Novel Criteria of Urine Osmolality Effectively Predict Response to Tolvaptan in Decompensated Heart Failure Patients

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1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Heart Failure Novel Criteria of Urine Osmolality Effectively Predict Response to Tolvaptan in Decompensated Heart Failure Patients Association Between Non-Responders and Chronic Kidney Disease Teruhiko Imamura, MD; Koichiro Kinugawa, MD, PhD; Taro Shiga, MD, PhD; Naoko Kato, PhD; Hironori Muraoka, MD; Shun Minatsuki, MD; Toshiro Inaba, MD; Hisataka Maki, MD; Masaru Hatano, MD; Atsushi Yao, MD, PhD; Shunei Kyo, MD, PhD; Ryozo Nagai, MD, PhD Background: A newly-developed vasopressin type 2 receptor antagonist, tolvaptan (TLV), has a unique feature of diuresis, but the response to this drug can be unpredictable. Methods and Results: Data were collected from hospitalized patients with decompensated congestive heart failure who were administered TLV at mg/day (n=61). A responder/non-responder to TLV was determined as having any increase/decrease in urine volume (UV) during the next 24 h after TLV treatment on the first day. Logistic regression analyses for increases in UV were performed, and independent predictors of the responder were the following: C1, baseline urine osmolality (U-OSM) >352 mosm/l; and C2, %decrease in U-OSM >26% at 4 6 h after TLV administration. Criteria consisting of C1 and C2 had a good predictability for responders by receiver-operating characteristic analysis (area under the curve=0.960). Kidneys of the non-responders no longer had diluting ability (%decrease of U-OSM at 4 6 h=2.7±14.6%*), but also barely kept concentrating ability (baseline U-OSM= 296.4±68.7* mosm/l) with markedly reduced estimated glomerular filtration ratio (35.5±29.4 ml min m 2 *) (*P<0.05 vs. patients who had at least 1 positive condition [n=42]). Conclusions: More than 26% decrease in U-OSM from a baseline >352 mosm/l for the first 4 6 h predicts responders to TLV. Unresponsiveness to TLV is attributable to nephrogenic diabetes insipidus complicated by chronic renal disease. (Circ J 2013; 77: ) Key Words: Nephrogenic diabetes insipidus; Renal dysfunction; Vasopressin Decline of effective blood flow associated with low cardiac output in heart failure (HF) patients triggers secretion of a variety of hypovolemic hormones including renin, norepinephrine, and arginine vasopressin (AVP). 1 4 These hormones activate the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and aquaporin (AQP)-associated water reabsorption system, and constitute a vicious cycle of HF with ventricular remodeling and increased afterload/preload. With the view to breaking this vicious cycle, inhibitors of the RAAS and β-blockers have been established as first-line standard therapy for HF with left ventricular systolic dysfunction. 5 On the other hand, inhibition of the vasopressin type 1 receptor, even though the receptor stimulates a signaling cascade virtually identical to that of the angiotensin II type 1 receptor, has nevertheless failed to show efficacy in HF patients. Editorial p 313 Recently, vasopressin type 2 (V2) receptor antagonists have been developed, and one of these drugs, tolvaptan (TLV), has been available for HF patients with hyponatremia or symptomatic congestion. 6 9 TLV has been shown in several studies to ameliorate congestion through increased excretion of free water in the urine, 7 to stabilize hemodynamics, 10 and to correct hyponatremia. 6,11 As such, the mechanism of this drug is noteworthy, but it is ineffective in a certain number of patients with HF. 12 To our best knowledge, there has not been a report Received July 26, 2012; revised manuscript received September 5, 2012; accepted October 1, 2012; released online November 3, 2012 Time for primary review: 18 days Department of Cardiovascular Medicine (T. Imamura, T.S., N.K., H. Muraoka, S.M., T. Inaba, H. Maki, M.H., A.Y.), Department of Therapeutic Strategy for Heart Failure (K.K., S.K.), Graduate School of Medicine, University of Tokyo, Tokyo; and Jichi Medical University, Shimotsuke (R.N.), Japan Mailing address: Koichiro Kinugawa, MD, PhD, Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo , Japan. kinugawa-tky@umin.ac.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 398 IMAMURA T et al. on how to predict a responder/non-responder to TLV. We here sought to construct new criteria that could predict the efficacy of TLV in patients with HF. Methods Patient Population We enrolled consecutive 61 in-hospital patients with decompensated HF who received TLV between February 2011 and July 2012 at the University of Tokyo Hospital. All patients had been treated with standard therapy consisting of β-blockers, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) unless contraindicated or intolerant. All patients had lower limb edema, pulmonary congestion or jugular venous distension because of excess body fluid despite administration of conventional diuretics, including loop diuretics and/or thiazides. Doses of these medications, including the diuretics, were not changed for at least 7 days before TLV administration and during the study period (ie, through the week after TLV administration). We excluded the following: patients with any mechanical support (eg, ventricular assist device, intra-aortic balloon pumping, extracorporeal membranous oxygenation, and mechanical ventilation); patients who were suspected of having hypovolemia; patients with hemodynamically significant valvular stenosis; patients who had a history of acute coronary syndrome within 30 days before enrollment; patients with active systemic infection; and patients undergoing hemodialysis. Concomitant use of intravenous drugs, such as human atrial natriuretic peptides, phosphodiesterase III inhibitors, dobutamine, and dopamine, as well as furosemide, was continued and the doses were not changed for at least 2 days before TLV administration or during the study period. Attending physicians determined the initial dose of TLV, and the doses were maintained during the study period. During the administration of TLV, restriction of water intake was loosened according to the weight loss of the patient to avoid hypernatremia. The study protocol was approved by the Ethics Committee of Graduate School of Medicine, the University of Tokyo [application number 779 (1)]. Variables Evaluated Baseline clinical data included patients demographics, laboratory and echocardiographic parameters that were obtained within the 24 h before the administration of TLV. No patient was placed urinary catheter, and urine samples were obtained at the time of each urination. All patients urinated 4 6 h after TLV treatment. Baseline urine osmolality (U-OSM) was defined as the U-OSM measured just before the administration of TLV in the early morning. U-OSM was again measured at 4 6 h after TLV treatment, and the relative decrease at that time point compared with the baseline U-OSM was recorded as the %decrease in U-OSM. A responder/non-responder to TLV was defined as having any increase/decrease in 24-h urine volume (UV) during day 0 compared with UV during day 1. TLV was administered in the morning of day 0. HF symptom score was calculated as the summation of scores that were assigned to patients symptoms caused by HF if complicated. The symptoms were: (1) leg pitting edema [1 point], (2) pulmonary congestion [1 point], (3) jugular venous distention [1 point], (4) dyspnea [1 point], and (5) degree of NYHA (assigned 1 4 points to each class, ex, assigned 4 points to NYHA IV). The score was calculated just before the administration of TLV and at 1 week after TLV treatment in all patients. Serum sodium concentration and plasma levels of B-type natriuretic peptide (BNP) were also measured in all patients at 1 week after the administration of TLV. Statistical Analysis All statistical analyses were calculated with PASW Statistics 18 (SPSS Inc, Chicago, IL, USA) and JMP9 (SAS Institute, Cary, NC, USA). Continuous variables of responders/non-responders were compared by unpaired t-test or Mann-Whitney test as appropriate. Categorical variables of responders/nonresponders were compared by chi-square test or Fisher s exact test as appropriate. Univariable and multivariable analyses with logistic regression models were performed to calculate the adjusted odds ratio (OR) to assess the influence of various parameters of the efficacy of TLV. To construct categorical variables from continuous data, a cutoff point was obtained by receiver-operating characteristic (ROC) analysis. Data with P<0.05 in univariable analyses were enrolled in the multivariable analysis. Considering the results of univariable and multivariable analyses, we constructed new criteria for predicting the efficacy of TLV. Comparison among 3 groups stratified with our new criteria was executed by analysis of variance with Tukey s test or Kruskal-Wallis test with Chi-square test as appropriate. Unless otherwise specified, all data are expressed as mean ± standard deviation. Probability was 2-tailed, with P<0.05 regarded as statistically significant. Results Baseline Characteristics of Enrolled Patients and Logistic Analyses for Increases in UV After Administration of TLV (Table 1) Data from a total of 61 patients were analyzed. The mean age was 58.3 years (range years), and most patients were male (78.7%); 48 patients (78.7%) had HF of non-ischemic etiology (dilated cardiomyopathy, 17; dilated phase of hypertrophic cardiomyopathy, 5; restrictive cardiomyopathy, 3; cardiac sarcoidosis, 2; constrictive pericarditis, 4; adult congenital heart disease, 5; hypertensive heart disease, 7; any other etiology, 5). Plasma levels of AVP were 5.45±3.78 pg/ml on average (range pg/ml) and mean serum osmolality was 278.3±12.9 mosm/l (range mosm/l). With regard to medications, 55 patients (88.5%) received β-blockers, and 48 patients (78.7%) were prescribed ACEIs or ARBs. The mean dose of furosemide was 70.9 mg daily (range mg daily). A total of 27 patients (44.3%) were infused with intravenous catecholamine, and 28 patients (45.9%) had NYHA class IV symptoms; the remainder were assigned to NYHA class III. There were 37 (60.7%) responders to TLV. As shown in Table 1, elderly patients were significantly resistant to TLV treatment compared with younger patients. There were no significant differences in the doses of diuretics, NYHA functional class, plasma BNP levels, or echocardiographic parameters between responders and non-responders. Baseline HF symptom scores were indistinguishable among responders/non-responders (6.73±1.19 vs. 6.75±0.99, P=0.945). Renal function represented by serum creatinine or estimated glomerular filtration ratio (egfr) was less impaired in responders. Baseline U-OSM was significantly higher in responders compared with non-responders (500.3±154.0 vs ±68.7 mosm/l, P<0.001). Higher U-OSM was largely dependent on a higher concentration of urine urea nitrogen, if we calculated the contribution of 3 major factors to U-OSM as: 2 (urine sodium [meq/l]), (urine urea nitrogen [mg/dl]) / 2.8, and (urine creatinine [mg/dl]) 2/3. 13

3 Prediction of Efficacy of TLV by U-OSM 399 Table 1. Demographic, Laboratory, and Echocardiographic Parameters Before and During the Administration of Tolvaptan and Univariable Analyses for Increase in UV % Increase in UV >0% (n=37) % Increase in UV <0% (n=24) P value OR 95% CI Demographic parameters Dose of tolvaptan, mg/day 5.98± ± Age, years 53.1± ± * Age >66 years, n (%) 6 (16.2) 14 (58.3) 0.001* Male, n (%) 31 (83.8) 17 (70.8) Body mass index 22.1± ± Etiology of ischemia, n (%) 8 (21.6) 5 (20.8) Concomitant medications Furosemide, mg/day 73.2 (20 240) 61.5 (0 80) Spironolactone, mg/day 32.1 (0 75) 25.9 (0 50) Trichlormethiazide, mg/day 0.60 (0 4) 0.47 (0 1) β-blocker, n (%) 34 (91.9) 20 (83.3) ACEI/ARB, n (%) 31 (83.8) 17 (70.8) Catecholamine infusion, n (%) 16 (43.2) 11 (45.8) Laboratory parameters Serum sodium, meq/l 132.4± ± Serum potassium, meq/l 4.2± ± Serum BUN, mg/dl 31.8± ± * Serum BUN >44 mg/dl, n (%) 6 (16.2) 14 (58.3) 0.001* Serum creatinine, mg/dl 1.27± ± * Serum creatinine >1.3 mg/dl, n (%) 16 (43.2) 20 (74.1) 0.003* egfr, ml min m ± ± * egfr <38 ml min m 2, n (%) 9 (2.4) 17 (62.9) 0.001* Serum albumin, g/dl 3.4± ± Serum total bilirubin, mg/dl 1.5± ± Serum osmolality, mosm/l 277.6± ± Plasma arginine vasopressin, pg/ml 6.04± ± Plasma BNP, log10 pg/ml 2.78± ± Urine parameters UV day 1, ml/day 1,450±346 1,381± UV day 0, ml/day 2,360±1,042 1,180±472 <0.001* U-OSM, mosm/l 500.3± ± * U-OSM >352 mosm/l, n (%) 35 (94.6) 2 (8.3) <0.001* ,467 %decrease of U-OSM, % 41.4± ±14.6 <0.001* %decrease of U-OSM >26%, n (%) 31 (83.8) 1 (4.2) <0.001* ,056 U-sodium, meq/l 51.3± ± U-sodium after 4 h, meq/l 52.6± ± U-potassium, meq/l 30.2± ± U-potassium after 4 h, meq/l 32.1± ± U-urea nitrogen, mg/dl 797.2± ±160.9 <0.001* U-urea nitrogen after 4 h, mg/dl 318.4± ± U-creatinine, mg/dl 90.2± ± * U-creatinine after 4 h, mg/dl 34.4± ± Echocardiographic parameters LV diastolic diameter, mm 61.4± ± Ejection fraction, % 34.5± ± Ejection fraction >50%, n (%) 6 (16.2) 4 (16.7) Cardiac index, L min 1 m ± ± ervsp, mmhg 49.6± ± E/e ratio 12.8± ± Symptoms NYHA class IV, n (%) 17 (45.9) 11 (45.8) HF symptom score (pre) 6.73± ± ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; CI, confidence interval; E/e ratio, ratio of early diastolic filling velocity to early mitral lateral annulus velocity; egfr, estimated glomerular filtration ratio; ervsp, estimated right ventricular systolic pressure; HF, heart failure; LV, left ventricle; NYHA, New York Heart Association; OR, odds ratio; U-OSM, urine osmolality; UV, urine volume.

4 400 IMAMURA T et al. Table 2. Multivariable Analysis for Increase in UV Among Parameters Obtained Before and During the Administration of Tolvaptan P value OR 95% CI U-OSM >352 meq/l, n (%) %decrease of U-OSM >26%, n (%) Serum creatinine >1.3 mg/dl, n (%) Serum BUN >44 mg/dl, n (%) 0.003* , * , Age >69 years, n (%) Abbreviations as in Table 1. Consistently, the correlation of U-OSM with urine urea nitrogen was much stronger (r=0.865, P<0.001) than with urine sodium (r=0.245, P=0.007). Non-responders received relatively higher dose of TLV compared with responders (7.19±4.41 vs. 5.98±3.36, P=0.231). Relative increases in UV were indistinguishable among patients who received 3.75 mg, 7.5 mg, and 15 mg of TLV (136.5±75.4, 144.2±87.0, and 164.5±33.0, respectively, P=0.419). No adverse events, including hypernatremia and hypovolemic shock, occurred during the study period. According to the univariable analysis, age >66 years, serum blood urea nitrogen >44 mg/dl, serum creatinine >1.3 mg/dl, and egfr <38 ml min m 2 were predictive factors for a non-responder. In addition, there were 4 urine parameters significantly associated with increases in UV: baseline U- OSM, %decrease of U-OSM at 4 6 h after the administration of TLV, urine urea nitrogen concentration, and urine creatinine concentration. Categorical evaluation of these parameters showed that baseline U-OSM >352 mosm/l (OR 192.5) and %decrease of U-OSM >26% (OR 118.8) were significant predictors of a responder. Multivariable analysis confirmed that baseline U-OSM >352 meq/l (P=0.003) and %decrease of U-OSM >26% (P=0.045) were independent predictors of a responder to TLV (Table 2). Relationship Between U-OSM and Effects of TLV and Creating the New Criteria Figure 1A shows that baseline U-OSM significantly correlated with increases in UV after TLV treatment (P=0.001, r=0.411), and a cutoff level of U-OSM (=352 mosm/l) that was calculated by ROC analysis had a high sensitivity and specificity for the prediction of UV increases (0.946 and 0.917, respectively). Relative decreases in U-OSM after the administration of TLV also had a positive correlation with increases in UV (P<0.001, r=0.698) (Figure 1B). A cutoff level of %decrease of U-OSM (=26%) again had a high sensitivity and specificity for the prediction of UV increases (0.838 and 1.000, respectively). We constructed new criteria to predict a responder/non-responder that consisted of Condition 1: baseline U- OSM >352 mosm/l, and Condition 2: %decrease of U-OSM >26% at 4 6 h after the administration of TLV, which were both independent predictors for the response to TLV in the multivariable analysis. The 31 patients that satisfied both conditions (double-positive group) were responders to TLV except for 1, and the 19 patients who met neither condition (double-negative group) were uniformly non-responders. As also shown in Figure 2A, patients in the double-positive group significantly had a larger volume of UV than those in the other group. Our criteria had a high area under the curve (AUC; 0.960) in the ROC analysis and showed good predictability (OR 39.3) for responders to TLV in logistic regression analysis (P<0.001). The egfr had a positive correlation with increases in UV by TLV (P=0.008, r=0.336) (Figure 3A), and patients in the double-positive group had relatively preserved egfr compared with those in the double-negative group (58.8±29.3 vs. 29.0±20.8 ml min m 2, P<0.001) (Figure 3B). However, the cutoff level of egfr at 38 ml min m 2 did not efficiently discriminate responders from non-responders (in- Figure 1. Relationship between increases in urine volume after administration of tolvaptan and baseline urine osmolality (U-OSM) (A) and %decrease in urine volume at 4 6 h after the administration of tolvaptan (B).

5 Prediction of Efficacy of TLV by U-OSM 401 Figure 2. Increases in urine volume after the administration of tolvaptan among patients stratified by the new criteria (A) and ROC curves of the new criteria and egfr (B). *P<0.05 by analysis of variance with Tukey s test compared with the double-negative group. egfr, estimated glomerular filtration rate; ROC, receiver-operating characteristic. creases in UV, 53.7±85.8% in egfr >38 ml min m 2, and 13.6±46.1% in egfr <38 ml min m 2, P=0.064) (Figure 3C), and had a significantly lower AUC compared with our new criteria (0.754 vs , P=0.0027) (Figure 2B). We performed a subanalysis of the patients with serum sodium <135 meq/l (n=38), in whom baseline U-OSM >347 mosm/l (P=0.019) and %decrease of U-OSM >26% (P=0.042) were independent predictors for being a responder in the multivariable analysis. Criteria that were constructed in the same manner had a high AUC (0.978) in ROC analysis and good predictability (OR 45.0) for responders to TLV in logistic analysis (P<0.001). Relationship Between New Criteria and Efficacy at 1 Week After Administration of TLV (Table 3) HF symptom scores, serum sodium concentrations, and plasma BNP levels were examined just before the administration of TLV and at 1 week later. HF-related symptoms and hyponatremia improved significantly after 1 week of TLV treatment in patients with increases in UV for the first 24 h (Table 3A) or in those in the double-positive group (Table 3B) (P<0.05 for each). In contrast, HF symptom score or hyponatremia after 1 week of TLV treatment no longer improved but rather worsened in non-responders defined by the UV response (Table 3A) or in those assigned to the double-negative group (Table 3B). Decreases in the body weight of responders were significantly larger compared with those of non-responders after 1 week s administration of TLV ( 1.6±2.1 vs. 0.4±1.9 kg, P=0.023). Discussion Based on our logistic regression analyses of predictors for increases in UV by TLV, we constructed new criteria that consist of 2 conditions, as follows: C1=baseline U-OSM >352 mosm/l and C2=%decrease of U-OSM >26% at 4 6 h after the administration of TLV. Our criteria had excellent predictability for a responder/non-responder to TLV. We defined a responder/non-responder as an increase/decrease in UV during the first 24 h after the administration of TLV. Both HF symptom scores and serum sodium levels measured at 1 week later were significantly improved in responders, whereas in non-responders these 2 factors remained at the same levels or even worsened compared with before treatment with TLV. Therefore, we considered that an increase in UV during the first 24 h after administration was closely associated with the clinical efficacy of TLV. In other words, clinical responders to TLV normally had an increase in UV during the first day, which implied that intestinal congestion did not appear to significantly inhibit the absorption of TLV. AVP regulates water permeability by stimulation of V2 receptors that are located in the basolateral membrane of renal tubular cells in the collecting duct. AVP, which triggers water reabsorption via AQP-2 translocation, 14 and is secreted inappropriately in patients with advanced HF against low or normal serum osmolality because of non-osmotic triggers. 2 Consistently, we observed detectable levels of AVP against low or normal serum osmolality, which might be sufficient to activate reabsorption of free water through the aforementioned pathway and exacerbate congestion in patients with advanced HF.

6 402 IMAMURA T et al. Figure 3. Relationship between increase in urine volume and egfr (A), egfr and the criteria (B), and increase in urine volume stratified by cutoff of egfr (=38 ml min m 2 ) (C). (B) P<0.05 by analysis of variance with Tukey s test compared with the double-negative group. egfr, estimated glomerular filtration rate. Table 3. Changes in HF Symptom Score, Serum Sodium Concentration, and Plasma BNP Concentration at 1 Week After the Administration of Tolvaptan in Responders/Non-Responders A. Increase in UV B. New criteria % Increase in UV >0% (responder) % Increase in UV <0% (non-responder) Double positive Either positive Double negative Changes in HF symptom score Score decreased (improved), n * 6* 1 Score maintained or increased (worsened), n * 5* 18 Changes in serum sodium concentration, meq/l Sodium increased (improved), n * 4* 3 Sodium maintained or decreased (worsened), n * 7* 16 Changes in plasma BNP, log10 pg/ml BNP decreased (improved), n BNP maintained or increased (worsened), n All P<0.05 in chi-square test. *P<0.01 in Tukey s test with chi-square test compared with double-negative group. Abbreviations as in Table 1. TLV inhibits the V2 receptor-mediated pathway, 15,16 and usually induces a large volume of hyposmotic urine. 17 Several authors have reported that U-OSM levels decreased within 4 6 h after the administration of TLV. 10,18 In our univariable and multivariable analyses, baseline U-OSM and %decrease of U-OSM 4 6 h after TLV treatment were independent predictors for a responder/non-responder to TLV. It has been reported that expression levels of V2 receptor and AQP-2 are elevated in animal models of HF Urinary AQP-2 secretion was reported to be higher in patients with HF. 22 Such enhancement of the V2/AQP-2 system may explain the highly concentrated urine regardless of relatively low levels of AVP in HF patients. TLV is especially effective in these patients by blocking reabsorption of free water with the resultant markedly decreased U-OSM. We call these patients responders because they fulfil both conditions of our new criteria.

7 Prediction of Efficacy of TLV by U-OSM 403 On the other hand, our study demonstrated that there were a certain number of non-responders to TLV, who had relatively low U-OSM (296.7±68.7 mosm/l) even in the presence of detectable serum AVP (3.12±1.83 pg/ml). In patients with preserved renal function who have an ability to concentrate urine, urine osmolality is expected to reach mosm/l under such levels of serum AVP. 23 There are 3 possible explanations for the inability to concentrate urine in non-responders. The first is a reduction in the osmotic gradient in the renal medulla. A sodium/chloride cotransporter in the ascending limb of the loop of Henle in the inner medulla reabsorbs sodium ions, which increases the osmolality of the inner medullary interstitium and facilitates osmolality-induced water reabsorption in the collecting duct. Loop diuretics causes natriuresis by inhibiting the sodium/chloride cotransporter and this may result in the reduction of the osmotic gradient in the inner medulla. 24 Therefore, long-term administration of high-dose loop diuretics may possibly decrease the ability to concentrate urine in the collecting duct. 25 However, there were no significant differences in the doses of loop diuretics between responders and non-responders in our study. The second explanation is related to the fact that decreases in functioning nephrons are inevitably associated with larger solute load per each remaining nephron in patients with advanced chronic kidney disease (CKD). Larger solute load makes medullary blood flow faster and the medullary interstitium less concentrated because of insufficient reabsorption of solute in the ascending limb of the loop of Henle. The lower osmotic gradient may impair the concentrating ability of urine as discussed above. Larger solute load is also associated with faster urinary flow in the collecting duct, which may shorten the time for urine to contact water-permeable AQP-2 channels, and as a consequence the concentrating ability by AVP may be attenuated. However, such mechanisms leading to loss of urinary concentrating ability are believed to be applicable to patients with advanced stage CKD. 23 Only 4 (6.6%) patients with CKD stage 5 (ie, egfr <15 ml min m 2 ) were enrolled in our study, but all of them were non-responders, consistent with the above hypothesis. The third possible mechanism is an attenuated V2/AQP-2 system in the collecting duct. Decreased expression levels of the V2 receptor and/or AQP-2 have been observed in both animal models and patients with CKD, 20,26,27 and an inability to concentrate urine in non-responders can be well explained by this mechanism. However, there has not been any single report that investigates the expression levels of V2 receptor or AQP-2 in HF patients complicated with CKD, and further studies are necessary in this regard. Non-responders to TLV have similar renal physiology as in acquired nephrogenic diabetes insipidus (NDI), because they lose the ability to concentrate urine. Unlike common NDI patients, our non-responders never developed polyuria. Of course, patients with NDI do not necessarily have polyuria in general because daily solute excretion (600 mosm/day) only requires 2L of urine when it remains isosmotic (~300 mosm/l). Previous studies have shown that many patients with CKD lose the diluting ability as well as the concentrating one, 28 which is consistent with our second condition that U-OSM does not decrease against the administration of TLV. Impaired ability to dilute the urine may also be explained by a depressed V2/ AQP-2 system in the collecting duct. U-OSM is determined mainly by urine sodium concentration and urine urea nitrogen. 13,29 In the present study, urine urea nitrogen significantly decreased, along with lowered U- OSM after the administration of TLV. On the other hand, urine sodium concentration did not change after the administration of TLV, even in the responders. TLV treatment may not only result in water diuresis, but may also enhance excretion of sodium ions in the urine. Amelioration of renal congestion by TLV may be associated with the improved efficacy of natriuresis by concomitantly prescribed loop diuretics. Moreover, AVP has been recently demonstrated to have a stimulatory effect on epithelial Na-channel (ENaC)-mediated sodium reabsorption. 30 Inhibition of the V2 receptor by TLV may repress ENaC activity in the distal nephrons and result in increased sodium excretion. 31 Finally, we emphasize 2 advantages of the new criteria. These are the first-ever reported predictors of TLV efficacy, and could successfully stratify responders/non-responders to TLV. The second advantage is that no invasive or expensive examination is necessary for testing the criteria. The procedure consists of only twice measuring U-OSM (ie, before and after the administration of TLV). Study Limitations First, this study was conducted retrospectively in a single center, and consequently included a limited number of patients. Our criteria should be analyzed prospectively for their predictability of TLV response. Second, we speculated that non-responders might have lower expression levels of V2 receptor or AQP-2, but no data were available to support this hypothesis. Third, we regarded increases in UV during the first 24 h after the administration of TLV as a sign of response to TLV in this study. The long-term effects of TLV among responders is a future concern. Fourth, this study was conducted in considerably sick patients and approximately half of them received a continuous infusion of inotropes or had NYHA class IV symptoms. Therefore, the result may not be necessarily applicable to less sick patients in general. Particularly, nonresponders may be fewer among less sick HF patients because they are usually complicated with an earlier stage of CKD. Fifth, TLV is indicated for all HF patients with congestive symptoms in Japan, but is only applicable to patients with hyponatremia in the United States. Therefore, there may be some discrepancy in the results when the study population is limited to hyponatremic patients. In fact, the subanalysis of hyponatremic patients showed that similar criteria were useful, but the cutoff value of baseline U-OSM was different. Sixth, the cardiac index, right ventricular systolic pressure, and E/e ratio (ratio of early diastolic filling velocity to early mitral lateral annulus velocity) that were calculated from echocardiographic data were not significantly different between responders/non-responders. In addition, 10 patients with the most severe HF who eventually needed left ventricular assist device implantation were all responders to TLV in this study. However, we did not perform an invasive hemodynamic study in most of the patients, and we can not exclude the possibility that severe low cardiac output might result in apparent unresponsiveness to TLV because of insufficient renal perfusion in some cases. Finally, we did not observe dose-dependent responses to TLV in terms of UV increases. This phenomenon may be explained by the fact that we included many non-responders to whom a relatively higher dose of TLV was administered. A different study design is needed to assess dose-dependent effects of TLV in the range of mg/day. In conclusion, our new criteria that include the U-OSM before and after the administration of TLV were an excellent predictor of a responder/non-responder to TLV. Unresponsiveness to TLV may be attributable to NDI complicated with CKD. This knowledge would be useful for optimal patient

8 404 IMAMURA T et al. selection and for determining the therapeutic strategy when TLV is being used as therapy for HF patients. Acknowledgments This work was supported in part by the FUGAKU trust for medicinal research to K.K., a Grant-in-Aid for the JSPS Postdoctoral Research Fellow from the Japan Society for the Promotion of Science (no ) to N.K., and the Japan Society for the Promotion of Science (JSPS) through its Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) to R.N.. None. Disclosure References 1. Goldsmith SR, Gheorghiade M. Vasopressin antagonism in heart failure. J Am Coll Cardiol 2005; 46: Leier CV, Dei Cas L, Metra M. Clinical relevance and management of the major electrolyte abnormalities in congestive heart failure: Hyponatremia, hypokalemia, and hypomagnesemia. Am Heart J 1994; 128: Tada Y, Nakamura T, Funayama H, Sugawara Y, Ako J, Ishikawa SE, et al. 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