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Clinical manifestations and causes of nephrogenic diabetes insipidus

Daniel G Bichet, MD
Section Editor
Richard H Sterns, MD
Deputy Editor
John P Forman, MD, MSc


Nephrogenic diabetes insipidus (DI) refers to a decrease in urinary concentrating ability that results from resistance to the action of antidiuretic hormone (ADH). This problem can reflect resistance at the ADH site of action in the collecting tubules, or interference with the countercurrent mechanism due, for example, to medullary injury or to decreased sodium chloride reabsorption in the medullary aspect of the thick ascending limb of the loop of Henle (figure 1) [1]. (See "Diagnosis of polyuria and diabetes insipidus".)

Nephrogenic DI, in its mild form, is relatively common since almost all patients who are elderly, sick, or have acute or chronic kidney disease have a reduction in maximum concentrating ability [1]. As an example, the maximum urine osmolality that can be achieved may fall from the normal value of 800 to 1200 mosmol/kg down to 350 to 600 mosmol/kg in these settings [1]. In chronic kidney disease, this defect is due in part to increased solute excretion per functioning nephron and to decreased expression of mRNA for the V2 vasopressin receptor [1,2].

The clinical manifestations and causes of nephrogenic DI will be reviewed here. The treatment of nephrogenic DI, the diagnostic approach to polyuria and diabetes insipidus, and the clinical manifestations and causes of central DI are discussed separately. (See "Treatment of nephrogenic diabetes insipidus" and "Diagnosis of polyuria and diabetes insipidus" and "Clinical manifestations and causes of central diabetes insipidus".)


Patients with moderate to severe nephrogenic or central DI typically present with polyuria, nocturia, and polydipsia. Polyuria is arbitrarily defined as a urine output exceeding 3 L/day in adults or 2 L/m2 in children. Causes of polyuria other than DI include primary polydipsia and increased solute excretion due to one or more of the following: glucosuria in uncontrolled diabetes mellitus, urea with a high-protein diet, or sodium chloride and urea in a postobstructive diuresis. In addition, glucosuria can contribute to polyuria in patients with severe DI when hyperglycemia is induced by the administration of large volumes of intravenous dextrose in water. (See "Diagnosis of polyuria and diabetes insipidus", section on 'Solute diuresis'.)

The urine is normally most concentrated in the morning due to lack of fluid ingestion overnight and increased vasopressin secretion during the late sleep period [3]. As a result, the first manifestation of a mild to moderate loss of concentrating ability is often nocturia. However, nocturia is not diagnostic of a defect in concentrating ability since it can also be caused by other factors such as drinking before going to bed or, in men, by prostatic hypertrophy, which is characterized by urinary frequency rather than polyuria.

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Literature review current through: Nov 2017. | This topic last updated: Nov 07, 2016.
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  1. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.754.
  2. Teitelbaum I, McGuinness S. Vasopressin resistance in chronic renal failure. Evidence for the role of decreased V2 receptor mRNA. J Clin Invest 1995; 96:378.
  3. Trudel E, Bourque CW. Central clock excites vasopressin neurons by waking osmosensory afferents during late sleep. Nat Neurosci 2010; 13:467.
  4. Garofeanu CG, Weir M, Rosas-Arellano MP, et al. Causes of reversible nephrogenic diabetes insipidus: a systematic review. Am J Kidney Dis 2005; 45:626.
  5. van Lieburg AF, Knoers NV, Monnens LA. Clinical presentation and follow-up of 30 patients with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 1999; 10:1958.
  6. Morello JP, Salahpour A, Laperrière A, et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 2000; 105:887.
  7. Devonald MA, Karet FE. Renal epithelial traffic jams and one-way streets. J Am Soc Nephrol 2004; 15:1370.
  8. Bichet DG. Hereditary polyuric disorders: new concepts and differential diagnosis. Semin Nephrol 2006; 26:224.
  9. Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat Rev Nephrol 2015; 11:576.
  10. Bichet DG, Razi M, Lonergan M, et al. Hemodynamic and coagulation responses to 1-desamino[8-D-arginine] vasopressin in patients with congenital nephrogenic diabetes insipidus. N Engl J Med 1988; 318:881.
  11. Fujiwara TM, Bichet DG. Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol 2005; 16:2836.
  12. Bichet DG. Vasopressin receptor mutations in nephrogenic diabetes insipidus. Semin Nephrol 2008; 28:245.
  13. Sasaki S. Nephrogenic diabetes insipidus: update of genetic and clinical aspects. Nephrol Dial Transplant 2004; 19:1351.
  14. Nomura Y, Onigata K, Nagashima T, et al. Detection of skewed X-inactivation in two female carriers of vasopressin type 2 receptor gene mutation. J Clin Endocrinol Metab 1997; 82:3434.
  15. Li JH, Chou CL, Li B, et al. A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus. J Clin Invest 2009; 119:3115.
  16. Klein JD, Wang Y, Blount MA, et al. Metformin, an AMPK activator, stimulates the phosphorylation of aquaporin 2 and urea transporter A1 in inner medullary collecting ducts. Am J Physiol Renal Physiol 2016; 310:F1008.
  17. Robben JH, Kortenoeven ML, Sze M, et al. Intracellular activation of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists. Proc Natl Acad Sci U S A 2009; 106:12195.
  18. Wesche D, Deen PM, Knoers NV. Congenital nephrogenic diabetes insipidus: the current state of affairs. Pediatr Nephrol 2012; 27:2183.
  19. Deen PM, Verdijk MA, Knoers NV, et al. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 1994; 264:92.
  20. Deen PM, Croes H, van Aubel RA, et al. Water channels encoded by mutant aquaporin-2 genes in nephrogenic diabetes insipidus are impaired in their cellular routing. J Clin Invest 1995; 95:2291.
  21. Asai T, Kuwahara M, Kurihara H, et al. Pathogenesis of nephrogenic diabetes insipidus by aquaporin-2 C-terminus mutations. Kidney Int 2003; 64:2.
  22. Yamamoto T, Sasaki S. Aquaporins in the kidney: emerging new aspects. Kidney Int 1998; 54:1041.
  23. Kozono D, Yasui M, King LS, Agre P. Aquaporin water channels: atomic structure molecular dynamics meet clinical medicine. J Clin Invest 2002; 109:1395.
  24. Oksche A, Möller A, Dickson J, et al. Two novel mutations in the aquaporin-2 and the vasopressin V2 receptor genes in patients with congenital nephrogenic diabetes insipidus. Hum Genet 1996; 98:587.
  25. Hochberg Z, Van Lieburg A, Even L, et al. Autosomal recessive nephrogenic diabetes insipidus caused by an aquaporin-2 mutation. J Clin Endocrinol Metab 1997; 82:686.
  26. Loonen AJ, Knoers NV, van Os CH, Deen PM. Aquaporin 2 mutations in nephrogenic diabetes insipidus. Semin Nephrol 2008; 28:252.
  27. Fenton RA, Moeller HB, Hoffert JD, et al. Acute regulation of aquaporin-2 phosphorylation at Ser-264 by vasopressin. Proc Natl Acad Sci U S A 2008; 105:3134.
  28. Tamma G, Robben JH, Trimpert C, et al. Regulation of AQP2 localization by S256 and S261 phosphorylation and ubiquitination. Am J Physiol Cell Physiol 2011; 300:C636.
  29. Nielsen S, Kwon TH, Christensen BM, et al. Physiology and pathophysiology of renal aquaporins. J Am Soc Nephrol 1999; 10:647.
  30. de Mattia F, Savelkoul PJ, Kamsteeg EJ, et al. Lack of arginine vasopressin-induced phosphorylation of aquaporin-2 mutant AQP2-R254L explains dominant nephrogenic diabetes insipidus. J Am Soc Nephrol 2005; 16:2872.
  31. Bichet DG, Oksche A, Rosenthal W. Congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 1997; 8:1951.
  32. Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009; 5:270.
  33. Rao R, Patel S, Hao C, et al. GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity. J Am Soc Nephrol 2010; 21:428.
  34. Berl T. The cAMP system in vasopressin-sensitive nephron segments of the vitamin D-treated rat. Kidney Int 1987; 31:1065.
  35. Peterson LN, McKay AJ, Borzecki JS. Endogenous prostaglandin E2 mediates inhibition of rat thick ascending limb Cl reabsorption in chronic hypercalcemia. J Clin Invest 1993; 91:2399.
  36. Rosen S, Greenfeld Z, Bernheim J, et al. Hypercalcemic nephropathy: chronic disease with predominant medullary inner stripe injury. Kidney Int 1990; 37:1067.
  37. Hebert SC. Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney. Kidney Int 1996; 50:2129.
  38. Wang WH, Lu M, Hebert SC. Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL. Am J Physiol 1996; 271:C103.
  39. Mangat H, Peterson LN, Burns KD. Hypercalcemia stimulates expression of intrarenal phospholipase A2 and prostaglandin H synthase-2 in rats. Role of angiotensin II AT1 receptors. J Clin Invest 1997; 100:1941.
  40. Sands JM, Naruse M, Baum M, et al. Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest 1997; 99:1399.
  41. Brown EM, Hebert SC. A cloned Ca(2+)-sensing receptor: a mediator of direct effects of extracellular Ca2+ on renal function? J Am Soc Nephrol 1995; 6:1530.
  42. Earm JH, Christensen BM, Frøkiaer J, et al. Decreased aquaporin-2 expression and apical plasma membrane delivery in kidney collecting ducts of polyuric hypercalcemic rats. J Am Soc Nephrol 1998; 9:2181.
  43. Marples D, Frøkiaer J, Dørup J, et al. Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex. J Clin Invest 1996; 97:1960.
  44. Luke RG, Booker BB, Galla JH. Effect of potassium depletion on chloride transport in the loop of Henle in the rat. Am J Physiol 1985; 248:F682.
  45. Elkjaer ML, Kwon TH, Wang W, et al. Altered expression of renal NHE3, TSC, BSC-1, and ENaC subunits in potassium-depleted rats. Am J Physiol Renal Physiol 2002; 283:F1376.
  46. Jung JY, Madsen KM, Han KH, et al. Expression of urea transporters in potassium-depleted mouse kidney. Am J Physiol Renal Physiol 2003; 285:F1210.
  47. Khositseth S, Uawithya P, Somparn P, et al. Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus. Sci Rep 2015; 5:18311.
  48. Berl T, Linas SL, Aisenbrey GA, Anderson RJ. On the mechanism of polyuria in potassium depletion. The role of polydipsia. J Clin Invest 1977; 60:620.
  49. Frøkiaer J, Marples D, Knepper MA, Nielsen S. Bilateral ureteral obstruction downregulates expression of vasopressin-sensitive AQP-2 water channel in rat kidney. Am J Physiol 1996; 270:F657.
  50. Gabow PA, Kaehny WD, Johnson AM, et al. The clinical utility of renal concentrating capacity in polycystic kidney disease. Kidney Int 1989; 35:675.
  51. Scolari F, Caridi G, Rampoldi L, et al. Uromodulin storage diseases: clinical aspects and mechanisms. Am J Kidney Dis 2004; 44:987.
  52. CARONE FA, EPSTEIN FH. Nephrogenic diabetes insipidus caused by amyloid disease. Evidence in man of the role of the collecting ducts in concentrating urine. Am J Med 1960; 29:539.
  54. Fine LG, Schlondorff D, Trizna W, et al. Functional profile of the isolated uremic nephron. Impaired water permeability and adenylate cyclase responsiveness of the cortical collecting tubule to vasopressin. J Clin Invest 1978; 61:1519.
  55. Tannen RL, Regal EM, Dunn MJ, Schrier RW. Vasopressin-resistant hyposthenuria in advanced chronic renal disease. N Engl J Med 1969; 280:1135.
  56. KLEEMAN CR, ADAMS DA, MAXWELL MH. An evaluation of maximal water diuresis in chronic renal disease. I. Normal solute intake. J Lab Clin Med 1961; 58:169.
  57. DORHOUT MEES EJ. Relation between maximal urine concentration, maximal water reabsorption capacity, and mannitol clearance in patients with renal disease. Br Med J 1959; 1:1159.
  58. Schliefer K, Rockstroh JK, Spengler U, Sauerbruch T. Nephrogenic diabetes insipidus in a patient taking cidofovir. Lancet 1997; 350:413.
  59. Navarro JF, Quereda C, Quereda C, et al. Nephrogenic diabetes insipidus and renal tubular acidosis secondary to foscarnet therapy. Am J Kidney Dis 1996; 27:431.
  60. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355:2099.
  61. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010; 21:705.
  62. D'Ythurbide G, Goujard C, Méchaï F, et al. Fanconi syndrome and nephrogenic diabetes insipidus associated with didanosine therapy in HIV infection: a case report and literature review. Nephrol Dial Transplant 2007; 22:3656.
  63. Brewster UC, Hayslett JP. Diabetes insipidus in the third trimester of pregnancy. Obstet Gynecol 2005; 105:1173.
  64. Aleksandrov N, Audibert F, Bedard MJ, et al. Gestational diabetes insipidus: a review of an underdiagnosed condition. J Obstet Gynaecol Can 2010; 32:225.
  65. Ghirardello S, Hopper N, Albanese A, Maghnie M. Diabetes insipidus in craniopharyngioma: postoperative management of water and electrolyte disorders. J Pediatr Endocrinol Metab 2006; 19 Suppl 1:413.
  66. Seckl JR, Dunger DB, Bevan JS, et al. Vasopressin antagonist in early postoperative diabetes insipidus. Lancet 1990; 335:1353.
  67. Anadoliiska A, Roussinov D. Clinical aspects of renal involvement in Bardet-Biedl syndrome. Int Urol Nephrol 1993; 25:509.
  68. Parfrey PS, Davidson WS, Green JS. Clinical and genetic epidemiology of inherited renal disease in Newfoundland. Kidney Int 2002; 61:1925.
  69. Marion V, Schlicht D, Mockel A, et al. Bardet-Biedl syndrome highlights the major role of the primary cilium in efficient water reabsorption. Kidney Int 2011; 79:1013.
  70. Peters M, Jeck N, Reinalter S, et al. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med 2002; 112:183.
  71. Jeck N, Schlingmann KP, Reinalter SC, et al. Salt handling in the distal nephron: lessons learned from inherited human disorders. Am J Physiol Regul Integr Comp Physiol 2005; 288:R782.
  72. Hildebrandt F, Attanasio M, Otto E. Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 2009; 20:23.
  73. Bodaghi E, Honarmand MT, Ahmadi M. Infantile nephronophthisis. Int J Pediatr Nephrol 1987; 8:207.
  74. Knoepfelmacher M, Rocha R, Salgado LR, et al. [Nephropathic cystinosis: report of 2 cases and review of the literature]. Rev Assoc Med Bras (1992) 1994; 40:43.
  75. Praga M, Vara J, González-Parra E, et al. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Kidney Int 1995; 47:1419.
  76. Dave-Sharma S, Wilson RC, Harbison MD, et al. Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess. J Clin Endocrinol Metab 1998; 83:2244.
  77. Bockenhauer D, van't Hoff W, Dattani M, et al. Secondary nephrogenic diabetes insipidus as a complication of inherited renal diseases. Nephron Physiol 2010; 116:p23.
  78. Gissen P, Johnson CA, Morgan NV, et al. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. Nat Genet 2004; 36:400.
  79. Cullinane AR, Straatman-Iwanowska A, Zaucker A, et al. Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization. Nat Genet 2010; 42:303.