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

Background Leukotrienes are 5-lipoxygenated (5-LO) metabolites of arachidon ic acid that mediate some of the glomerular hemodynamic and structural chan ges 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 activati ng protein (FLAP) antagonist (MK-591) on glomerular function in patients wi th glomerulonephritis. Eleven adult patients (seven women, median age 35 ye ars) with glomerulonephritis (5 lupus nephritis, 2 IgA nephropathy, 1 membr anoproliferative, 1 membranous, 1 C1q-deficiency, and 1 idiopathic crescent ic) and moderate renal insufficiency [glomerular filtration rate (GFR) 62 /- 9 ml/min/1.73 m(2)] were given MK-591 at a dose of 100 mg orally twice a day for four days. Results. MK-591 reduced proteinuria (albumin and IgG excretion rates) from 3223 +/- 1074 to 1702 +/- 555 mu g/min and from 196 +/- 78 to 148 +/- 55 mu g/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 pla sma flow. By analysis of the fractional clearance of polydisperse dextrans, baseline proteinuria resulted from a loss of size selectivity with enhance d passage of large (>52 Angstrom) dextrans as compared with healthy control s. Treatment with MK-591 caused a selective improvement in the enhanced pas sage of large (>58 Angstrom) dextrans without affecting the handling of sma ller 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 reduces proteinuria by restorin g glomerular size selectivity and thus reduces transglomerular protein traf ficking. These benefits may result from glomerular leukotriene biosynthesis inhibition, but other MK-591-specific actions cannot be excluded.