□ ORIGINAL ARTICLE □

Dual Impact of Tolvaptan on Intracellular and
Extracellular Water in Chronic Kidney Disease
Patients with Fluid Retention

Takahiro Masuda 1, Takuya Murakami 1, Yusuke Igarashi 1, Kyochika Okabe 1,
Takahisa Kobayashi 1, Shin-ichi Takeda 1, Takako Saito 2, Chuji Sekiguchi 3,
Yasuharu Miyazawa 3, Tetsu Akimoto 1, Osamu Saito 1, Shigeaki Muto 1 and Daisuke Nagata 1

Abstract

Objective Tolvaptan, an oral selective V2-receptor antagonist, is a water diuretic that ameliorates fluid re-
tention with a lower risk of a worsening renal function than conventional loop diuretics. Although loop diu-
retics predominantly decrease extracellular water (ECW) compared with intracellular water (ICW), the effect
of tolvaptan on fluid distribution remains unclear. We therefore examined how tolvaptan changes ICW and
ECW in accordance with the renal function.
Methods Six advanced chronic kidney disease patients (stage 4 or 5) with fluid retention were enrolled in
this study. Tolvaptan (7.5 mg/day) added to conventional diuretic treatment was administered to remove fluid
retention. The fluid volume was measured using a bioimpedance analysis device before (day 0) and after (day
5 or 6) tolvaptan treatment.
Results Body weight decreased by 2.6%±1.3% (64.4±6.5 vs. 62.8±6.3 kg, p=0.06), and urine volume in-
creased by 54.8%±23.9% (1,215±169 vs. 1,709±137 mL/day, p=0.03) between before and after tolvaptan
treatment. Tolvaptan significantly decreased ICW (6.5%±1.5%, p=0.01) and ECW (7.5%±1.4%, p=0.02),
which had similar reduction rates (p=0.32). The estimated glomerular filtration rate remained unchanged dur-
ing the treatment (14.6±2.8 vs. 14.9±2.7 mL/min/1.732 m, p=0.35).
Conclusion Tolvaptan ameliorates body fluid retention, and induces an equivalent reduction rate of ICW
and ECW without a worsening renal function. Tolvaptan is a novel water diuretic that has a different effect
on fluid distribution compared with conventional loop diuretics.

Key words: fluid retention, bioimpedance analysis, extracellular water, intracellular water, tolvaptan, water
diuretic

(Intern Med 55: 2759-2764, 2016)
(DOI: 10.2169/internalmedicine.55.7133)

the treatment of fluid retention; however, these agents are
Introduction associated with worsening renal failure (3, 4), which is criti-
cal in advanced CKD patients. Transient depletion of the in-
Fluid retention is a frequent and important clinical issue travascular volume is one of the promising mechanisms for
in advanced chronic kidney disease (CKD), because it is a worsening renal failure (5). Several studies using bioelectric
risk factor for end-stage renal disease, cardiovascular dis- impedance analysis (BIA), a non-invasive method for the
ease, and all-cause death (1, 2). Loop diuretics, such as fu- measurement of body composition, have shown that fu-
rosemide, are traditionally and commonly used agents for rosemide predominantly lowers extracellular water (ECW),


Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan, 2 Kawashima Naika Clinic, Japan and 3 Nasu Minami
Hospital, Japan
Received for publication January 16, 2016; Accepted for publication February 23, 2016
Correspondence to Dr. Takahiro Masuda, takam@jichi.ac.jp

2759

9 mOsm/kg and urine osmolarity 276.7133 Table 1. total body water (TBW: ICW+ECW) and the ratio of ECW to TBW (ECW/TBW) were calculated from the sum of each Patients segment.4±6. 7. After en- rollment. pleural effusion and ascites. fu. ening renal function (10).7 mOsm/kg (Table 1. se- treatments remained constant throughout the study.1±2. 18). The initial dose of tolvaptan in all patients was as follows: age 72.6±2. BIA measurements of resistance ICW in advanced CKD patients with fluid retention. serum cre- tion due to heart failure and liver cirrhosis (3. Cary. 250. including Statistical analysis generalized edema. tolvaptan in addition to conventional treatment was Results administered to improve fluid retention. eGFR 14. tolvaptan has been used in CKD patients with heart atinine clearance. blocks Blood and 24-hour urine samples plus body weight (BW) the effect of arginine vasopressin on renal collecting tubes data were collected before tolvaptan dosing on day 0 and af- and results in water diuresis. 2). liver cirrhosis and nephrotic syndrome. p values of less than 0. Unlike loop diuretics. 22). and this 1. 50. tion coefficients modified for Japanese patients (20).7 mEq/L. CKD patients (stage 4 or 5) with fluid retention.55. atinine. The blood urea nitrogen.05 were considered to be pan) or Jichi Medical University (n=2.5 mg/day. formed using the JMP 12 software package version (SAS ceived any diuretic treatment except for tolvaptan (e. Tokyo. statistically significant.49 mg/dL. rosemide. serum Na. Re. Shimotsuke.0±0. Intern Med 55: 2759-2764. and the dosage of tolvaptan and other diuretic BW 64. 2016 DOI: 10. including the intravascular volume.3 years.13±0. The cluded. rum creatinine 3.6± 19. 9-11). terwards on day 5 or 6. All pa. Primary diseases included neph- 2760 . tolvap. We (day 5 or 6) tolvaptan administration. azosemide or spironolactone) (Table 1). and had re. which ameliorates fluid reten. In- to the different effect on fluid distribution compared with Body Japan.215±169 mL/day.g. 5.8±5. appropriate. as previously re. ICW. gender (male 2.0±11. similar to a previous therefore examined the effect of tolvaptan on both ECW and study on furosemide (6).8 mL/min/ tients provided their written informed consent.7 mL/min. Nasukarasuyama.2169/internalmedicine. compared with intracel- Blood and urine sample collection lular water (ICW) (6-8). The statistical analyses were per- Japan) between December 2013 and July 2015. At enrollment. Institute. 500. all patients had been admitted to paired or unpaired t-test was used to compare variables as Nasu Minami Hospital (n=4. The baseline characteristics of the 6 CKD patients were ported (19). Furthermore. USA). Ja. The data are expressed as the mean ± standard error. the details remain unclear. Baseline Profile of Patients.6±2. ECW. cre- cently. an oral selective V2-receptor antagonist..732 m. Japan) (21-23) before (day 0) and after loop diuretics (5). estimated glomerular filtration rate (eGFR). 17. serum Na study was conducted in accordance with the Declaration of 141. however. We evaluated the ef- fect of tolvaptan for 5 or 6 days. blood urea nitrogen 59. creatinine clearance 13.000 kHz). serum osmolarity and urine os- failure. Tochigi. Modification of Diet in Renal Disease (MDRD) study equa- tan can ameliorate fluid retention with a low risk of a wors. urine volume 1.1 mg/dL. serum Helsinki. Patients with prior renal replacement or current dialysis were ex. Tochigi. including molarity were measured. A recent review proposed that the Fluid volume analyses were carried out using a BIA de- mechanism for the favorable action of tolvaptan may be due vice using eight tactile electrodes (InBody S10 or S20. tolvaptan added to Measurement of the fluid volume using bioimped- conventional diuretic therapy could reduce the risk of a ance analysis worsening renal function compared with conventional ther- apy alone (14. female 4).5 kg. using the equations in the BIA software pro- This was a prospective study that enrolled 6 advanced gram (21. Tolvaptan. and reactance were taken with the patient in the recumbent position after 5 minutes of rest using a multifrequency ana- Materials and Methods lyzer (1. osmolarity 307. and 1. The eGFR was calculated using the diabetic nephropathy (12-16).

55.01). Intern Med 55: 2759-2764.8± 2. 7.8±6.709±137 mL/day.7±2.1 vs. p=0.5% (20. n=3).4 vs. diabetic nephropathy (n=2) and liver cir.4 pg/mL.3±23. p=0. and consequently. 3).06). 1.4% (104. 14. 2). p=0. 165. The ratio of ECW to TBW (ECW/TBW) was similar among the treatments (B).9% (1.8%±23. BIA showed that tolvaptan significantly decreased ICW.8 pg/mL. 1. p=0. p=0. serum creatinine.37%.3 vs.4% (36. BIA confirmed that tolvaptan ameliorates 1. 2016 DOI: 10. body fluid retention and induces a similar reduction rate in ICW and ECW exhibited a similar reduction rate (6. 2). urine vol- 2761 . and atrial natriuretic peptide (ANP) decreased by 28. Discussion 19. and the urine volume increased by remained unchanged during the treatment (Table 2 and 54. Figure 1. Fig.3 kg. suggesting a novel mechanism for tolvaptan as a water ECW/TBW was not significantly changed before and after diuretic. 34. this is the first study in Plasma brain natriuretic peptide (BNP) decreased by 21. eGFR and serum Na 62.7±2.4%.4%± which BIA detected the amelioration of body fluid retention 13. Change in the absolute body water before (day 0) and after (day 5 or 6) tolvaptan treat- ment (A).7133 Table 2. Change of Clinical Parameters before and after Tolvaptan Administration.215±169 vs. ICW: intracellular water. The changes in BW. between before and after tolvaptan treatment (Table 2).05 vs.12) (Fig. BIA showed that ICW decreased by 6.6±99. 1.5%± ICW and ECW without an adverse effect on the renal func- 1. tion. ECW decreased by 7.2±197.48%±0.5% vs. tolvaptan treatment (-0.7 L.22.5 vs. The mean BW decreased by 2. 75. p=0.9%± In this study.8 vs.32) (Fig.03) Fig.5%±1.3%± rhosis (n=2).1±4. ECW and TBW. p=0.14. before tolvaptan treat- ment. and TBW decreased by 6. 11.9 L.6±29.5%±1.2169/internalmedicine. TBW: total body water rosclerosis (n=2).3 L. p=0.02).5 vs.4% (263. p=0. Blood urea nitrogen.4% (15. *p<0. n=3) during tolvaptan treatment.3% (64.5±5.6%±1. To the best of our knowledge.4±2.01) (Table 2. 2). ECW: extracellular water.5%±1.4±6.

Therefore.022). Furthermore. On the other sessment of body composition (28-30). and recent from that of furosemide. the fluid movement from the extravascular to vas- cular space will be lower. and cardiac biomarkers (such as plasma BNP and ECW-7.072). ministration of furosemide for 7 days (dosage of 26. Change in the rate of body water before and after rum osmolality and resultant fluid shift from intracellular to tolvaptan treatment. 28). are to conventional diuretic treatment. The reduction rate was similar between ICW and ECW. The tech. # p<0. Similar to ment of the fluid volume and muscle mass in hemodialysis other cases. after the administration of tolvaptan.9 mL/min/1. tolvaptan equally decreased ECW and ICW.05 before vs. showed that tolvaptan ameliorated showed that furosemide did not significantly change ICW. but remains uncertain. expensive. sample size are necessary to confirm our results.) significantly decreased ECW (-13. BIA has been widely used tolvaptan itself on fluid distribution than the simultaneous in various clinical and animal research settings for the as.. there was rate quantitative measurement of the body fluid status in the also a different in the reduction rate between ECW and ICW course of tolvaptan treatment is required. particu- 2762 . mg/day i. and require multiple blood were administered at the same dosage throughout the study. the enrolled patients. we experienced rough estimate of the body fluid content. In these cases. the change in body water (ICW -6. BIA is a useful (p=0. along with furosemide. and its effect was clearly different body fluid status and plasma volume (24-26). some interaction on fluid distribution In this study. tolvaptan was added ods.3%. Loop diuretics induce a reduction in the may contribute to preserve the renal function. two cases in our study had used a potassium-sparing ported that the BIA device InBody is useful for the assess.4%.7%. which would accelerate the oncotic forces lead- ing to the fluid movement from the interstitial to intravascu- lar compartment (5). 3 cases (eGFR 38. p=0. draws (28). Further studies are tively.5% ± 1. e. BW only provides a although it decreased ECW (6-8). spironolactone. Therefore. fat mass and muscle mass (1.32). and all diuretic agents time-consuming. are required to evaluate the detailed mecha- the primary driving force of fluid movement from the ex.9%). Generally. nonin. BIA is almost as precise as the di. In the present study. nique is based on the measurement of the resistance gener. diuretics have been associated with adverse effects.5±1. diuretic. these parameters (13. unlike loop diuretics.732 m) in whom the ad- tion of BNP requires a dissection of the relative contribu. A potential limitation associated with this study is the small sample size. tolvaptan pro- duces free-water diuresis and an increase in serum osmo- lality (32). An increase in interstitial fluid osmo- lality may then stimulate a fluid shift from the intracellular to interstitial compartment.5% and 7. because loop diuretics pre. 2016 DOI: 10.0 tions of baseline cardiac disease and superimposed fluid re. These processes may cause a similar reduction rate in ECW and ICW in response to tolvaptan. Because loop diuretics predominantly plied by electrodes. Because both tolvaptan and spironolactone act on treatment. 19). Unfortunately. including ours. This protocol may more accurately evaluate the effect of lution methods (28). respec. Therefore. The BIA measurement is simple. Accordingly. travascular to intravascular compartment is the oncotic pres. the effect of lowering ICW in tolvap- vasive and easy to perform. ume. p=0. interstitial and intravascular spaces would occur immediately cantly decreased by 6. such as furosemide and dominantly decrease ECW. spironolactone. On the other hand.5 vs. Similarly.4%. the gold standard for fluid volume measurement. which might have affected the statistical results. We previously re.7133 and any change in the oncotic pressure would be small. However. We used the same device in this study and these patients equally decreased ICW (-5.5% ± 1. loop diuretics were prescribed in all ated in the body against a low voltage electrical current ap. after tolvaptan treatment. BIA showed that ICW and ECW signifi. Indeed. but not ICW (6-8). administration with other diuretics. Further studies with a larger ECW. needed to evaluate these mechanisms. we were unable to detect a signifi- cant increase in serum osmolality measured 5 or 6 days af- ter tolvaptan administration.5±1. the additional administration of tolvaptan on patients (22. 31).027) tention to the elevated BNP level (27). nism of tolvaptan on fluid distribution. including TBW. However. p=0. The equivalent efficacy of tolvaptan on ICW and ECW sure gradient (5). ICW. administration of tolvaptan and other diuretics. whereas isotope dilution meth. may exist. lently acts on ICW and ECW.g.2169/internalmedicine. an accu.v. hand. Although loop intravascular volume accompanying urinary Na excretion. and the interpreta. comparative suggesting a quite different mechanism of fluid distribution studies of single administration of tolvaptan and co- compared with loop diuretics.55.3%) and ECW revealed the amelioration of fluid retention after tolvaptan (-5. previous studies using BIA studies. the effect of tolvaptan ANP) have been traditionally used as parameters for the on ICW was obvious. but not ICW (-5. We presumed that a rise in se- Figure 2.7±3. Intern Med 55: 2759-2764.3±16. tolvaptan equiva- method to measure the body composition. However. tan may be underestimated. the collecting ducts. decrease ECW (6-8). Therefore.

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