Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments.
Endothelin 1 promotes the development and progression of
chronic kidney disease and associated
cardiovascular disease. We, therefore, studied the effects of selective
endothelin-A receptor antagonism in proteinuric
chronic kidney disease patients, assessing
proteinuria, blood pressure (BP), and arterial stiffness, key independent,
surrogate markers of
chronic kidney disease progression and
cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of
sitaxsentan, and 30 mg once daily of
nifedipine long acting. Twenty-four-hour
proteinuria,
protein:
creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period. Compared with placebo,
sitaxsentan reduced 24-hour
proteinuria (-0.56±0.20 g/d; P=0.0069),
protein:
creatinine ratio (-38±15 mg/mmol; P=0.0102), BP (-3.4±1.2 mm Hg; P=0.0069), and pulse wave velocity (-0.64±0.24 m/s; P=0.0052).
Nifedipine matched the BP and pulse wave velocity reductions seen with
sitaxsentan but did not reduce
proteinuria.
Sitaxsentan alone reduced both glomerular filtration rate and filtration fraction. It caused no clinically significant adverse effects.
Endothelin-A receptor antagonism may provide additional cardiovascular and renal protection by reducing
proteinuria, BP, and arterial stiffness in optimally treated
chronic kidney disease subjects. The antiproteinuric effects of
sitaxsentan likely relate to changes in BP and renal hemodynamics.