New Insights Into Tolvaptan Treatment and the Renin-Angiotensin-Aldosterone System

Abstract

B ody fluids are regulated by the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and arginine vasopressin (AVP) in patients with congestive heart failure (HF). Angiotensin-converting enzyme inhibitors (ACE-I) have been shown to reduce mortality and morbidity in patients with HF and should be up-titrated to the maximum tolerated dose in order to achieve adequate inhibition of the RAAS.1) Angiotensin II receptor blockers (ARB) are recommended only as an alternative in patients intolerant of ACE-I. Meanwhile, tolvaptan, a vasopressin V2-receptor antagonist which inhibits vasopressin-mediated water reabsorption in the renal collecting duct 2) and leads to increased free water clearance (aquaresis),3) is available as a diuretic drug in the treatment of fluid accumulation in HF.4) Our recent pharmacokinetic and pharmacodynamic studies have reported the effectiveness and safety of add-on tolvaptan to furosemide in HF patients with advanced kidney dysfunction. 5,6) As compared with furosemide, tolvaptan in patients with acute HF is associated with comparable decongestion, better preservation of renal function, and less activation of the RAAS; 7) however, the efficacy of tolvaptan with or without ARB/ACE-I therapy in hospitalized patients with acute decompensated HF has not been fully investigated. The most recently published study of Adachi, et al 8) suggested that a single use of tolvaptan might induce an increase in urine volume in acute decompensated HF patients who were not previously treated with ARB/ACE-I. This result is quite surprising because ARB/ACE-I are the firstchoice drugs for the treatment of HF recommended by the guidelines.1) Their study retrospectively included 44 patients with acute decompensated HF who were treated with 7.0 mg (initial doses) of tolvaptan. The authors demonstrated that a response to the use of tolvaptan was independently associated with the non-use of ARB/ACE-I. They also reported single-use tolvaptan had an adequate diuretic effect on their study patients who did not receive ARB/ACE-I before the initiation of tolvaptan administration. Article p.385Several studies have reported on tolvaptan treatment and RAAS. Kadota, et al 9) provided new insights into the predictors of a response to tolvaptan using the AVP/plasma aldosterone concentration (PAC) ratio. Their study prospectively included 26 patients with decompensated HF who were treated with 15 mg of tolvaptan. They investigated the effects of tolvaptan on the RAAS and predictors for the response to tolvaptan treatment based on multiple laboratory factors, such as plasma renin activity, aldosterone concentration, and AVP. Imamura, et al 10) described the usefulness of the urine aquaporin (AQP) -2/AVP ratio for predicting the tolvaptan response. These results demonstrate that the potential ability to concentrate urine in the renal collecting duct is essential for the tolvaptan response. High urine osmolality basically indicates high secretion of AVP, although AVP alone cannot predict a response to tolvap...

Tolvaptan treatment in an adult Fontan patient with protein-losing enteropathy: a serial 23Na-MRI investigation

“…The current standard treatment of volume restriction and diuretics may even exacerbate this condition by further enhancing RAAS and especially the aldosterone pathway. 27,28 We believe that our results support the rationale of a TLV trial in univentricular patients with hyponatraemia and volume overload due to PLE. Due to the clinical improvements in our patient, we continued TLV therapy beyond this described study period.…”

“…spironolactone). 26,27 The decreased aldosterone level in our patient might represent a favourable TLV mechanism. The current standard treatment of volume restriction and diuretics may even exacerbate this condition by further enhancing RAAS and especially the aldosterone pathway.…”

“…The current standard treatment of volume restriction and diuretics may even exacerbate this condition by further enhancing RAAS and especially the aldosterone pathway. 27,28…”

Relationship between Soluble (Pro)Renin Receptor and Renin Activity in Patients with Severe Heart Failure

“…Tolvaptan may be an ideal diuretic for HF from the viewpoint of RAS activity minimization [16]. However, single prescription of tolvaptan is not allowed, and therefore thiazide is selected as a combination partner rather than furosemide because thiazide is a weak sodium diuretic that shows only 5% GFR inhibition (i.e., 5% increasing effect on urinary volume).…”