title: Regression of albuminuria and hypertension and arrest of severe renal injury by a losartan-hydrochlorothiazide association in a model of very advanced nephropathy.
abstract: Treatments that effectively prevent chronic kidney disease (CKD) when initiated early often yield disappointing results when started at more advanced phases. We examined the long-term evolution of renal injury in the 5/6 nephrectomy model (Nx) and the effect of an association between an AT-1 receptor blocker, losartan (L), and hydrochlorothiazide (H), shown previously to be effective when started one month after Nx. Adult male Munich-Wistar rats underwent Nx, being divided into four groups: Nx+V, no treatment; Nx+L, receiving L monotherapy; Nx+LH, receiving the L+H association (LH), and Nx+AHHz, treated with the calcium channel blocker, amlodipine, the vascular relaxant, hydralazine, and H. This latter group served to assess the effect of lowering blood pressure (BP). Rats undergoing sham nephrectomy (S) were also studied. In a first protocol, treatments were initiated 60 days after Nx, when CKD is at a relatively early stage. In a second protocol, treatments were started 120 days after Nx, when glomerulosclerosis and interstitial fibrosis are already advanced. In both protocols, L treatment promoted only partial renoprotection, whereas LH brought BP, albuminuria, tubulointerstitial cell proliferation and plasma aldosterone below pretreatment levels, and completely detained progression of renal injury. Despite normalizing BP, the AHHz association failed to prevent renal damage, indicating that the renoprotective effect of LH was not due to a systemic hemodynamic action. These findings are inconsistent with the contention that thiazides are innocuous in advanced CKD. In Nx, LH promotes effective renoprotection even at advanced stages by mechanisms that may involve anti-inflammatory and intrarenal hemodynamic effects, but seem not to require BP normalization.
authors: Laboratory of Renal Pathophysiology, LIM-16, Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
authors: Simone Costa Alarcon
authors: SC
authors: Arias
authors: Carla Perez
authors: CP
authors: Valente
authors: Flavia Gomes
authors: FG
authors: Machado
authors: Camilla
authors: C
authors: Fanelli
authors: Clarice Silvia Taemi
authors: CS
authors: Origassa
authors: Thales
authors: T
authors: de Brito
authors: Niels Olsen Saraiva
authors: NO
authors: Camara
authors: Denise Maria Avancini Costa
authors: DM
authors: Malheiros
authors: Roberto
authors: R
authors: Zatz
authors: Clarice Kazue
authors: CK
authors: Fujihara
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000419:Albuminuria / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000450:Aldosterone / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D005921:Glomerulonephritis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006852:Hydrochlorothiazide / Q000008:administration & dosage*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D018809:Proliferating Cell Nuclear Antigen; D006852:Hydrochlorothiazide; D000450:Aldosterone; D019808:Losartan