An association of losartan-hydrochlorothiazide, but not losartan-furosemide, completely arrests progressive injury in the remnant kidney

Abstract

We have previously shown that an association of losartan and hydrochlorothiazide, initiated 1 mo after 5/6 nephrectomy (Nx), reversed hypertension and albuminuria and promoted lasting renoprotection. In this new study, we investigated whether equal or even better protection could be obtained by combining losartan and furosemide. Nx was performed in 58 Munich-Wistar rats. One month later, tail-cuff pressure and albuminuria were markedly elevated. At this time, Nx rats were distributed among the following four groups: untreated Nx rats, Nx rats that received losartan, Nx rats that received losartan + hydrochlorothiazide, and Nx rats that received losartan + furosemide. Seven months later, Nx rats exhibited high mortality, severe hypertension, albuminuria, glomerulosclerosis, and interstitial fibrosis. Losartan treatment limited mortality and attenuated the renal and hemodynamic abnormalities associated with Nx. As previously shown, the losartan + hydrochlorothiazide association normalized tail-cuff pressure and albumin, prevented renal injury, and reduced mortality to zero. The losartan + furosemide treatment failed to reduce tail-cuff pressure or albumin to normal and prevented renal injury less efficiently than the losartan and hydrochlorothiazide regimen. The reasons for the differing efficacies of the losartan + furosemide and losartan + hydrochlorothiazide schemes are unclear and may include beneficial nondiuretic actions of thiazides, such as vasorelaxation and antiproliferative activity. These results refute the established concept that thiazides and thiazide-like diuretics are ineffective at advanced chronic kidney disease stages. Rather, they suggest that, in view of their renoprotective action, these compounds may even be preferable to loop diuretics in the management of hypertension in advanced chronic kidney disease.

Combined Inhibition of Soluble Epoxide Hydrolase and Renin-Angiotensin System Exhibits Superior Renoprotection to Renin-Angiotensin System Blockade in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats with Established Chronic Kidney Disease

“…Nevertheless, there are recent reports that indicate that the cardio- and renoprotective effects of RAS blockade can be entirely attributed to BP reduction, [14, 28–30] and advanced CKD regression of renal damage is limited [12, 13, 15, 17, 31–33]. This points to the need for more multifaceted pharmacological strategies that target neurohormonal systems other than RAS and thereby bring additional renoprotective effects, especially in advanced CKD.…”

A Novel Aldosterone Antagonist Limits Renal Injury in 5/6 Nephrectomy

“…Moreover, we showed recently that normalization of blood pressure in Nx with a triple therapy was unable to reproduce the renoprotective action of a combined L/thiazide scheme 12 . Lastly, a more vigorous volume depletion by L + Ly compared to L + Eple, suggested by the observed effects on PRA, may have mimicked the beneficial effect exerted by diuretics when combined with ACEI or ARBs 12 , 13 , 29 .…”

Renoprotection Provided by Additional Diuretic Treatment in Partially Nephrectomized Ren-2 Transgenic Rats Subjected to the Combined RAS and ETA Blockade

“…It remains to be determined, whether the combination of other diuretics and RAS blockers would be similarly effective, since a combination of losartan with hydrochlorothiazide, but not with furosemide, was beneficial in rats with subtotal nephrectomy (Arias et al, 2013, 2016). Moreover, the benefits of hydrochlorothiazide against furosemide were demonstrated also in human studies (Fuwa et al, 2016).…”