TY - JOUR
T1 - MK-591 acutely restores glomerular size selectivity and reduces proteinuria in human glomerulonephritis
AU - Guasch, Antonio
AU - Zayas, Carlos F.
AU - Badr, Kamal F.
PY - 1999
Y1 - 1999
N2 - 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 (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.
AB - 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 (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.
KW - Dextran sieving
KW - Glomerular inflammation
KW - Leukotrienes
KW - Transglomerular protein trafficking
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U2 - 10.1046/j.1523-1755.1999.00537.x
DO - 10.1046/j.1523-1755.1999.00537.x
M3 - Article
C2 - 10411701
AN - SCOPUS:0033000883
SN - 0085-2538
VL - 56
SP - 261
EP - 267
JO - Kidney International
JF - Kidney International
IS - 1
ER -