1932

Abstract

The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization.

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2015-01-14
2024-05-09
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Literature Cited

  1. Yamamura Y, Ogawa H, Chihara T. 1.  et al. 1991. OPC-21268, an orally effective, nonpeptide vasopressin V1 receptor antagonist. Science 252:572–74 [Google Scholar]
  2. Yamamura Y, Ogawa H, Yamashita H. 2.  et al. 1992. Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist. Br. J. Pharmacol. 105:787–91 [Google Scholar]
  3. Ohnishi A, Orita Y, Okahara R. 3.  et al. 1993. Potent aquaretic agent. A novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men. J. Clin. Invest. 92:2653–59 [Google Scholar]
  4. Serradeil-Le Gal C, Wagnon J, Garcia C. 4.  et al. 1993. Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors. J. Clin. Invest. 92:224–31 [Google Scholar]
  5. Braunwald E.5.  2013. Heart failure. JACC Heart Failure 1:1–20 [Google Scholar]
  6. Schrier RW, Abraham WT. 6.  1999. Hormones and hemodynamics in heart failure. N. Engl. J. Med. 341:577–85 [Google Scholar]
  7. Schrier RW.7.  2009. Renal volume, renin-angiotensin-aldosterone system, hypertension, and left ventricular hypertrophy in patients with autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 20:1888–93 [Google Scholar]
  8. Klein IH, Ligtenberg G, Oey PL. 8.  et al. 2001. Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J. Am. Soc. Nephrol. 12:2427–33 [Google Scholar]
  9. Grassi G, Bertoli S, Seravalle G. 9.  2012. Sympathetic nervous system: role in hypertension and in chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 21:46–51 [Google Scholar]
  10. Boertien WE, Meijer E, Li J. 10.  et al. 2013. Relationship of copeptin, a surrogate marker for arginine vasopressin, with change in total kidney volume and GFR decline in autosomal dominant polycystic kidney disease: results from the CRISP cohort. Am. J. Kidney Dis. 61:420–29 [Google Scholar]
  11. Miller WL, Grill DE, Struck J, Jaffe AS. 11.  2013. Association of hyponatremia and elevated copeptin with death and need for transplantation in ambulatory patients with chronic heart failure. Am. J. Cardiol. 111:880–85 [Google Scholar]
  12. Marks AR.12.  2013. Calcium cycling proteins and heart failure: mechanisms and therapeutics. J. Clin. Invest. 123:46–52 [Google Scholar]
  13. Yan C, Miller CL, Abe J. 13.  2007. Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart. Circ. Res. 100:489–501 [Google Scholar]
  14. Paavola J, Schliffke S, Rossetti S. 14.  et al. 2013. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J. Mol. Cell. Cardiol. 58:199–208 [Google Scholar]
  15. Anyatonwu GI, Estrada M, Tian X. 15.  et al. 2007. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc. Natl. Acad. Sci. USA 104:6454–59 [Google Scholar]
  16. Weber KH, Lee EK, Basavanna U. 16.  et al. 2008. Heterologous expression of polycystin-1 inhibits endoplasmic reticulum calcium leak in stably transfected MDCK cells. Am. J. Physiol. Ren. Physiol. 294:F1279–86 [Google Scholar]
  17. Torres VE, Harris PC. 17.  2014. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J. Am. Soc. Nephrol. 25:18–32 [Google Scholar]
  18. Grimmelikhuijzen CJ, Hauser F. 18.  2012. Mini-review: the evolution of neuropeptide signaling. Regul. Pept. 177:Suppl.S6–9 [Google Scholar]
  19. Beets I, Janssen T, Meelkop E. 19.  et al. 2012. Vasopressin/oxytocin-related signaling regulates gustatory associative learning in C. elegans. Science 338:543–45 [Google Scholar]
  20. Garrison JL, Macosko EZ, Bernstein S. 20.  et al. 2012. Oxytocin/vasopressin-related peptides have an ancient role in reproductive behavior. Science 338:540–43 [Google Scholar]
  21. Antunes-Rodrigues J, de Castro M, Elias LL. 21.  et al. 2004. Neuroendocrine control of body fluid metabolism. Physiol. Rev. 84:169–208 [Google Scholar]
  22. Morgenthaler NG, Struck J, Alonso C, Bergmann A. 22.  2006. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin. Chem. 52:112–19 [Google Scholar]
  23. Koshimizu TA, Nakamura K, Egashira N. 23.  et al. 2012. Vasopressin V1a and V1b receptors: from molecules to physiological systems. Physiol. Rev. 92:1813–64 [Google Scholar]
  24. Juul KV, Bichet DG, Nielsen S, Norgaard JP. 24.  2014. The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am. J. Physiol. Ren. Physiol. 306:F931–40 [Google Scholar]
  25. Share L.25.  1988. Role of vasopressin in cardiovascular regulation. Physiol. Rev. 68:1248–84 [Google Scholar]
  26. Goldsmith SR, Gheorghiade M. 26.  2005. Vasopressin antagonism in heart failure. J. Am. Coll. Cardiol. 46:1785–91 [Google Scholar]
  27. Francis GS, Benedict C, Johnstone DE. 27.  et al. 1990. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 82:1724–29 [Google Scholar]
  28. Lanfear DE, Sabbah HN, Goldsmith SR. 28.  et al. 2013. Association of arginine vasopressin levels with outcomes and the effect of V2 blockade in patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial. Circ. Heart Fail. 6:47–52 [Google Scholar]
  29. Zhu W, Tilley DG, Myers VD. 29.  et al. 2014. Increased vasopressin 1A receptor expression in failing human hearts. J. Am. Coll. Cardiol. 63:375–76 [Google Scholar]
  30. Li X, Chan TO, Myers V. 30.  et al. 2011. Controlled and cardiac-restricted overexpression of the arginine vasopressin V1A receptor causes reversible left ventricular dysfunction through Gαq-mediated cell signaling. Circulation 124:572–81 [Google Scholar]
  31. Tahara A, Tomura Y, Wada KI. 31.  et al. 1997. Pharmacological profile of YM087, a novel potent nonpeptide vasopressin V1A and V2 receptor antagonist, in vitro and in vivo. J. Pharmacol. Exp. Ther. 282:301–8 [Google Scholar]
  32. Yamamura Y, Nakamura S, Itoh S. 32.  et al. 1998. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J. Pharmacol. Exp. Ther. 287:860–67 [Google Scholar]
  33. Albright JD, Reich MF, Delos Santos EG. 33.  et al. 1998. 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): an orally active arginine vasopressin antagonist with selectivity for V2 receptors. J. Med. Chem. 41:2442–44 [Google Scholar]
  34. Naitoh M, Suzuki H, Murakami M. 34.  et al. 1994. Effects of oral AVP receptor antagonists OPC-21268 and OPC-31260 on congestive heart failure in conscious dogs. Am. J. Physiol. 267:H2245–54 [Google Scholar]
  35. Udelson JE, Smith WB, Hendrix GH. 35.  et al. 2001. Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 104:2417–23 [Google Scholar]
  36. Goldsmith SR, Gilbertson DT, Mackedanz SA, Swan SK. 36.  2011. Renal effects of conivaptan, furosemide, and the combination in patients with chronic heart failure. J. Card. Fail. 17:982–89 [Google Scholar]
  37. Costello-Boerrigter LC, Smith WB, Boerrigter G. 37.  et al. 2006. Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am. J. Physiol. Ren. Physiol. 290:F273–78 [Google Scholar]
  38. Udelson JE, Orlandi C, Ouyang J. 38.  et al. 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. 52:1540–45 [Google Scholar]
  39. Onogawa T, Sakamoto Y, Nakamura S. 39.  et al. 2011. Effects of tolvaptan on systemic and renal hemodynamic function in dogs with congestive heart failure. Cardiovasc. Drugs Ther./Sponsored Int. Soc. Cardiovasc. Pharmacother. 25:Suppl. 1S67–76 [Google Scholar]
  40. Veeraveedu PT, Watanabe K, Ma M. 40.  et al. 2007. Effects of nonpeptide vasopressin V2 antagonist tolvaptan in rats with heart failure. Biochem. Pharmacol. 74:1466–75 [Google Scholar]
  41. Veeraveedu PT, Watanabe K, Ma M. 41.  et al. 2008. Effects of V2-receptor antagonist tolvaptan and the loop diuretic furosemide in rats with heart failure. Biochem. Pharmacol. 75:1322–30 [Google Scholar]
  42. Yamazaki T, Izumi Y, Nakamura Y. 42.  et al. 2012. Tolvaptan improves left ventricular dysfunction after myocardial infarction in rats. Circ. Heart Fail. 5:794–802 [Google Scholar]
  43. Yamazaki T, Nakamura Y, Shiota M. 43.  et al. 2013. Tolvaptan attenuates left ventricular fibrosis after acute myocardial infarction in rats. J. Pharmacol. Sci. 123:58–66 [Google Scholar]
  44. Morooka H, Iwanaga Y, Tamaki Y. 44.  et al. 2012. Chronic administration of oral vasopressin type 2 receptor antagonist tolvaptan exerts both myocardial and renal protective effects in rats with hypertensive heart failure. Circ. Heart Fail. 5:484–92 [Google Scholar]
  45. Ishikawa M, Kobayashi N, Sugiyama F. 45.  et al. 2013. Renoprotective effect of vasopressin V2 receptor antagonist tolvaptan in Dahl rats with end-stage heart failure. Int. Heart J. 54:98–106 [Google Scholar]
  46. Udelson JE, McGrew FA, Flores E. 46.  et al. 2007. Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral tolvaptan on left ventricular dilation and function in patients with heart failure and systolic dysfunction. J. Am. Coll. Cardiol. 49:2151–59 [Google Scholar]
  47. Gheorghiade M, Gattis WA, O'Connor CM. 47.  et al. 2004. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA 291:1963–71 [Google Scholar]
  48. Gheorghiade M, Konstam MA, Burnett JC Jr. 48.  et al. 2007. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials. JAMA 297:1332–43 [Google Scholar]
  49. Konstam MA, Gheorghiade M, Burnett JC Jr. 49.  et al. 2007. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. JAMA 297:1319–31 [Google Scholar]
  50. 50. US Food and Drug Administration 2012. September 13, 2012: Cardiovascular and Renal Drugs Advisory Committee meeting announcement http://www.fda.gov/AdvisoryCommittees/Calendar/ucm313273.htm
  51. Rossi J, Bayram M, Udelson JE. 51.  et al. 2007. Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial. Acute Card. Care 9:82–86 [Google Scholar]
  52. Filippatos G, Rossi J, Lloyd-Jones DM. 52.  et al. 2007. Prognostic value of blood urea nitrogen in patients hospitalized with worsening heart failure: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) study. J. Card. Fail. 13:360–64 [Google Scholar]
  53. Hauptman PJ, Burnett J, Gheorghiade M. 53.  et al. 2013. Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan. J. Card. Fail. 19:390–97 [Google Scholar]
  54. Vaduganathan M, Gheorghiade M, Pang PS. 54.  et al. 2012. Efficacy of oral tolvaptan in acute heart failure patients with hypotension and renal impairment. J. Cardiovasc. Med. 13:415–22 [Google Scholar]
  55. Feldman AM, Hamad E, Tsai EJ. 55.  et al. 2014. Vasopressin antagonists for patients with acute heart failure: interpreting new clinical and translational data. Clin. Pharmacol. Ther. 95:373–75 [Google Scholar]
  56. Kinugawa K, Imamura T, Komuro I. 56.  2013. Experience of a vasopressin receptor antagonist, tolvaptan, under the unique indication in Japanese heart failure patients. Clin. Pharmacol. Ther. 94:449–51 [Google Scholar]
  57. Yamaguchi T, Nagao S, Kasahara M. 57.  et al. 1997. Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease. Am. J. Kidney Dis. 30:703–9 [Google Scholar]
  58. Gattone VH, Wang X, Harris PC, Torres VE. 58.  2003. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat. Med. 9:1323–26 [Google Scholar]
  59. Smith LA, Bukanov NO, Husson H. 59.  et al. 2006. Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease. J. Am. Soc. Nephrol. 17:2821–31 [Google Scholar]
  60. Starremans PG, Li X, Finnerty PE. 60.  et al. 2008. A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5′ end of Pkd1. Kidney Int. 73:1394–405 [Google Scholar]
  61. Hopp K, Ward CJ, Hommerding CJ. 61.  et al. 2012. Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J. Clin. Invest. 122:4257–73 [Google Scholar]
  62. Wang X, Ward CJ, Harris PC, Torres VE. 62.  2010. Cyclic nucleotide signaling in polycystic kidney disease. Kidney Int. 77:129–40 [Google Scholar]
  63. Rees S, Kittikulsuth W, Roos K. 63.  et al. 2014. Adenylyl cyclase 6 deficiency ameliorates polycystic kidney disease. J. Am. Soc. Nephrol. 25:232–37 [Google Scholar]
  64. Ye H, Wang X, Sussman CR. 64.  et al. 2012. Genetic approach to evaluate the role of the PDE3 subfamilies in polycystic kidney disease (PKD) Presented at ASN Kidney Week, San Diego, CA [Google Scholar]
  65. Talbot JJ, Song X, Wang X. 65.  et al. 2014. The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation. J. Am. Soc. Nephrol. 25:1737–48 [Google Scholar]
  66. Mutig K, Paliege A, Kahl T. 66.  et al. 2007. Vasopressin V2 receptor expression along rat, mouse, and human renal epithelia with focus on TAL. Am. J. Physiol. Ren. Physiol. 293:F1166–F77 [Google Scholar]
  67. Carmosino M, Brooks HL, Cai Q. 67.  et al. 2007. Axial heterogeneity of vasopressin-receptor subtypes along the human and mouse collecting duct. Am. J. Physiol. Ren. Physiol. 292:F351–60 [Google Scholar]
  68. Yasuda G, Jeffries WB. 68.  1998. Regulation of cAMP production in initial and terminal inner medullary collecting ducts. Kidney Int. 54:80–86 [Google Scholar]
  69. Wang X, Wu Y, Ward CJ. 69.  et al. 2008. Vasopressin directly regulates cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 19:102–8 [Google Scholar]
  70. Nagao S, Nishii K, Katsuyama M. 70.  et al. 2006. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J. Am. Soc. Nephrol. 17:2220–27 [Google Scholar]
  71. Gattone VH, Maser RL, Tian C. 71.  et al. 1999. Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease. Dev. Gen. 24:309–18 [Google Scholar]
  72. Aihara M, Fujiki H, Mizuguchi H. 72.  et al. 2014. Tolvaptan delays the onset of end-stage renal disease in a polycystic kidney disease model by suppressing increases in kidney volume and renal injury. J. Pharmacol. Exp. Ther. 349:258–67 [Google Scholar]
  73. Wang X, Gattone V 2nd, Harris PC, Torres VE. 73.  2005. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J. Am. Soc. Nephrol. 16:846–51 [Google Scholar]
  74. Torres VE, Wang X, Qian Q. 74.  et al. 2004. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat. Med. 10:363–64 [Google Scholar]
  75. Meijer E, Gansevoort RT, de Jong PE. 75.  et al. 2011. Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug. Nephrol. Dial. Transplant. 26:2445–53 [Google Scholar]
  76. Hopp K, Hommerding CJ, Wang X. 76.  et al. 2014. Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J. Am. Soc. Nephrol. In press
  77. Reif GA, Yamaguchi T, Nivens E. 77.  et al. 2011. Tolvaptan inhibits ERK-dependent cell proliferation, Cl secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am. J. Physiol. Ren. Physiol. 301:F1005–13 [Google Scholar]
  78. Torres VE.78.  2008. Role of vasopressin antagonists. Clin. J. Am. Soc. Nephrol. 3:1212–18 [Google Scholar]
  79. Higashihara E, Torres VE, Chapman AB. 79.  et al. 2011. Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience. Clin. J. Am. Soc. Nephrol. 6:2499–507 [Google Scholar]
  80. Irazabal MV, Torres VE, Hogan MC. 80.  et al. 2011. Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. Kidney Int. 80:295–301 [Google Scholar]
  81. Boertien WE, Meijer E, de Jong PE. 81.  et al. 2013. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 84:1278–86 [Google Scholar]
  82. Torres VE, Meijer E, Bae KT. 82.  et al. 2011. Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3–4 Study. Am. J. Kidney Dis. 57:692–99 [Google Scholar]
  83. Torres VE, Chapman AB, Devuyst O. 83.  et al. 2012. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 367:2407–18 [Google Scholar]
  84. 84. US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research 2009. Guidance for industry. Drug-induced liver injury: premarketing clinical evaluation. http://www.fda.gov/downloads/Drugs/…/Guidances/UCM174090.pdf
  85. 85. US Food and Drug Administration 2013. Cardiovascular and renal drugs advisory committee meeting announcement. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm357806.htm
  86. Irazabal MV, Rangel LJ, Bergstralh EJ. 86.  et al. 2014. Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J. Am. Soc. Nephrol. In press
  87. Bankir L, Bouby N, Ritz E. 87.  2013. Vasopressin: a novel target for the prevention and retardation of kidney disease?. Nat. Rev. Nephrol. 9:223–39 [Google Scholar]
  88. Bouby N, Bachmann S, Bichet D, Bankir L. 88.  1990. Effect of water intake on the progression of chronic renal failure in the 5/6 nephrectomized rat. Am. J. Physiol. 258:F973–79 [Google Scholar]
  89. Bouby N, Hassler C, Bankir L. 89.  1999. Contribution of vasopressin to progression of chronic renal failure: study in Brattleboro rats. Life Sci. 65:991–1004 [Google Scholar]
  90. Bardoux P, Martin H, Ahloulay M. 90.  et al. 1999. Vasopressin contributes to hyperfiltration, albuminuria, and renal hypertrophy in diabetes mellitus: study in vasopressin-deficient Brattleboro rats. Proc. Natl. Acad. Sci. USA 96:10397–402 [Google Scholar]
  91. Sugiura T, Yamauchi A, Kitamura H. 91.  et al. 1999. High water intake ameliorates tubulointerstitial injury in rats with subtotal nephrectomy: possible role of TGF-b. Kidney Int. 55:1800–10 [Google Scholar]
  92. Perico N, Coja C, Corna D. 92.  et al. 2009. V1/V2 vasopressin receptor antagonism potentiates renoprotection of renin-angiotensin system inhibition in rats with renal mass reduction. Kidney Int. 76:960–67 [Google Scholar]
  93. Clark WF, Sontrop JM, Macnab JJ. 93.  et al. 2011. Urine volume and change in estimated GFR in a community-based cohort study. Clin. J. Am. Soc. Nephrol. 6:2634–41 [Google Scholar]
  94. Strippoli GF, Craig JC, Rochtchina E. 94.  et al. 2011. Fluid and nutrient intake and risk of chronic kidney disease. Nephrology 16:326–34 [Google Scholar]
  95. Sontrop JM, Dixon SN, Garg AX. 95.  et al. 2013. Association between water intake, chronic kidney disease, and cardiovascular disease: a cross-sectional analysis of NHANES data. Am. J. Nephrol. 37:434–42 [Google Scholar]
  96. Plischke M, Kohl M, Bankir L. 96.  et al. 2014. Urine osmolarity and risk of dialysis initiation in a chronic kidney disease cohort—a possible titration target?. PLOS ONE 9:e93226 [Google Scholar]
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