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To the Editor, The arginine vasopressin (AVP) type 2 receptor antagonist tolvaptan (TLV) ameliorates congestion and normalizes hyponatremia in patients with congestive heart failure (HF). However, the clinical benefit of TLV on renal function remains controversial. We reported an optimal patient selection procedure for TLV treatment by using urine aquaporin 2 (U-AQP2) relative to plasma AVP level, and the AQP-defined “responders” could enjoy increases in urine output accompanied by better clinical outcome compared with “non-responders”. Thus, we speculate that TLV treatment may improve renal function only in the AQP-defined responders. This letter to the editor is a supplement to the previous paper. Among the patients who had been hospitalized at our institute between August 2011 and August 2013 for decompensated HF refractory to guideline-directed medical treatment with a considerable number of conventional diuretics, data were obtained from 60 patients who had received TLV on a de novo basis for > 30 days [TLV (+) group]. Baseline data were obtained within 24 hours prior to the TLV treatment. Blood and urine samples were obtained in the early morning before medication intake at day-1 and day-30. The U-AQP2 level was measured using a sandwich enzyme-linked immunosorbent assay (human aquaporin-2 ELISA kit, LSI medience) and was corrected by the urine creatinine concentration. The cutoff level of responders was U-AQP2/P-AVP ≥ 1.4 × 10 L/gCre as previously reported. Of consecutive 120 patients who were hospitalized for decompensated HF with NYHA class III/IV and underwent the above-described same measurements at our hospital, 60 patients were selected as a propensity-matched control group [TLV (-) group]. Propensity score matching analysis was performed as described in our previous paper. In the TLV (+) group, there were 43 AQP-defined responders and 17 non-responders. In the TLV (-) group, there were 40 AQP-defined responders and 20 non-responders. Among the AQP-defined responders, there were no significant differences in background characteristics irrespective of TLV administration (Table). Daily doses of furosemide decreased significantly only in responders receiving TLV (Figure A). Among responders, the serum level of creatinine (S-Cre) improved significantly during 1-month TLV therapy (Figure B, P < 0.05). Changes in S-Cre were comparable in AQP-defined non-responders irrespective of TLV administration. Advanced HF often complicates chronic kidney disease (CKD) because of congestion and reduced perfusion of kidney, and concomitant CKD worsens patient prognosis. Considerable amount of diuretics such as furosemide is often administered to ameliorate congestion in such a population, and diuretics at high dose are associated with poor clinical outcomes because of activation of sympathetic nerves and the renin-angiotensin-aldosterone (RAA) system, worsening of renal function, and progression of hyponatremia. Therefore, improvement of renal function and dose reduction in diuretics are major concerns for clinicians when they treat patients with congestive HF. Some investigators showed favorable effects of TLV over conventional diuretics. Miyazaki, et al demonstrated in a canine model that TLV induced aquaresis maintaining renal function without activating sympathetic nerves and the RAA system compared with furosemide. In an open-label, randomized placebo-controlled crossover trial, Costello-Boerrigter, et al showed that TLV preserved renal blood flow without activation of the RAA system compared with furosemide therapy. Theoretically, TLV therapy along with reduced diuretics may be a promising strategy to improve renal function in patients with congestive HF. However, clinical studies have not shown improvement of renal function by TLV-incorporated diuretic therapy in patients with congestive HF except for some very acute phase (~several days) ones. We in contrast showed here significant improvement in S-Cre during 1-month TLV treatment in AQPdefined responders, mainly due to a significant reduction in furosemide dose. Previous studies may contain several non-responders, in whom dose reduction of diuretics cannot be achieved because of refractoriness to TLV therapy due to impaired function of the collecting ducts. Therefore, optimal patient selection using U-AQP2 must be a promising strategy to improve clinical outcome during TLV therapy. We previously showed a better long-term survival rate during TLV treatment in AQP-defined responders over the control group. Improved renal function by TLV should be one of the major reasons for the better prognosis. Whether TLV improves renal function in the responders with more advanced CKD would be a future concern. In conclusion, mid-term TLV treatment improved renal function in AQP-defined responders.

Mid-Term Administration of Tolvaptan Improves Renal Function Accompanied by Dose-Reduction in Furosemide in Aquaporin-Defined Responders