MK-591 acutely restores glomerular size selectivity and reduces proteinuria in human glomerulonephritis

Abstract

Background. Leukotrienes are 5-lipoxygenated (5-LO) metabolites of arachidonic acid that mediate some of the glomerular hemodynamic and structural changes in experimental and human glomerulonephritis. Methods. We conducted an open-label, pilot study of the short-term effects of leukotriene biosynthesis inhibition using an orally active 5-LO activating protein (FLAP) antagonist (MK-591) on glomerular function in patients with glomerulonephritis. Eleven adult patients (seven women, median age 38 years) with glomerulonephritis (5 Jupus nephritis, 2 IgA nephropathy, 1 membranoproliferative, 1 membranous, 1 C1q-deficiency, and 1 idiopathic crescentic) and moderate renal insufficiency [glomerular filtration rate (GFR) 62 ± 9 ml/min/1.73 m2] were given MK-591 at a dose of 100 mg orally twice a day for four days. Results. MK-591 reduced proteinuria (albumin IgG excretion rates) from 3233 ± 1074 to 1702 ± 555 μg/min and from 196 ± 78 to 148 ± 55 μg/min for albumin and IgG respectively (P < 0.05 for both). This was not accompanied by a reduction in systemic arterial pressure, GFR, or renal plasma flow. By analysis of the fractional clearance of polydisperse , dextrans, baseline proteinuria resulted from a loss of size selectivity with enhanced passage of large (<52 Å) dextrans as compared with healthy controls. Treatment with MK-591 caused a selective improvement in the enhanced passage of large (>59 Å) dextrans without affecting the handling of smaller dextrans, indicating an improvement in glomerular size selectivity. MK-591 was well tolerated, and no adverse effects were observed. Conclusions. Short-term therapy with MK-591 reduced proteinuria by restoring glomerular size selectivity and thus reduced transglomerular protein trafficking. These benefits may result from glomerular leukotriene biosynthesis inhibition, but other MK-591-specific actions cannot be excluded.