Pediatric Nephrology

, Volume 33, Issue 3, pp 395–408 | Cite as

Expanding the role of vasopressin antagonism in polycystic kidney diseases: From adults to children?

  • Peter Janssens
  • Caroline Weydert
  • Stephanie De Rechter
  • Karl Martin Wissing
  • Max Christoph Liebau
  • Djalila Mekahli
Educational Review


Polycystic kidney disease (PKD) encompasses a group of genetic disorders that are common causes of renal failure. The two classic forms of PKD are autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD). Despite their clinical differences, ARPKD and ADPKD share many similarities. Altered intracellular Ca2+ and increased cyclic adenosine monophosphate (cAMP) concentrations have repetitively been described as central anomalies that may alter signaling pathways leading to cyst formation. The vasopressin V2 receptor (V2R) antagonist tolvaptan lowers cAMP in cystic tissues and slows renal cystic progression and kidney function decline when given over 3 years in adult ADPKD patients. Tolvaptan is currently approved for the treatment of rapidly progressive disease in adult ADPKD patients. On the occasion of the recent initiation of a clinical trial with tolvaptan in pediatric ADPKD patients, we aim to describe the most important aspects in the literature regarding the AVP-cAMP axis and the clinical use of tolvaptan in PKD.


Polycystic kidney disease ADPKD ARPKD Vasopressin Tolvaptan cAMP 



Intracellular cAMP concentration


Intracellular calcium concentration


Adenylyl cyclase


Autosomal-dominant polycystic kidney disease


Autosomal-recessive polycystic kidney disease


Aquaporin 2






Cyclic adenosine monophosphate


Collecting duct


Cystic fibrosis transmembrane conductance regulator


Estimated glomerular filtration rate


Extracellular signal-regulated kinase


End-stage renal disease (ESRD)




Food and drug administration


Glycogen synthase kinase-3


Mitogen-activated protein kinase


Mammalian target of rapamycin






Planar-cell polarity




Protein kinase A


Polycystic kidney disease


Suppressor of cytokine signaling 3


Signal transducer and activator of transcription 3


Stromal interaction molecule 1


Total kidney volume


Urine osmolality


Vasopressin V2 receptor



MCL receives funding support from the Köln Fortune Program of the Medical Faculty and from the Center for Molecular Medicine of the University of Cologne, as well as from the Marga and Walter Boll Foundation and the German Federal Ministry for Education and Research (Grant No. 01GM1515E, NEOCYST consortium). SDR is supported by the Fund for Scientific Research, Flanders 11M5214N. DM is supported by the Clinical Research Fund of UZ Leuven, the Fund for Scientific Research G0B1313N, and a research grant from the European Society for Pediatric Nephrology.

Compliance with ethical standards

Conflict of interest statement

None to declare.

Supplementary material

467_2017_3672_MOESM1_ESM.docx (37 kb)
ESM 1 (DOCX 36 kb)


  1. 1.
    Barua M, Cil O, Paterson AD, Wang K, He N, Dicks E, Parfrey P, Pei Y (2009) Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol 20:1833–1838PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Porath B, Gainullin VG, Cornec-Le Gall E, Dillinger EK, Heyer CM, Hopp K, Edwards ME, Madsen CD, Mauritz SR, Banks CJ, Baheti S, Reddy B, Herrero JI, Banales JM, Hogan MC, Tasic V, Watnick TJ, Chapman AB, Vigneau C, Lavainne F, Audrezet MP, Ferec C, Le Meur Y, Torres VE, Genkyst Study Group, HALT Progression of Polycystic Kidney Disease Group; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease, Harris PC (2016) Mutations in GANAB, encoding the glucosidase IIalpha subunit, cause autosomal-dominant polycystic kidney and liver disease. Am J Hum Genet 98:1193–1207PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Cornec-Le Gall E, Audrezet MP, Le Meur Y, Chen JM, Ferec C (2014) Genetics and pathogenesis of autosomal dominant polycystic kidney disease: 20 years on. Hum Mutat 35:1393–1406PubMedCrossRefGoogle Scholar
  4. 4.
    Consugar MB, Wong WC, Lundquist PA, Rossetti S, Kubly VJ, Walker DL, Rangel LJ, Aspinwall R, Niaudet WP, Ozen S, David A, Velinov M, Bergstralh EJ, Bae KT, Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Sampson JR, Dawson BD, Harris PC, CRISP Consortium (2008) Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int 74:1468–1479PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Schrier RW (2009) Renal volume, renin-angiotensin-aldosterone system, hypertension, and left ventricular hypertrophy in patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol 20:1888–1893PubMedCrossRefGoogle Scholar
  6. 6.
    Grantham JJ (2008) Clinical practice. Autosomal dominant polycystic kidney disease. N Engl J Med 359:1477–1485PubMedCrossRefGoogle Scholar
  7. 7.
    Mekahli D, Bacchetta J (2013) From bone abnormalities to mineral metabolism dysregulation in autosomal dominant polycystic kidney disease. Pediatr Nephrol 28:2089–2096PubMedCrossRefGoogle Scholar
  8. 8.
    Guay-Woodford LM, Bissler JJ, Braun MC, Bockenhauer D, Cadnapaphornchai MA, Dell KM, Kerecuk L, Liebau MC, Alonso-Peclet MH, Shneider B, Emre S, Heller T, Kamath BM, Murray KF, Moise K, Eichenwald EE, Evans J, Keller RL, Wilkins-Haug L, Bergmann C, Gunay-Aygun M, Hooper SR, Hardy KK, Hartung EA, Streisand R, Perrone R, Moxey-Mims M (2014) Consensus expert recommendations for the diagnosis and management of autosomal recessive polycystic kidney disease: report of an international conference. J Pediatr 165:611–617PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Liebau MC, Serra AL (2013) Looking at the (w)hole: magnet resonance imaging in polycystic kidney disease. Pediatr Nephrol 28:1771–1783PubMedCrossRefGoogle Scholar
  10. 10.
    Sweeney WE, Avner ED (1993) Polycystic Kidney Disease, Autosomal Recessive. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K (eds) GeneReviews(R), Seattle (WA)Google Scholar
  11. 11.
    Bergmann C, Senderek J, Windelen E, Kupper F, Middeldorf I, Schneider F, Dornia C, Rudnik-Schoneborn S, Konrad M, Schmitt CP, Seeman T, Neuhaus TJ, Vester U, Kirfel J, Buttner R, Zerres K, Arbeitsgemeinschaft für Pädiatrische Nephrologie (2005) Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney Int 67:829–848PubMedCrossRefGoogle Scholar
  12. 12.
    O’Brien K, Font-Montgomery E, Lukose L, Bryant J, Piwnica-Worms K, Edwards H, Riney L, Garcia A, Daryanani K, Choyke P, Mohan P, Heller T, Gahl WA, Gunay-Aygun M (2012) Congenital hepatic fibrosis and portal hypertension in autosomal dominant polycystic kidney disease. J Pediatr Gastroenterol Nutr 54:83–89PubMedCrossRefGoogle Scholar
  13. 13.
    Gunay-Aygun M (2009) Liver and kidney disease in ciliopathies. Am J Med Genet C Semin Med Genet 151C:296–306PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Kaimori JY, Germino GG (2008) ARPKD and ADPKD: first cousins or more distant relatives? J Am Soc Nephrol 19:416–418PubMedCrossRefGoogle Scholar
  15. 15.
    Waters AM, Beales PL (2011) Ciliopathies: an expanding disease spectrum. Pediatr Nephrol 26:1039–1056PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Harris PC, Torres VE (2014) Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease. J Clin Invest 124:2315–2324PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Wu Y, Dai XQ, Li Q, Chen CX, Mai W, Hussain Z, Long W, Montalbetti N, Li G, Glynne R, Wang S, Cantiello HF, Wu G, Chen XZ (2006) Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin. Hum Mol Genet 15:3280–3292PubMedCrossRefGoogle Scholar
  18. 18.
    Wang S, Zhang J, Nauli SM, Li X, Starremans PG, Luo Y, Roberts KA, Zhou J (2007) Fibrocystin/polyductin, found in the same protein complex with polycystin-2, regulates calcium responses in kidney epithelia. Mol Cell Biol 27:3241–3252PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Garcia-Gonzalez MA, Menezes LF, Piontek KB, Kaimori J, Huso DL, Watnick T, Onuchic LF, Guay-Woodford LM, Germino GG (2007) Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway. Hum Mol Genet 16:1940–1950PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Bergmann C, von Bothmer J, Ortiz Bruchle N, Venghaus A, Frank V, Fehrenbach H, Hampel T, Pape L, Buske A, Jonsson J, Sarioglu N, Santos A, Ferreira JC, Becker JU, Cremer R, Hoefele J, Benz MR, Weber LT, Buettner R, Zerres K (2011) Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. J Am Soc Nephrol 22:2047–2056PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Torres VE, Harris PC (2014) Strategies targeting cAMP signaling in treating polycystic kidney disease. J Am Soc Nephrol 25:18–32PubMedCrossRefGoogle Scholar
  22. 22.
    Hildebrandt F, Benzing T, Katsanis N (2011) Ciliopathies. N Engl J Med 364:1533–1543PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Wesche D, Deen PM, Knoers NV (2012) Congenital nephrogenic diabetes insipidus: the current state of affairs. Pediatr Nephrol 27:2183–2204PubMedCrossRefGoogle Scholar
  24. 24.
    Gattone VH 2nd, Wang X, Harris PC, Torres VE (2003) Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 9:1323–1326PubMedCrossRefGoogle Scholar
  25. 25.
    Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE (2015) Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol 26:39–47PubMedCrossRefGoogle Scholar
  26. 26.
    Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, Horie S, Nutahara K, Ouyang J, Krasa HB, Czerwiec FS, TEMPOFormula and 156-05-002 Study Investigators (2011) Tolvaptan in autosomal dominant polycystic kidney disease: three years experience. Clin J Am Soc Nephrol 6:2499–2507PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS, TEMPO 3:4 Trial Investigators (2012) Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 367:2407–2418PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Chebib FT, Sussman CR, Wang X, Harris PC, Torres VE (2015) Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat Rev Nephrol 11:451–464PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Mekahli D, Parys JB, Bultynck G, Missiaen L, De Smedt H (2013) Polycystins and cellular Ca2+ signaling. Cell Mol Life Sci 70:2697–2712PubMedCrossRefGoogle Scholar
  30. 30.
    Sanchez I, Dynlacht BD (2016) Cilium assembly and disassembly. Nat Cell Biol 18:711–717PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Pazour GJ (2004) Intraflagellar transport and cilia-dependent renal disease: the ciliary hypothesis of polycystic kidney disease. J Am Soc Nephrol 15:2528–2536PubMedCrossRefGoogle Scholar
  32. 32.
    Nauli SM, Rossetti S, Kolb RJ, Alenghat FJ, Consugar MB, Harris PC, Ingber DE, Loghman-Adham M, Zhou J (2006) Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J Am Soc Nephrol 17:1015–1025PubMedCrossRefGoogle Scholar
  33. 33.
    Kottgen M, Buchholz B, Garcia-Gonzalez MA, Kotsis F, Fu X, Doerken M, Boehlke C, Steffl D, Tauber R, Wegierski T, Nitschke R, Suzuki M, Kramer-Zucker A, Germino GG, Watnick T, Prenen J, Nilius B, Kuehn EW, Walz G (2008) TRPP2 and TRPV4 form a polymodal sensory channel complex. J Cell Biol 182:437–447PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Delling M, Indzhykulian AA, Liu X, Li Y, Xie T, Corey DP, Clapham DE (2016) Primary cilia are not calcium-responsive mechanosensors. Nature 531:656–660PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S (2013) Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet 45:1004–1012PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Lee SH, Somlo S (2014) Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease. Kidney Res Clin Pract 33:73–78PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ward CJ, Yuan D, Masyuk TV, Wang X, Punyashthiti R, Whelan S, Bacallao R, Torra R, LaRusso NF, Torres VE, Harris PC (2003) Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum Mol Genet 12:2703–2710PubMedCrossRefGoogle Scholar
  38. 38.
    Kaimori JY, Nagasawa Y, Menezes LF, Garcia-Gonzalez MA, Deng J, Imai E, Onuchic LF, Guay-Woodford LM, Germino GG (2007) Polyductin undergoes notch-like processing and regulated release from primary cilia. Hum Mol Genet 16:942–956PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Hiesberger T, Gourley E, Erickson A, Koulen P, Ward CJ, Masyuk TV, Larusso NF, Harris PC, Igarashi P (2006) Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C. J Biol Chem 281:34357–34364PubMedCrossRefGoogle Scholar
  40. 40.
    Kim I, Li C, Liang D, Chen XZ, Coffy RJ, Ma J, Zhao P, Wu G (2008) Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin. J Biol Chem 283:31559–31566PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Kim I, Fu Y, Hui K, Moeckel G, Mai W, Li C, Liang D, Zhao P, Ma J, Chen XZ, George AL Jr, Coffey RJ, Feng ZP, Wu G (2008) Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function. J Am Soc Nephrol 19:455–468PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Grantham JJ, Geiser JL, Evan AP (1987) Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int 31:1145–1152PubMedCrossRefGoogle Scholar
  43. 43.
    Rossetti S, Kubly VJ, Consugar MB, Hopp K, Roy S, Horsley SW, Chauveau D, Rees L, Barratt TM, van’t Hoff WG, Niaudet P, Torres VE, Harris PC (2009) Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int 75:848–855PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Pei Y, Watnick T, He N, Wang K, Liang Y, Parfrey P, Germino G, St George-Hyslop P (1999) Somatic PKD2 mutations in individual kidney and liver cysts support a “two-hit” model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 10:1524–1529PubMedGoogle Scholar
  45. 45.
    Thivierge C, Kurbegovic A, Couillard M, Guillaume R, Cote O, Trudel M (2006) Overexpression of PKD1 causes polycystic kidney disease. Mol Cell Biol 26:1538–1548PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Low SH, Vasanth S, Larson CH, Mukherjee S, Sharma N, Kinter MT, Kane ME, Obara T, Weimbs T (2006) Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev Cell 10:57–69PubMedCrossRefGoogle Scholar
  47. 47.
    Talbot JJ, Song X, Wang X, Rinschen MM, Doerr N, LaRiviere WB, Schermer B, Pei YP, Torres VE, Weimbs T (2014) The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation. J Am Soc Nephrol 25:1737–1748PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Rotondo F, Butz H, Syro LV, Yousef GM, Di Ieva A, Restrepo LM, Quintanar-Stephano A, Berczi I, Kovacs K (2016) Arginine vasopressin (AVP): a review of its historical perspectives, current research and multifunctional role in the hypothalamo-hypophysial system. Pituitary 19:345–355PubMedCrossRefGoogle Scholar
  49. 49.
    Yasuda G, Jeffries WB (1998) Regulation of cAMP production in initial and terminal inner medullary collecting ducts. Kidney Int 54:80–86PubMedCrossRefGoogle Scholar
  50. 50.
    Wang X, Ward CJ, Harris PC, Torres VE (2010) Cyclic nucleotide signaling in polycystic kidney disease. Kidney Int 77:129–140PubMedCrossRefGoogle Scholar
  51. 51.
    Rees S, Kittikulsuth W, Roos K, Strait KA, Van Hoek A, Kohan DE (2014) Adenylyl cyclase 6 deficiency ameliorates polycystic kidney disease. J Am Soc Nephrol 25:232–237PubMedCrossRefGoogle Scholar
  52. 52.
    Ye H, Wang X, Sussman CR, Hopp K, Irazabal MV, Bakeberg JL, LaRiviere WB, Manganiello VC, Vorhees CV, Zhao H, Harris PC, van Deursen J, Ward CJ, Torres VE (2016) Modulation of polycystic kidney disease severity by phosphodiesterase 1 and 3 subfamilies. J Am Soc Nephrol 27:1312–1320PubMedCrossRefGoogle Scholar
  53. 53.
    Choi YH, Suzuki A, Hajarnis S, Ma Z, Chapin HC, Caplan MJ, Pontoglio M, Somlo S, Igarashi P (2011) Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases. Proc Natl Acad Sci U S A 108:10679–10684PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Spirli C, Locatelli L, Fiorotto R, Morell CM, Fabris L, Pozzan T, Strazzabosco M (2012) Altered store operated calcium entry increases cyclic 3′,5′-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes. Hepatology 55:856–868PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Wang X, Wu Y, Ward CJ, Harris PC, Torres VE (2008) Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol 19:102–108PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Streets AJ, Wessely O, Peters DJ, Ong AC (2013) Hyperphosphorylation of polycystin-2 at a critical residue in disease reveals an essential role for polycystin-1-regulated dephosphorylation. Hum Mol Genet 22:1924–1939PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Carroll TJ, Das A (2011) Planar cell polarity in kidney development and disease. Organ 7:180–190Google Scholar
  58. 58.
    Wallingford JB, Mitchell B (2011) Strange as it may seem: the many links between Wnt signaling, planar cell polarity, and cilia. Genes Dev 25:201–213PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Weimbs T (2007) Polycystic kidney disease and renal injury repair: common pathways, fluid flow, and the function of polycystin-1. Am J Physiol Renal Physiol 293:F1423–F1432PubMedCrossRefGoogle Scholar
  60. 60.
    Happe H, Leonhard WN, van der Wal A, van de Water B, Lantinga-van Leeuwen IS, Breuning MH, de Heer E, Peters DJ (2009) Toxic tubular injury in kidneys from Pkd1-deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways. Hum Mol Genet 18:2532–2542PubMedCrossRefGoogle Scholar
  61. 61.
    Belibi FA, Reif G, Wallace DP, Yamaguchi T, Olsen L, Li H, Helmkamp GM Jr, Grantham JJ (2004) Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells. Kidney Int 66:964–973PubMedCrossRefGoogle Scholar
  62. 62.
    Yamaguchi T, Wallace DP, Magenheimer BS, Hempson SJ, Grantham JJ, Calvet JP (2004) Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem 279:40419–40430PubMedCrossRefGoogle Scholar
  63. 63.
    Grantham JJ (2015) Rationale for early treatment of polycystic kidney disease. Pediatr Nephrol 30:1053–1062PubMedCrossRefGoogle Scholar
  64. 64.
    Ye M, Grantham JJ (1993) The secretion of fluid by renal cysts from patients with autosomal dominant polycystic kidney disease. N Engl J Med 329:310–313PubMedCrossRefGoogle Scholar
  65. 65.
    Happe H, Peters DJ (2014) Translational research in ADPKD: lessons from animal models. Nat Rev Nephrol 10:587–601PubMedCrossRefGoogle Scholar
  66. 66.
    Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH 2nd (2004) Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 10:363–364PubMedCrossRefGoogle Scholar
  67. 67.
    Wang X, Gattone V 2nd, Harris PC, Torres VE (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 16:846–851PubMedCrossRefGoogle Scholar
  68. 68.
    Park F, Mattson DL, Skelton MM, Cowley AW Jr (1997) Localization of the vasopressin V1a and V2 receptors within the renal cortical and medullary circulation. Am J Phys 273:R243–R251Google Scholar
  69. 69.
    Rinschen MM, Schermer B, Benzing T (2014) Vasopressin-2 receptor signaling and autosomal dominant polycystic kidney disease: from bench to bedside and back again. J Am Soc Nephrol 25:1140–1147PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Yamamura Y, Ogawa H, Yamashita H, Chihara T, Miyamoto H, Nakamura S, Onogawa T, Yamashita T, Hosokawa T, Mori T, Tominaga M, Yabuuchi Y (1992) Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist. Br J Pharmacol 105:787–791PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Gattone VH 2nd, Maser RL, Tian C, Rosenberg JM, Branden MG (1999) Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease. Dev Genet 24:309–318PubMedCrossRefGoogle Scholar
  72. 72.
    Zittema D, Versteeg IB, Gansevoort RT, van Goor H, de Heer E, Veraar KA, Peters DJ, Meijer E (2016) Dose-titrated vasopressin V2 receptor antagonist improves Renoprotection in a mouse model for autosomal dominant polycystic kidney disease. Am J Nephrol 44:194–203PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Meijer E, Gansevoort RT, de Jong PE, van der Wal AM, Leonhard WN, de Krey SR, van den Born J, Mulder GM, van Goor H, Struck J, de Heer E, Peters DJ (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 26:2445–2453PubMedCrossRefGoogle Scholar
  74. 74.
    Aihara M, Fujiki H, Mizuguchi H, Hattori K, Ohmoto K, Ishikawa M, Nagano K, Yamamura Y (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 349:258–267PubMedCrossRefGoogle Scholar
  75. 75.
    Upadhya P (2003) Models of polycystic kidney disease. Methods Mol Med 86:13–28PubMedGoogle Scholar
  76. 76.
    Ward CJ, Hogan MC, Rossetti S, Walker D, Sneddon T, Wang X, Kubly V, Cunningham JM, Bacallao R, Ishibashi M, Milliner DS, Torres VE, Harris PC (2002) The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 30:259–269PubMedCrossRefGoogle Scholar
  77. 77.
    Wu G, D’Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou H Jr, Kucherlapati R, Edelmann W, Somlo S (1998) Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93:177–188PubMedCrossRefGoogle Scholar
  78. 78.
    Sabbatini M, Russo L, Cappellaio F, Troncone G, Bellevicine C, De Falco V, Buonocore P, Riccio E, Bisesti V, Federico S, Pisani A (2014) Effects of combined administration of rapamycin, tolvaptan, and AEZ-131 on the progression of polycystic disease in PCK rats. Am J Physiol Renal Physiol 306:F1243–F1250PubMedCrossRefGoogle Scholar
  79. 79.
    Devuyst O, Wang X, Serra A (2011) Vasopressin-2 receptor antagonists in autosomal dominant polycystic kidney disease: from man to mouse and back. Nephrol Dial Transplant 26:2423–2425PubMedCrossRefGoogle Scholar
  80. 80.
    Yang B, Bankir L (2005) Urea and urine concentrating ability: new insights from studies in mice. Am J Physiol Renal Physiol 288:F881–F896PubMedCrossRefGoogle Scholar
  81. 81.
    Watnick T, Germino GG (2010) mTOR inhibitors in polycystic kidney disease. N Engl J Med 363:879–881PubMedCrossRefGoogle Scholar
  82. 82.
    Bankir L (2001) Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2 receptor-mediated effects. Cardiovasc Res 51:372–390PubMedCrossRefGoogle Scholar
  83. 83.
    Ahrabi AK, Terryn S, Valenti G, Caron N, Serradeil-Le Gal C, Raufaste D, Nielsen S, Horie S, Verbavatz JM, Devuyst O (2007) PKD1 haploinsufficiency causes a syndrome of inappropriate antidiuresis in mice. J Am Soc Nephrol 18:1740–1753PubMedCrossRefGoogle Scholar
  84. 84.
    Seeman T, Dusek J, Vondrak K, Blahova K, Simkova E, Kreisinger J, Dvorak P, Kyncl M, Hribal Z, Janda J (2004) Renal concentrating capacity is linked to blood pressure in children with autosomal dominant polycystic kidney disease. Physiol Res 53:629–634PubMedGoogle Scholar
  85. 85.
    Ho TA, Godefroid N, Gruzon D, Haymann JP, Marechal C, Wang X, Serra A, Pirson Y, Devuyst O (2012) Autosomal dominant polycystic kidney disease is associated with central and nephrogenic defects in osmoregulation. Kidney Int 82:1121–1129PubMedCrossRefGoogle Scholar
  86. 86.
    Devuyst O, Chapman AB, Gansevoort RT, Higashihara E, Perrone RD, Torres VE, Blais JD, Zhou W, Ouyang J, Czerwiec FS (2016) Urine osmolality, response to Tolvaptan, and outcome in autosomal dominant polycystic kidney disease: results from the TEMPO 3:4 trial. J Am Soc Nephrol. doi: 10.1681/ASN.2016040448 Google Scholar
  87. 87.
    Zittema D, Boertien WE, van Beek AP, Dullaart RP, Franssen CF, de Jong PE, Meijer E, Gansevoort RT (2012) Vasopressin, copeptin, and renal concentrating capacity in patients with autosomal dominant polycystic kidney disease without renal impairment. Clin J Am Soc Nephrol 7:906–913PubMedCrossRefGoogle Scholar
  88. 88.
    Morgenthaler NG, Struck J, Alonso C, Bergmann A (2006) Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 52:112–119PubMedCrossRefGoogle Scholar
  89. 89.
    Christ-Crain M, Fenske W (2016) Copeptin in the diagnosis of vasopressin-dependent disorders of fluid homeostasis. Nat Rev Endocrinol 12:168–176PubMedCrossRefGoogle Scholar
  90. 90.
    Roussel R, Fezeu L, Marre M, Velho G, Fumeron F, Jungers P, Lantieri O, Balkau B, Bouby N, Bankir L, Bichet DG (2014) Comparison between copeptin and vasopressin in a population from the community and in people with chronic kidney disease. J Clin Endocrinol Metab 99:4656–4663PubMedCrossRefGoogle Scholar
  91. 91.
    Zittema D, van den Berg E, Meijer E, Boertien WE, Muller Kobold AC, Franssen CF, de Jong PE, Bakker SJ, Navis G, Gansevoort RT (2014) Kidney function and plasma copeptin levels in healthy kidney donors and autosomal dominant polycystic kidney disease patients. Clin J Am Soc Nephrol 9:1553–1562PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Meijer E, Bakker SJ, van der Jagt EJ, Navis G, de Jong PE, Struck J, Gansevoort RT (2011) Copeptin, a surrogate marker of vasopressin, is associated with disease severity in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 6:361–368PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Boertien WE, Meijer E, Zittema D, van Dijk MA, Rabelink TJ, Breuning MH, Struck J, Bakker SJ, Peters DJ, de Jong PE, Gansevoort RT (2012) Copeptin, a surrogate marker for vasopressin, is associated with kidney function decline in subjects with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 27:4131–4137PubMedCrossRefGoogle Scholar
  94. 94.
    Boertien WE, Meijer E, Li J, Bost JE, Struck J, Flessner MF, Gansevoort RT, Torres VE, Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (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 61:420–429PubMedCrossRefGoogle Scholar
  95. 95.
    Cornec-Le Gall E, Audrezet MP, Rousseau A, Hourmant M, Renaudineau E, Charasse C, Morin MP, Moal MC, Dantal J, Wehbe B, Perrichot R, Frouget T, Vigneau C, Potier J, Jousset P, Guillodo MP, Siohan P, Terki N, Sawadogo T, Legrand D, Menoyo-Calonge V, Benarbia S, Besnier D, Longuet H, Ferec C, Le Meur Y (2016) The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 27:942–951PubMedCrossRefGoogle Scholar
  96. 96.
    Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP (2011) Tolvaptan inhibits ERK-dependent cell proliferation, cl(−) secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am J Physiol Renal Physiol 301:F1005–F1013PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Torres VE (2005) Vasopressin antagonists in polycystic kidney disease. Kidney Int 68:2405–2418PubMedCrossRefGoogle Scholar
  98. 98. drug information database (2016) tolvaptanGoogle Scholar
  99. 99.
    European Medicines Agency (2015) European public assessment report for Jinarc.Google Scholar
  100. 100.
    Gansevoort RT, Arici M, Benzing T, Birn H, Capasso G, Covic A, Devuyst O, Drechsler C, Eckardt KU, Emma F, Knebelmann B, Le Meur Y, Massy ZA, Ong AC, Ortiz A, Schaefer F, Torra R, Vanholder R, Wiecek A, Zoccali C, Van Biesen W (2016) Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA working groups on inherited kidney disorders and European renal best practice. Nephrol Dial Transplant 31:337–348PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Grantham JJ, Torres VE (2016) The importance of total kidney volume in evaluating progression of polycystic kidney disease. Nat Rev Nephrol 12:667–677PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Bae KT, Tao C, Zhu F, Bost JE, Chapman AB, Grantham JJ, Torres VE, Guay-Woodford LM, Meyers CM, Bennett WM, Consortium for Radiologic Imaging Studies Polycystic Kidney Disease (2009) MRI-based kidney volume measurements in ADPKD: reliability and effect of gadolinium enhancement. Clin J Am Soc Nephrol 4:719–725PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Chapman AB, Bost JE, Torres VE, Guay-Woodford L, Bae KT, Landsittel D, Li J, King BF, Martin D, Wetzel LH, Lockhart ME, Harris PC, Moxey-Mims M, Flessner M, Bennett WM, Grantham JJ (2012) Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 7:479–486PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, Bae KT, Chapman AB, Grantham JJ, Mrug M, Hogan MC, El-Zoghby ZM, Harris PC, Erickson BJ, King BF, Torres VE, Investigators CRISP (2015) Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol 26:160–172PubMedCrossRefGoogle Scholar
  105. 105.
    Chapman AB (2012) The fetal environment: a critical phase that determines future renal outcomes in autosomal dominant polycystic kidney disease. Kidney Int 81:814–815PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Orskov B, Christensen KB, Feldt-Rasmussen B, Strandgaard S (2012) Low birth weight is associated with earlier onset of end-stage renal disease in Danish patients with autosomal dominant polycystic kidney disease. Kidney Int 81:919–924PubMedCrossRefGoogle Scholar
  107. 107.
    Cadnapaphornchai MA, Masoumi A, Strain JD, McFann K, Schrier RW (2011) Magnetic resonance imaging of kidney and cyst volume in children with ADPKD. Clin J Am Soc Nephrol 6:369–376PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Grantham JJ, Cook LT, Wetzel LH, Cadnapaphornchai MA, Bae KT (2010) Evidence of extraordinary growth in the progressive enlargement of renal cysts. Clin J Am Soc Nephrol 5:889–896PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, Winklhofer FT, Brosnahan G, Czarnecki PG, Hogan MC, Miskulin DC, Rahbari-Oskoui FF, Grantham JJ, Harris PC, Flessner MF, Bae KT, Moore CG, Chapman AB, Trial Investigators HALT-PKD (2014) Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med 371:2255–2266PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Cadnapaphornchai MA, George DM, McFann K, Wang W, Gitomer B, Strain JD, Schrier RW (2014) Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 9:889–896PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Gunay-Aygun M, Font-Montgomery E, Lukose L, Tuchman M, Graf J, Bryant JC, Kleta R, Garcia A, Edwards H, Piwnica-Worms K, Adams D, Bernardini I, Fischer RE, Krasnewich D, Oden N, Ling A, Quezado Z, Zak C, Daryanani KT, Turkbey B, Choyke P, Guay-Woodford LM, Gahl WA (2010) Correlation of kidney function, volume and imaging findings, and PKHD1 mutations in 73 patients with autosomal recessive polycystic kidney disease. Clin J Am Soc Nephrol 5:972–984PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Guay-Woodford LM, Desmond RA (2003) Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics 111:1072–1080PubMedCrossRefGoogle Scholar
  113. 113.
    Adeva M, El-Youssef M, Rossetti S, Kamath PS, Kubly V, Consugar MB, Milliner DM, King BF, Torres VE, Harris PC (2006) Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Medicine (Baltimore) 85:1–21CrossRefGoogle Scholar
  114. 114.
    Ebner K, Feldkoetter M, Ariceta G, Bergmann C, Buettner R, Doyon A, Duzova A, Goebel H, Haffner D, Hero B, Hoppe B, Illig T, Jankauskiene A, Klopp N, Konig J, Litwin M, Mekahli D, Ranchin B, Sander A, Testa S, Weber LT, Wicher D, Yuzbasioglu A, Zerres K, Dotsch J, Schaefer F, Liebau MC, ESCAPE Study Group; GPN Study Group (2015) Rationale, design and objectives of ARegPKD, a European ARPKD registry study. BMC Nephrol 16:22PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Liebau MC (2014) An emerging molecular understanding and novel targeted treatment approaches in pediatric kidney diseases. Front Pediatr 2:68PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Masyuk TV, Radtke BN, Stroope AJ, Banales JM, Gradilone SA, Huang B, Masyuk AI, Hogan MC, Torres VE, Larusso NF (2013) Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases. Hepatology 58:409–421PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Myint TM, Rangan GK, Webster AC (2014) Treatments to slow progression of autosomal dominant polycystic kidney disease: systematic review and meta-analysis of randomized trials. Nephrology (Carlton) 19:217–226CrossRefGoogle Scholar
  118. 118.
    Tao S, Kakade VR, Woodgett JR, Pandey P, Suderman ED, Rajagopal M, Rao R (2015) Glycogen synthase kinase-3beta promotes cyst expansion in polycystic kidney disease. Kidney Int 87:1164–1175PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Kakade VR, Tao S, Rajagopal M, Zhou X, Li X, Yu AS, Calvet JP, Pandey P, Rao R (2016) A cAMP and CREB-mediated feed-forward mechanism regulates GSK3beta in polycystic kidney disease. J Mol Cell Biol 8:464–476PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© IPNA 2017

Authors and Affiliations

  1. 1.Laboratory of PediatricsUniversity Hospitals LeuvenLeuvenBelgium
  2. 2.Department of NephrologyUniversity Hospitals BrusselBrusselBelgium
  3. 3.Department of Pediatric NephrologyUniversity Hospitals LeuvenLeuvenBelgium
  4. 4.Pediatric Nephrology, Department of Pediatrics and Center for Molecular MedicineUniversity Hospital of CologneCologneGermany
  5. 5.Department II of Internal MedicineUniversity Hospital of CologneCologneGermany
  6. 6.Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol)University of CologneCologneGermany

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