabolic defect that are developed, such as chaperones or substrate reducing therapy.
Ideally clinical trials should address the safety and efficacy of these approaches in Fabry disease. However, clinical trials of these add-on therapies are unlikely given the low frequency of the disease.
In addition, special attention should be paid to elucidating the mechanisms of generation and actions of suspected pro-fibrotic molecules such as lyso-Gb3 as well as in characterizing their receptors, since limiting their production or preventing their pro-fibrotic action might be beneficial in Fabry disease.
The standard of treatment of proteinuric chronic kidney disease ( CKD ), including diabetic nephropathy and focal and segmental glomerular fibrosis and sclerosis ( FSGS ), involves anti-proteinuric therapy with drugs targeting the RAAS such as angiotensin converting enzyme inhibitors ( ACEi ) or angiotensin receptor blockers ( ARBs; sartans ).
Components of the RAAS have direct pro-fibrotic effect that can be demonstrated in cultured cells and animal models in diverse organs that can be prevented by Ace inhibitors, sartans and anti-aldosterone agents, suggesting a general profibrotic effect of the RAAS beyond specific roles in the biology of specific organs.
In Fabry nephropathy the combination of ERT and RAAS targeting to decrease proteinuria prevented progression of chronic kidney disease in patients with baseline estimated GFR less than 60 ml/min/1.73 m2.
An ongoing clinical trial is validating this clinical observation ( The Fabrazyme and Arbs and ACE Inhibitor Treatment [ FAACET ] Study ).
However, neither study assessed renal fibrosis.
Meanwhile RAAS targeting is recommended to lower proteinuria in Fabry disease, in association to ERT. Furthermore, RAAS targeting is also beneficial in chronic cardiomyopathies. Fabry patients with a fibrotic cardiomyopathy generally require comprehensive management of hypertension with angiotensin-converting enzyme inhibitors and beta-adrenergic blocking agents, in addition to ERT.
A pacemaker implantation might be necessary in cases with symptomatic bradycardia. In addition, patients with late-stage cardiomyopathy who develop life threatening arrhythmias should be evaluated for and eventually provided with insertion of an implantable-cardio-defibrillator ( ICD ), in addition to pharmacological therapy and enzyme replacement therapy. ( Xagena )
Weidemann F et al, Orphanet Journal of Rare Diseases 2013, 8:116
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