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Published in: Clinical and Experimental Nephrology 3/2018

01-06-2018 | Original article

Tolvaptan promotes urinary excretion of sodium and urea: a retrospective cohort study

Authors: Satoshi Minami, Takayuki Hamano, Hirotsugu Iwatani, Masayuki Mizui, Yoshiki Kimura, Yoshitaka Isaka

Published in: Clinical and Experimental Nephrology | Issue 3/2018

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Abstract

Background

Tolvaptan (TLV) promotes aquaresis; however, little is known about its effect on solute excretion in chronic kidney disease (CKD).

Methods

We retrospectively studied CKD patients with decompensated heart failure (HF) or those with autosomal dominant polycystic kidney disease (ADPKD) receiving TLV. Patients with an increased urine volume of more than twice of daily variance were defined as “responders” in HF. We compared the ability of the urinary osmolality (U-OSM) change and urinary creatinine concentration ([U-Cr]) change to discriminate “responders”. The fractional excretion of sodium (FeNa) and urea nitrogen (FeUN), and blood urea nitrogen (BUN) were monitored.

Results

In 30 responders among 53 HF patients, TLV increased FeUN significantly from 36.1 to 44.2% after starting TLV, but not FeNa. Since U-OSM is determined partially by urinary UN concentration, the decrease of [U-Cr] after treatment outperformed the U-OSM decrement to discriminate responders, as shown in receiver operating characteristic curve analysis and significantly higher net reclassification index. In 13 ADPKD patients, TLV increased FeUN (34.8, 47.3%, p = 0.02), and significant decrease of BUN by 2.3 (95% confidence interval 0.4–4.2) mg/dL was observed even 3 months after the intervention. Systolic blood pressure decreased significantly by 14.2 (95% confidence interval 4.0–24.4) mmHg along with the increase in FeNa, leading to reduced dosage of antihypertensives in 6 patients.

Conclusion

TLV promotes the excretion of sodium and urea. The change in [U-Cr] is useful for early discrimination of responders. Hypotension should be carefully monitored during high-dose TLV therapy.
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Literature
1.
go back to reference Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407–18.CrossRefPubMedPubMedCentral Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407–18.CrossRefPubMedPubMedCentral
2.
go back to reference Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003;9:1323–6.CrossRefPubMed Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003;9:1323–6.CrossRefPubMed
3.
go back to reference Wang X, Gattone V 2nd, Harris PC, Torres VE. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J Am Soc Nephrol. 2005;16:846–51.CrossRefPubMed Wang X, Gattone V 2nd, Harris PC, Torres VE. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J Am Soc Nephrol. 2005;16:846–51.CrossRefPubMed
4.
go back to reference Perucca J, Bichet DG, Bardoux P, Bouby N, Bankir L. Sodium excretion in response to vasopressin and selective vasopressin receptor antagonists. J Am Soc Nephrol. 2008;19:1721–31.CrossRefPubMedPubMedCentral Perucca J, Bichet DG, Bardoux P, Bouby N, Bankir L. Sodium excretion in response to vasopressin and selective vasopressin receptor antagonists. J Am Soc Nephrol. 2008;19:1721–31.CrossRefPubMedPubMedCentral
5.
go back to reference Ecelbarger CA, Kim GH, Terris J, Masilamani S, Mitchell C, Reyes I, et al. Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney. Am J Physiol Renal Physiol. 2000;279:F46–53.CrossRefPubMed Ecelbarger CA, Kim GH, Terris J, Masilamani S, Mitchell C, Reyes I, et al. Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney. Am J Physiol Renal Physiol. 2000;279:F46–53.CrossRefPubMed
6.
go back to reference Sun A, Grossman EB, Lombardi M, Hebert SC. Vasopressin alters the mechanism of apical Cl− entry from Na+:Cl− to Na+:K+:2Cl− cotransport in mouse medullary thick ascending limb. J Membr Biol. 1991;120:83–94.CrossRefPubMed Sun A, Grossman EB, Lombardi M, Hebert SC. Vasopressin alters the mechanism of apical Cl entry from Na+:Cl to Na+:K+:2Cl cotransport in mouse medullary thick ascending limb. J Membr Biol. 1991;120:83–94.CrossRefPubMed
7.
go back to reference Bankir LT, Trinh-Trang-Tan MM. Renal urea transporters Direct and indirect regulation by vasopressin. Exp Physiol. 2000;85:243s–52s.CrossRefPubMed Bankir LT, Trinh-Trang-Tan MM. Renal urea transporters Direct and indirect regulation by vasopressin. Exp Physiol. 2000;85:243s–52s.CrossRefPubMed
8.
go back to reference Kim SR, Hasunuma T, Sato O, Okada T, Kondo M, Azuma J. Pharmacokinetics, pharmacodynamics and safety of tolvaptan, a novel, oral, selective nonpeptide AVP V2-receptor antagonist: results of single- and multiple-dose studies in healthy Japanese male volunteers. Cardiovasc Drugs Ther. 2011;25(Suppl 1):S5–17.CrossRefPubMed Kim SR, Hasunuma T, Sato O, Okada T, Kondo M, Azuma J. Pharmacokinetics, pharmacodynamics and safety of tolvaptan, a novel, oral, selective nonpeptide AVP V2-receptor antagonist: results of single- and multiple-dose studies in healthy Japanese male volunteers. Cardiovasc Drugs Ther. 2011;25(Suppl 1):S5–17.CrossRefPubMed
9.
go back to reference Kajimoto K, Abe T. Blood urea nitrogen as a marker of the acute response to addition of tolvaptan to standard therapy in patients hospitalized for acute heart failure syndromes. Int J Cardiol. 2014;177:589–91.CrossRefPubMed Kajimoto K, Abe T. Blood urea nitrogen as a marker of the acute response to addition of tolvaptan to standard therapy in patients hospitalized for acute heart failure syndromes. Int J Cardiol. 2014;177:589–91.CrossRefPubMed
11.
go back to reference Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297:1319–31.CrossRefPubMed Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297:1319–31.CrossRefPubMed
12.
go back to reference Matsuzaki M, Hori M, Izumi T, Fukunami M, Tolvaptan I. Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study). Cardiovasc Drugs Ther. 2011;25(Suppl 1):S33–45.CrossRefPubMed Matsuzaki M, Hori M, Izumi T, Fukunami M, Tolvaptan I. Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study). Cardiovasc Drugs Ther. 2011;25(Suppl 1):S33–45.CrossRefPubMed
13.
go back to reference Imamura T, Kinugawa K, Shiga T, Kato N, Muraoka H, Minatsuki S, et al. Novel criteria of urine osmolality effectively predict response to tolvaptan in decompensated heart failure patients. Circ J. 2013;77:397–404.CrossRefPubMed Imamura T, Kinugawa K, Shiga T, Kato N, Muraoka H, Minatsuki S, et al. Novel criteria of urine osmolality effectively predict response to tolvaptan in decompensated heart failure patients. Circ J. 2013;77:397–404.CrossRefPubMed
14.
go back to reference Nishizawa Y, Nakamura T, Ohta H, Kushida K, Gorai I, Shiraki M, et al. Guidelines for the use of biochemical markers of bone turnover in osteoporosis (2004). J Bone Miner Metab. 2005;23:97–104.CrossRefPubMed Nishizawa Y, Nakamura T, Ohta H, Kushida K, Gorai I, Shiraki M, et al. Guidelines for the use of biochemical markers of bone turnover in osteoporosis (2004). J Bone Miner Metab. 2005;23:97–104.CrossRefPubMed
15.
go back to reference von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147:573–7.CrossRef von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147:573–7.CrossRef
16.
go back to reference Japanese Society of Nephrology. Evidence-based Clinical Practice Guideline for CKD 2013. Clin Exp Nephrol. 2014;18:346–423.CrossRef Japanese Society of Nephrology. Evidence-based Clinical Practice Guideline for CKD 2013. Clin Exp Nephrol. 2014;18:346–423.CrossRef
17.
go back to reference Mori T, Oba I, Koizumi K, Kodama M, Shimanuki M, Tanno M, et al. Beneficial role of tolvaptan in the control of body fluids without reductions in residual renal function in patients undergoing peritoneal dialysis. Adv Perit Dial. 2013;29:33–7.PubMed Mori T, Oba I, Koizumi K, Kodama M, Shimanuki M, Tanno M, et al. Beneficial role of tolvaptan in the control of body fluids without reductions in residual renal function in patients undergoing peritoneal dialysis. Adv Perit Dial. 2013;29:33–7.PubMed
18.
go back to reference Afsar B, Ortiz A, Covic A, Solak Y, Goldsmith D, Kanbay M. Focus on renal congestion in heart failure. Clin Kidney J. 2016;9:39–47.CrossRefPubMed Afsar B, Ortiz A, Covic A, Solak Y, Goldsmith D, Kanbay M. Focus on renal congestion in heart failure. Clin Kidney J. 2016;9:39–47.CrossRefPubMed
19.
go back to reference Schrier RW. Renal volume, renin-angiotensin-aldosterone system, hypertension, and left ventricular hypertrophy in patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2009;20:1888–93.CrossRefPubMed Schrier RW. Renal volume, renin-angiotensin-aldosterone system, hypertension, and left ventricular hypertrophy in patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2009;20:1888–93.CrossRefPubMed
20.
go back to reference Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, et al. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014;371:2255–66.CrossRefPubMedPubMedCentral Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, et al. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014;371:2255–66.CrossRefPubMedPubMedCentral
21.
go back to reference Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann Intern Med. 2005;142:342–51.CrossRefPubMed Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann Intern Med. 2005;142:342–51.CrossRefPubMed
22.
go back to reference Rinkel GJ. Natural history, epidemiology and screening of unruptured intracranial aneurysms. J Neuroradiol. 2008;35:99–103.CrossRefPubMed Rinkel GJ. Natural history, epidemiology and screening of unruptured intracranial aneurysms. J Neuroradiol. 2008;35:99–103.CrossRefPubMed
23.
go back to reference Yang B, Bankir L. Urea and urine concentrating ability: new insights from studies in mice. Am J Physiol Renal Physiol. 2005;288:F881–96.CrossRefPubMed Yang B, Bankir L. Urea and urine concentrating ability: new insights from studies in mice. Am J Physiol Renal Physiol. 2005;288:F881–96.CrossRefPubMed
24.
go back to reference Fenton RA, Flynn A, Shodeinde A, Smith CP, Schnermann J, Knepper MA. Renal phenotype of UT-A urea transporter knockout mice. J Am Soc Nephrol. 2005;16:1583–92.CrossRefPubMedPubMedCentral Fenton RA, Flynn A, Shodeinde A, Smith CP, Schnermann J, Knepper MA. Renal phenotype of UT-A urea transporter knockout mice. J Am Soc Nephrol. 2005;16:1583–92.CrossRefPubMedPubMedCentral
25.
go back to reference Gheorghiade M, Konstam MA, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007;297:1332–43.CrossRefPubMed Gheorghiade M, Konstam MA, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007;297:1332–43.CrossRefPubMed
26.
27.
go back to reference Drechsler C, Kalim S, Wenger JB, Suntharalingam P, Hod T, Thadhani RI, et al. Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease. Kidney Int. 2015;87:1201–8.CrossRefPubMedPubMedCentral Drechsler C, Kalim S, Wenger JB, Suntharalingam P, Hod T, Thadhani RI, et al. Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease. Kidney Int. 2015;87:1201–8.CrossRefPubMedPubMedCentral
28.
go back to reference Kalim S, Karumanchi SA, Thadhani RI, Berg AH. Protein carbamylation in kidney disease: pathogenesis and clinical implications. Am J Kidney Dis. 2014;64:793–803.CrossRefPubMedPubMedCentral Kalim S, Karumanchi SA, Thadhani RI, Berg AH. Protein carbamylation in kidney disease: pathogenesis and clinical implications. Am J Kidney Dis. 2014;64:793–803.CrossRefPubMedPubMedCentral
29.
go back to reference Pietrement C, Gorisse L, Jaisson S, Gillery P. Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD. PLoS One. 2013;8:e82506.CrossRefPubMedPubMedCentral Pietrement C, Gorisse L, Jaisson S, Gillery P. Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD. PLoS One. 2013;8:e82506.CrossRefPubMedPubMedCentral
30.
go back to reference Fenton RA, Chou CL, Stewart GS, Smith CP, Knepper MA. Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct. Proc Natl Acad Sci USA. 2004;101:7469–74.CrossRefPubMedPubMedCentral Fenton RA, Chou CL, Stewart GS, Smith CP, Knepper MA. Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct. Proc Natl Acad Sci USA. 2004;101:7469–74.CrossRefPubMedPubMedCentral
31.
go back to reference Li F, Lei T, Zhu J, Wang W, Sun Y, Chen J, et al. A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic. Kidney Int. 2013;83:1076–86.CrossRefPubMed Li F, Lei T, Zhu J, Wang W, Sun Y, Chen J, et al. A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic. Kidney Int. 2013;83:1076–86.CrossRefPubMed
Metadata
Title
Tolvaptan promotes urinary excretion of sodium and urea: a retrospective cohort study
Authors
Satoshi Minami
Takayuki Hamano
Hirotsugu Iwatani
Masayuki Mizui
Yoshiki Kimura
Yoshitaka Isaka
Publication date
01-06-2018
Publisher
Springer Singapore
Published in
Clinical and Experimental Nephrology / Issue 3/2018
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-017-1475-9

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