MK-591 acutely restores glomerular size selectivity and reduces proteinuria in human glomerulonephritis (original) (raw)

1999, Kidney International

MK-591 acutely restores glomerular size selectivity and reduces disease (ESRD) [1]. Despite an increasing understanding proteinuria in human glomerulonephritis. of the pathogenetic mechanisms that mediate immune Background. Leukotrienes are 5-lipoxygenated (5-LO) meglomerular damage, the treatment of glomerulonephritis tabolites of arachidonic acid that mediate some of the glomeruis still unsatisfactory. The treatment of glomerulonephrilar hemodynamic and structural changes in experimental and tis with nonselective immunosuppression, mostly with human glomerulonephritis. Methods. We conducted an open-label, pilot study of the cytotoxic agents, has yielded encouraging results in some short-term effects of leukotriene biosynthesis inhibition using forms of glomerulonephritis such as lupus nephritis [2], an orally active 5-LO activating protein (FLAP) antagonist but is associated with significant morbidity [2-4]. In the (MK-591) on glomerular function in patients with glomerulonelast 10 to 15 years, there have been significant advances phritis. Eleven adult patients (seven women, median age 38 in the understanding of the pathogenesis of glomerular years) with glomerulonephritis (5 lupus nephritis, 2 IgA nephropathy, 1 membranoproliferative, 1 membranous, 1 C1qinflammation, mostly gathered from experimental moddeficiency, and 1 idiopathic crescentic) and moderate renal els [5-8]. In animals with experimentally induced glomerinsufficiency [glomerular filtration rate (GFR) 62 Ϯ 9 ml/min/ ulonephritis, an initial deposition of immune complexes 1.73 m 2 ] were given MK-591 at a dose of 100 mg orally twice in the glomerulus is followed by recruitment and activaa day for four days. Results. MK-591 reduced proteinuria (albumin and IgG ex-tion of blood polymorphonuclear leukocytes (PMNs), cretion rates) from 3233 Ϯ 1074 to 1702 Ϯ 555 g/min and followed by influx of lymphocytes, macrophages, and from 196 Ϯ 78 to 148 Ϯ 55 g/min for albumin and IgG, platelets. These in turn generate a cascade of immune respectively (P Ͻ 0.05 for both). This was not accompanied mediators-interleukins, prostanoids, complement, oxyby a reduction in systemic arterial pressure, GFR, or renal gen radicals, etc.-that promotes further cellular events plasma flow. By analysis of the fractional clearance of polydisperse dextrans, baseline proteinuria resulted from a loss of size Key words: leukotrienes, glomerular inflammation, dextran sieving, transglomerular protein trafficking. filtration rate (GFR). Furthermore, an acute blockade of LTD 4 in models of nephrotoxic serum nephritis [10],