Perioperative urinary excretion of aquaporin-2 dependent upon vasopressin in cardiac surgery

A Letter to this article was published on 29 June 2020


Aquaporin-2 is found in the apical cell membranes of the principal cells of the collecting duct of the kidney. Plasma arginine vasopressin has been reported to be markedly elevated during cardiac surgery. However fluctuations in urine aquaporin-2 levels have never been reported. We aimed to determine the responses of urine aquaporin-2 and evaluated the relationship between urine aquaporin-2 and plasma arginine vasopressin levels during perioperative periods in cardiac surgical patients. Eight patients undergoing elective isolated aortic valve replacement in normothermia were enrolled prospectively. Blood and urine samples were collected preoperatively and on postoperative days 1, 4, and 7. Patients received furosemide and spironolactone, as needed, during the clinical course; tolvaptan was not needed. Median plasma arginine vasopressin levels [with interquartile range] significantly increased to 1.5 [1.3–2.0], 15.3 [11.4–22.2]*, 2.2 [2.1–2.3], 1.7 [1.5–1.9] pg/mL preoperatively, on postoperative days 1, 4, and 7, respectively (*: p = 0.0001). Similarly, levels of urine aquaporin-2 markedly increased in 3.4 [1.9–5.6], 25.8 [18.4–33.5]**, 9.3 [5.9–14.0], 5.4 [5.3–6.1] (ng/mL), respectively (**p = 0.0004). A significant correlation between plasma arginine vasopressin and urine aquaporin-2 was observed during the entire investigation (R2 = 0.616, p < 0.0001). Plasma arginine vasopressin and urine aquaporin-2 levels were significantly elevated on postoperative day 1 in patients who underwent aortic valve replacement with cardiopulmonary bypass. A significant correlation between plasma arginine vasopressin and urine aquaporin-2 was observed. Urine aquaporin-2 should be further investigated as a potential biomarker for postoperative cardiac dysfunction.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Butler J, Rocker GM, Westaby S (1993) Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 55:552–559

    CAS  Article  Google Scholar 

  2. 2.

    Edmunds LH Jr (1998) Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 66:S12–S16

    Article  Google Scholar 

  3. 3.

    Lehot JJ, Villard J, Piriz H, Philbin DM, Carry PY, Gauquelin G, Claustrat B, Sassolas G, Galliot J, Estanove S (1992) Hemodynamic and hormonal responses to hypothermic and normothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 6:132–139

    CAS  Article  Google Scholar 

  4. 4.

    Marumoto K, Hamada M, Hiwada K (1995) Increased secretion of atrial and brain natriuretic peptides during acute myocardial ischaemia induced by dynamic exercise in patients with angina pectoris. Clin Sci (Lond) 88:551–556

    CAS  Article  Google Scholar 

  5. 5.

    Morimoto K, Mori T, Ishiguro S, Matsuda N, Hara Y, Kuroda H (1998) Perioperative changes in plasma brain natriuretic peptide concentrations in patients undergoing cardiac surgery. Surg Today 28:23–29

    CAS  Article  Google Scholar 

  6. 6.

    Radin MJ, Yu MJ, Stoedkilde L, Miller RL, Hoffert JD, Frokiaer J, Pisitkun T, Knepper MA (2012) Aquaporin-2 regulation in health and disease. Vet Clin Pathol 41:455–470

    Article  Google Scholar 

  7. 7.

    Rai T, Sekine K, Kanno K, Hata K, Miura M, Mizushima A, Marumo F, Sasaki S (1997) Urinary excretion of aquaporin-2 water channel protein in human and rat. J Am Soc Nephrol 8:1357–1362

    CAS  PubMed  Google Scholar 

  8. 8.

    Novella S, Martínez AC, Pagán RM, Hernández M, García-Sacristán A, González-Pinto A, González-Santos JM, Benedito S (2007) Plasma levels and vascular effects of vasopressin in patients undergoing coronary artery bypass grafting. Eur J Cardiothorac Surg 32:69–76

    Article  Google Scholar 

  9. 9.

    Morrison WE, Simone S, Conway D, Tumulty J, Johnson C, Cardarelli M (2008) Levels of vasopressin in children undergoing cardiopulmonary bypass. Cardiol Young 18:135–140

    Article  Google Scholar 

  10. 10.

    Otsuka F, Morita K, Takeuchi M, Yamauchi T, Ogura T, Sekines K, Miura M, Hirakawa M, Makino H (1999) The effects of intrinsic vasopressin on urinary aquaporin-2 excretion and urine osmolality during surgery under general anesthesia. Anesth Analg 88:181–187

    CAS  PubMed  Google Scholar 

  11. 11.

    Sasaki S, Ohmoto Y, Mori T, Iwata F, Muraguchi M (2012) Daily variance of urinary excretion of AQP2 determined by sandwich ELISA method. Clin Exp Nephrol 16:406–410

    CAS  Article  Google Scholar 

  12. 12.

    Saito T, Ishikawa SE, Sasaki S, Nakamura T, Rokkaku K, Kawakami A, Honda K, Marumo F, Saito T (1997) Urinary excretion of aquaporin-2 in the diagnosis of central diabetes insipidus. J Clin Endocrinol Metab 82:1823–1827

    CAS  PubMed  Google Scholar 

  13. 13.

    Funayama H, Nakamura T, Saito T, Yoshimura A, Saito M, Kawakami M, Ishikawa SE (2004) Urinary excretion of aquaporin-2 water channel exaggerated dependent upon vasopressin in congestive heart failure. Kidney Int 66:1387–1392

    CAS  Article  Google Scholar 

  14. 14.

    Imamura T, Kinugawa K, Fujino T, Inaba T, Maki H, Hatano M, Yao A, Komuro I (2014) Increased urine aquaporin-2 relative to plasma arginine vasopressin is a novel marker of response to tolvaptan in patients with decompensated heart failure. Circ J 78:2240–2249

    CAS  Article  Google Scholar 

  15. 15.

    Matsuyama K, Koizumi N, Nishibe T, Iwasaki T, Iwahasi T, Toguchi K, Takahashi S, Iwahori A, Maruno K, Ogino H (2016) Effects of short-term administration of tolvaptan after open heart surgery. Int J Cardiol 220:192–195

    Article  Google Scholar 

  16. 16.

    Levine FH, Philbin DM, Kono K, Coggins CH, Emerson CW, Austen WG, Buckley MJ (1981) Plasma vasopressin levels and urinary sodium excretion during cardiopulmonary bypass with and without pulsatile flow. Ann Thorac Surg 32:63–67

    CAS  Article  Google Scholar 

  17. 17.

    Philbin DM, Levine FH, Emerson CW, Coggins CH, Buckley MJ, Austen WG (1979) Plasma vasopressin levels and urinary flow during cardiopulmonary bypass in patients with valvular heart disease: effect of pulsatile flow. J Thorac Cadiovasc Surg 78:779–783

    CAS  Article  Google Scholar 

  18. 18.

    Xu DL, Martin PY, Ohara M, St John J, Pattison T, Meng X, Morris K, Kim JK, Schrier RW (1997) Upregulation of aquaporin-2 water channel expression in chronic heart failure rat. J Clin Invest 99:1500–1505

    CAS  Article  Google Scholar 

  19. 19.

    Nielsen S, Terris J, Andersen D, Ecelbarger C, Frokiaer J, Jonassen T, Marples D, Knepper MA, Petersen JS (1997) Congestive heart failure in rats is associated with increased expression and targeting of aquaporin-2 water channel in collecting duct. Proc Natl Acad Sci USA 94:5450–5455

    CAS  Article  Google Scholar 

  20. 20.

    Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C, Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators (2007) Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. JAMA 297:1319–1331

    CAS  Article  Google Scholar 

  21. 21.

    Udelson JE, Orlandi C, Ouyang J, Krasa H, Zimmer CA, Frivold G, Haught WH, Meymandi S, Macarie C, Raef D, Wedge P, Konstam MA, Gheorghiade M (2008) Acute hemodynamic effects of tolvaptan, a vasopressin V2 receptor blocker, in patients with symptomatic heart failure and systolic dysfunction: an international, multicenter, randomized, placebo-controlled trial. J Am Coll Cardiol 52:1540–1545

    CAS  Article  Google Scholar 

  22. 22.

    Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C, SALT Investigators (2006) Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355:2099–2112

    CAS  Article  Google Scholar 

  23. 23.

    Matsuzaki M, Hori M, Izumi T, Fukunami M (2011) 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 25(Suppl 1):S33–S45

    Article  Google Scholar 

  24. 24.

    Mitsui M, Kataoka A, Nara Y, Nagura F, Kawashima H, Hioki H, Nakashima M, Watanabe Y, Yokoyama N, Kozuma K (2019) Clinical safety and efficacy of tolvaptan for acute phase therapy in patients with low-flow and normal-flow severe aortic stenosis. Heart Vessels 34:1684–1691

    Article  Google Scholar 

  25. 25.

    Takagi K, Sato N, Ishihara S, Sone M, Tokuyama H, Nakama K, Omote T, Kikuchi A, Ishikawa M, Amitani K, Takahashi N, Maruyama Y, Imura H, Shimizu W (2018) Effects of tolvaptan on urine output in hospitalized heart failure patients with hypoalbuminemia or proteinuria. Heart Vessels 33:413–420

    Article  Google Scholar 

  26. 26.

    Nishi H, Toda K, Miyagawa S, Yoshikawa Y, Fukushima S, Kawamura M, Yoshioka D, Saito T, Ueno T, Kuratani T, Sawa Y (2015) Effects of tolvaptan in the early postoperative stage after heart valve surgery: results of the STAR (Study of Tolvaptan for fluid retention AfteR valve surgery) trial. Surg Today 45:1542–1551

    CAS  Article  Google Scholar 

  27. 27.

    Kato TS, Ono S, Kajimoto K, Kuwaki K, Yamamoto T, Amano A (2015) Early introduction of tolvaptan after cardiac surgery: a renal sparing strategy in the light of the renal resistive index measured by ultrasound. J Cardiothorac Surg 10:143

    Article  Google Scholar 

  28. 28.

    Bellos I, Iliopoulos DC, Perrea DN (2019) The role of tolvaptan administration after cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth 33:2170–2179

    CAS  Article  Google Scholar 

Download references


The authors thank Dr. Kazutora Mizukami, president of Medical Data Management, Fukuoka, for the assistance in the statistical analysis. We would also like to thank Editage ( for English language editing.


This work was supported by JSPS KAKENHI Grant No. JP16K10642.

Author information




All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by MF and RA. Funding acquisition was performed by RA. Writing—review and supervision—were performed by RB. The first draft of the manuscript was written by MF and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Masahiro Fujii.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fujii, M., Amitani, R. & Bessho, R. Perioperative urinary excretion of aquaporin-2 dependent upon vasopressin in cardiac surgery. Heart Vessels 35, 712–718 (2020).

Download citation


  • Aquaporin 2
  • Arginine vasopressin
  • Brain natriuretic peptide
  • Cardiopulmonary bypass