MK-591 acutely restores glomerular size selectivity and reduces proteinuria in human glomerulonephritis.
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 lupus 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 and IgG excretion rates) from 3233 +/- 1074 to 1702 +/- 555 microg/min and from 196 +/- 78 to 148 +/- 55 microg/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 A) dextrans as compared with healthy controls. Treatment with MK-591 caused a selective improvement in the enhanced passage of large (>58 A) 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 reduces proteinuria by restoring glomerular size selectivity and thus reduces transglomerular protein trafficking. These benefits may result from glomerular leukotriene biosynthesis inhibition, but other MK-591-specific actions cannot be excluded.
Renal Division and Center for Glomerulonephritis, Emory University School of Medicine, Atlanta, Georgia 30333, USA.
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D000328:Adult; D000368:Aged; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000378:metabolism* / Q000652:urine; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010539:Permeability; D010865:Pilot Projects; D011507:Proteinuria / Q000209:etiology / Q000652:urine*; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C078266:MK 0591