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Effects of Tolvaptan in Patients with Chronic Kidney Disease and Chronic Heart Failure

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Effects of Tolvaptan in Patients with Chronic Kidney Disease and Chronic Heart Failure Clin Exp Nephrol DOI 10.1007/s10157-016-1379-0 ORIGINAL ARTICLE Effects of tolvaptan in patients with chronic kidney disease and chronic heart failure Mari Katsumata1 · Nobuhito Hirawa1 · Koichiro Sumida2 · Minako Kagimoto2 · Yosuke Ehara2 · Yuki Okuyama2 · Megumi Fujita1 · Akira Fujiwara1 · Mayumi Kobayashi1 · Yusuke Kobayashi3 · Yuichiro Yamamoto1 · Sanae Saka1 · Keisuke Yatsu2 · Tetsuya Fujikawa4 · Yoshiyuki Toya2 · Gen Yasuda1 · Kouichi Tamura2 · Satoshi Umemura5 Received: 24 October 2016 / Accepted: 30 December 2016 © The Author(s) 2017. This article is published with open access at Springerlink.com Abstract osmolality (r = −0.479, p = 0.038), the baseline urine vol- Background Tolvaptan, a vasopressin V2 receptor blocker, ume (r = −0.48, p = 0.028), and the baseline inferior vena has a diuretic effect for patients with heart failure. How- cava diameter (IVCD) (r = −0.622, p = 0.017). Hypona- ever, there were a few data concerning the effects of tolvap- tremia was improved to the normal value, and the augmen- tan in patients with chronic kidney disease (CKD). tations of the sodium concentration were negatively associ- Methods We retrospectively analyzed 21 patients with ated with the basal sodium levels (p = 0.01, r = −0.546). chronic heart failure and CKD. Tolvaptan was co-admin- Conclusions Tolvaptan is effective in increasing diuresis istered with other diuretics in-use, every day. We com- and improved hyponatremia, even in patients with CKD. pared clinical parameters before and after the treatments The baseline urine osmolality, urine volume, and IVCD with tolvaptan. Furthermore, we examined the correlations may be useful predictors for diuretic effects of tolvaptan. between baseline data and the change of body weight. Results Tolvaptan decreased the body weight and Keywords Chronic kidney disease · Tolvaptan · Urine increased the urine volume (p = 0.001). The urine osmo- osmolality · Hyponatremia lality significantly decreased throughout the study period. Urinary Na/Cr ratio and FENa changed significantly after 4 h, and more remarkable after 8 h (p = 0.003, both). Introduction Serum creatinine increased slightly after 1 week of treat- ment (p = 0.012). The alteration of body weight within the Tolvaptan is an oral diuretic with a new mechanism which study period correlated negatively with the baseline urine selectivity binds to the V2 receptor as an antagonist. V2 receptors are located in the renal collecting duct, where arginine vasopressin (AVP) binding to the V 2 receptor leads to a rise in intracellular cAMP. This promotes renal water reabsorption via translocation of intracellular vesi- * Nobuhito Hirawa cles containing the water channel aquaporin-2 into the apical plasma membrane and increased transcription of 1 Department of Nephrology and Hypertension, Yokohama City University Medical Center, 45-7 Urafune-cho, aquaporin-2 [1]. The compound’s aquaretic effects by sin- Minami-ku, Yokohama 232-0024, Japan gle administration were confirmed by an increase in urine 2 Department of Medical Science and Cardiorenal Medicine, volume and a decrease in urine osmolality, followed by Yokohama City University School of Medicine, Yokohama, an increase in serum sodium concentration [2]. Tolvaptan Japan has been demonstrated to ameliorate congestion in patients 3 Department of Nephrology, Yokosuka City Hospital, with heart failure [3, 4] and to correct hyponatremia [5, 6]. Yokosuka, Japan Patients with advanced CKD cannot produce enough 4 Center for Health Service Sciences, Yokohama National urine and often fall into volume overload. Loop diuretics University, Yokohama, Japan are conventionally used for these patients. However, there 5 Yokohama Rosai Hospital, Yokohama, Japan are several adverse effects with taking loop diuretics. One Vol.:(0123456789)1 3 Clin Exp Nephrol is electrolyte abnormalities, such as hypokalemia and performed before beginning tolvaptan. IVCD was visual- hyponatremia [7]. On the other hand, tolvaptan has been ized two-dimensionally and measured by M-mode echocar- reported to promote water excretion without changes in diography in expiration as described elsewhere [9]. In cases renal hemodynamics or sodium and potassium excretion of discharge or drug interruption, the data at discontinu- [1]. ance were substituted. However, the effects of tolvaptan on urine volume, and urinary and serum sodium excretions in advanced CKD Statistical analysis patients were not yet clarified. Furthermore, the parameters which relate to body weight reduction were also not suffi- The value of each measurement was expressed as the ciently evaluated. Thus, to clarify the effects of tolvaptan median (interquartile range). Comparisons of parameters on body weight, and urinary and serum electrolytes, as well between before and after treatment were analyzed with as to examine the predictors for efficacy, we retrospectively the Wilcoxon signed-rank test. Factors correlating with evaluated the medical records of CKD patients. changes of body weight and S-Na were analyzed with the Spearman rank correlation coefficient. We considered a p value <0.05 as significant. Data analysis was performed Materials and methods with SPSS 23 statistical software (SPSS Inc., Chicago, IL, USA). Study subjects This was a retrospective observational study. We included Results patients with CKD stage G3–5 and congestive heart failure, who were admitted to our hospital and received tolvaptan Table 1 shows the clinical characteristics of the study sub- for excess body fluid, despite administration of the conven- jects. The study consisted of 15 men and 6 women with tional diuretics between December 2010 and April 2015. a median age of 69 (interquartile range 60–76). Nineteen The definition of CKD G3–5 was eGFR less than 60 ml/ patients were in CKD stage 5; two patients were in stage min/1.73 m2 over 3 months despite the underlying disease. 3a or 3b respectively. The median serum creatinine level We excluded the following: patients undergoing hemodi- just before administration of tolvaptan was 3.82 mg/dl alysis and peritoneal dialysis, those whose dose of other (interquartile range 3.48–5.08). The average urine volume diuretics increased during the observation period (3 days for 3 days before tolvaptan administration was distributed before and a week after tolvaptan administration), and a between 292 and 1900 ml/day, and the median of all cases case of acute kidney injury. The initial tolvaptan dose was was 975 ml/day. One patient was in NYHA IV and eleven 15 mg/day, except one case that started at 3.75 mg/day. patients were in NYHA III, and five were in NYHA II. Pri- mary diseases included benign nephropathy (n = 10), dia- Measurements betic nephropathy (n = 7), polycystic kidney disease (n = 1), microscopic polyangitis (n = 1), membranous nephropathy The main endpoints of this study were changes of body (n = 1), and lupus nephritis (n = 1). Patients were treated weight after 1 week administration of tolvaptan, and we with the following diuretics: furosemide alone (median compared average urine volume for 3 days before and for dose of 140 mg, interquartile range 80–200, n = 17), 7 days after treatment. In addition, we compared values of spironolactone 25 mg/day and trichlormethiazide 1 mg/ blood pressure, urine osmolality, urine gravity, urea sodium day (n = 1); furosemide 40 or 320 mg/day and potassium excretion calculated by spot urine (U-Na, mEq/gCr), frac- canrenoate 400 mg/day (n = 2); or spironolactone alone tional excretion of sodium (FENa), serum creatinine, esti- (25 mg/day, n = 1). The renin–angiotensin–aldosterone sys- mated glomerular filtration rate (eGFR), serum sodium, tem (RAAS) inhibitor was prescribed for 12 patients. Only B-type natriuretic peptide (BNP), human atrial natriuretic 1 patient took digitalis. peptide (hANP), and antidiuretic hormone (ADH) before Body weight decreased (p < 0.001), and urine volume and after the administration of tolvaptan. We obtained data increased with tolvaptan treatment (p < 0.001) (Table 2). of urine osmolality, urine gravity, U-Na, and FENa after Reflecting water diuresis, urine osmolality decreased sig- tolvaptan treatment at 4, 8, and 24 h. eGFR was calcu- nificantly (Fig. 1a). The urine osmolality decreased after lated using the equation proposed by the Japanese Society 4 h (p = 0.001), and markedly at 8 h (p < 0.001). The of Nephrology as follows ; eGFR (ml/min/1.73 m2) = 194 effects on urine osmolality continued throughout the study × Cr− 1.094 × Age−0.287×0.739 (if female) [8]. We collected periods. The urine gravity significantly decreased 8 h data of the ejection fraction and inferior vena cava diam- (p = 0.043, n = 6) and 24 h (p = 0.002, n = 14), but not sig- eter (IVCD) in the case that heart ultrasonography was nificant at 1 week (Table 2). 1 3 Clin Exp Nephrol Table 1 Clinical characteristics Value of patients Age (median, IQR) 69 (60–76) Sex (male) [n (%)] 15 (71.4) Body weight (kg) (median, IQR) 62.6 (54.6–72.5) Body mass index (kg/m2) (median, IQR) 24.8 (20.1–29.0) Blood pressure (mmHg) (median, IQR) Systolic 136 (126–143) Diastolic 74 (64–78) NYHA [n (%)] I 4 (19.0) II 5 (23.8) III 11 (52.4) IV 1 (4.8) Primary disease [n (%)] Benign nephropathy 10 (47.6) Diabetic nephropathy 7 (33.3) Polycystic kidney disease 1 (4.8) Microscopic polyangitis 1 (4.8) Membranous nephropathy 1 (4.8) Lupus nephritis 1 (4.8) CKD stage [n (%)] G3a 1 (4.8) G3b 1 (4.8) G4 0 (0) G5 19 (90.5) Furosemide (mg/day) (median, IQR) (n = 19) 120 (60–200) Use of ARB, ACEI [n (%)] 12 (57.1) Ejection fraction (%) (median,
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