Published in UAB Insight, Winter 2008
Adjunctive Renal Therapy With ACEI/ARB
Less than 5 years ago UAB delivered the first infusion in the United States of Food and Drug Administration-approved enzyme replacement therapy (ERT) for Fabry disease, a rare life-threatening disorder for which there had been no effective treatment. UAB’s Fabry Clinic team — nephrologist David G. Warnock, MD, nurse coordinator Leslie J. Jackson, RN, and geneticist Maria Del Carmen Descartes, MD — once again is breaking ground in treatment of this X-linked lysosomal storage disorder caused by α-galactosidase deficiency.
The lipid accumulation that is the hallmark of Fabry disease damages the kidneys, causing focal, segmental, and global sclerosis; mesangial widening; epithelial deposits; ischemic changes; tubulointerstitial fibrosis; and vascular changes. In an observational study of 11 Fabry patients, Warnock’s team found a combination of antihypertensive drugs reduces urine protein excretion and stops the progressive loss of kidney function loss that occurs in those with moderate to severe kidney disease.
“In Fabry patients, nephropathy manifests as mild to severe proteinuria — an important marker of chronic kidney disease. Although ERT with agalsidase-β [Fabrazyme] effectively clears accumulating glycosphingolipids from patients’ organs, it does not slow kidney function decline, says Warnock, who notes he is a paid consultant for Genzyme Corp, the company that developed Fabrazyme. (Genzyme did not fund the combination therapy study.)
The study showed a combination of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) produced sustained reductions in proteinuria and a significant slowing of kidney function decline (J Am Soc Neph. 2007;18:2609-2617).
“Four patients had relatively mild kidney involvement, while seven had more severe loss of kidney function, with estimated glomerular filtration rates half that of normal and nearly 2 grams of protein in the urine — 10 times higher than typical rates,” he says. “With ERT alone, Fabry patients with severe disease lose 10% of their kidney function per year.”
Patients took ACEI/ARB therapy for an average of 30 months. In those with severe kidney involvement, combination therapy slowed the rate of kidney function loss to almost zero. ACEI/ARB therapy also stabilized kidney function in those with mild disease and proteinuria. A 16-site international study is underway to confirm results of the UAB investigation, the first study of antiproteinuric therapy in Fabry patients.
These patients typically have normal or low-normal blood pressure, and careful titration of the antiproteinuric drugs is necessary to avoid hypotensive side effects, Warnock says. “I credit our patients, who are actively engaged in their care and in research to advance treatment of this inherited disease.
“ACEI/ARB therapy can prevent worsening kidney damage in Fabry patients. Intervening before proteinuria develops is crucial,” he says. With answers to kidney function decline seemingly at hand, Warnock says scientists now need to address cardiac and brain involvement, infusion site reactions, and large-scale screening.
“Why not look at all men on dialysis? An estimated 0.5% have Fabry disease, as do about 6% of people who have idiopathic strokes,” he says. “The numbers are small, but not insignificant. Fabry disease can now be treated effectively, and screening high-risk populations is feasible.”
For more information:
Dr. David Warnock
1.800.UAB.MIST
mist@uabmc.edu