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.

Furosemide Increases the Risk of Hyperparathyroidism in Chronic Kidney Disease

“…This notion is largely based on a few clinical observations performed over 50 years ago [26,27] . However, several recent clinical [28,29] and experimental [11][12][13] observations indicate that, in patients with advanced CKD, TTLDs are not only effective as antihypertensives but can even exert a renoprotective action, especially in combination with ACE inhibitors or AT-1 receptor blockers, an effect only partially shared with LDs. The present study suggests that protection against the development of HPT2 could be an additional reason for the preferential use of TTLDs in CKD.…”

“…Hsu et al [9] showed that TTLDs accelerate the differentiation of osteoblasts. Other TTLD effects unrelated to calcium excretion include vasodilation [1] , increase of plasma Klotho [10] and renoprotection in experimental CKD [11][12][13] .…”

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

“…Furthermore, a variety of studies showed the presence of both Ang II and the receptor AT1 in the renal parenchyma of animals submitted to experimental models of CKD, leading to the discovery of a complex intrarenal pro-inflammatory RAAS that seems to become overactivated under kidney injury [18][19][20][21][22]. Accordingly, suppression of RAAS with both ACE inhibitors (ACEi) and/or AT1 receptor blockers (ARB) become a mainstay of treatment of progressive nephropathies and, although several innovative therapeutic measures have been recently proposed for the treatment of CKD, RAAS blockage, associated to diuretics or not, remains the best available resource in this regard [9,16,23,24].…”

Animal models of regression/progression of kidney disease

“…Combining the ARB with nonhyperkalemic doses of spironolactone failed to further increase the regression of glomerulosclerosis [11]. Combining ARB with hydrochlorothiazide completely prevented progression of renal injury, even when it was initiated at advanced stages of the nephropathy (120 days after 5/6 nephrectomy) [34]. …”