Losartan-hydrochlorothiazide association promotes lasting blood pressure normalization and completely arrests long-term renal injury in the 5/6 ablation model

Abstract

Fujihara CK, Malheiros DM, Zatz R. Losartan-hydrochlorothiazide association promotes lasting blood pressure normalization and completely arrests long-term renal injury in the 5/6 ablation model. Am J Physiol Renal Physiol 292: F1810 -F1818, 2007. First published March 6, 2007; doi:10.1152/ajprenal.00521.2006.-The possible long-term renoprotective effects of treatment with thiazides, either as monotherapy or associated with renin-angiotensin suppressors, have not been assessed. We investigated the effect of hydrochlorothiazide (H), alone or combined with losartan (L), in the 5/6 renal ablation model (Nx). Adult male Munich-Wistar rats underwent Nx, remaining untreated for 1 mo. At this time, functional and morphological studies were performed in 21 rats (group Nx pre). The remaining rats were distributed among groups: Nx, no treatment; NxϩL, receiving L, 50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in the drinking water; NxϩH, receiving H, 6 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in drinking water; and NxϩLϩH, receiving both L and H as described. At 30 days of treatment, systemic and glomerular pressures were markedly elevated in group Nx. Both H and L attenuated hypertension, whereas combined LϩH treatment completely normalized both pressures. Eight months after Nx, mortality approached 70% in untreated rats, whereas severe albuminuria, hypertension, glomerulosclerosis, and interstitial expansion were observed. H and L attenuated, but did not prevent, mortality, hypertension, and renal injury. Combined LϩH treatment completely prevented mortality, normalized albuminuria and blood pressure, and arrested renal injury at levels found 1 mo after ablation, despite the unusually long period of observation. Combined LϩH treatment may represent an effective therapeutic alternative to prevent progression of chronic nephropathies. chronic kidney disease; thiazide diuretics; 5/6 nephrectomy; chronic renal insufficiency SUPPRESSION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAS) by converting enzyme inhibitors (ACEI) or AT-1 receptor blockers (ARB) represents a major asset in the struggle to prevent or retard the progression of chronic kidney disease (CKD). Nevertheless, a substantial fraction of treated patients still progress to end-stage renal disease. The reasons why this renoprotective effect is only partial are unclear and may include incompleteness of ANG II suppression (9, 10), continuing stimulation of downstream intracellular events by factors independent of the RAS (35), and failure to completely normalize renal and/or systemic hemodynamics (9). The latter may result from overexpression of tubular sodium transporters (20), which may favor the perpetuation of extracellular volume expansion. We showed previously that, when administered at extremely high doses to rats subjected to 5/6 renal ablation (Nx), the ARB, losartan (L), provided more efficient renoprotection after 4 mo than treatment with "conventional" doses (9). However, even at these high doses protection was still incomplete, since albuminuria and tail-cuff pressure (TCP) never returned to co...

Characterization of an experimental model of progressive renal disease in rats

“…Especially in group 3, we observed pronounced microalbuminuria both two weeks and four weeks after surgery, as previous studies have also shown 12,13,21,23 .…”

“…With regard to MAP, we observed significant increase Renal histological analysis showed, as expected, histological patterns compatible with ESRD in group 3 11,13,21 . In the same way, rats of group 2 presented the same changes found in Further studies are necessary to evaluate molecular pathways related to renal changes in this experimental model.…”

“…in creatinine clearance in rats and mice four weeks after 5/6 nephrectomy 12,13,21 . Under our experimental conditions, the creatinine clearance reduction in the group of severe uremia was of 87%.…”

Early Brief Treatment with Losartan plus Mycophenolate Mofetil Provides Lasting Renoprotection in a Renal Ablation Model

“…Five-sixths renal ablation (Nx), widely utilized as a model of chronic kidney disease (CKD), is characterized by early hemodynamic and inflammatory alterations, comprising glomerular hypertension [1,2,3], exaggerated cell proliferation [4,5], infiltration by lymphocytes [2,6], and, later on, macrophages [2,4,5,7]. Angiotensin II (AngII) exerts a major role in the pathogenesis of renal injury in Nx and in other instances of CKD [1,8,9,10].…”

Efeito da associação de losartan e hidroclorotiazida em modelo experimetal de nefrologia crônica resultante da administração de losartan durante a lactação (LLact)

“…Os animais L Lact tratados com losartan na vida adulta apresentaram hipercalemia, provavelmente ocasionada em parte pela própria insuficiência renal e em parte pelo bloqueio do receptor AT1, possivelmente através de uma redução da síntese de aldosterona. Esse resultado difere do obtido no modelo NX, no qual a administração de BRAT1 não chega a elevar de modo sensível os níveis de potássio sérico, mesmo em doses extremamente elevadas [46].…”