Treatment of nephrogenic diabetes insipidus
- Daniel G Bichet, MD
Daniel G Bichet, MD
- Professor of Medicine
- Universite de Montreal
- Section Editors
- Richard H Sterns, MD
Richard H Sterns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Professor of Medicine
- University of Rochester School of Medicine and Dentistry
- Tej K Mattoo, MD, DCH, FRCP
Tej K Mattoo, MD, DCH, FRCP
- Section Editor — Pediatric Nephrology
- Professor of Pediatrics
- Wayne State University School of Medicine
Nephrogenic diabetes insipidus (DI) results from partial or complete resistance of the kidney to the effects of antidiuretic hormone. As a result, patients with this disorder are not likely to have a good response to hormone administration (as dDAVP) or to drugs that increase either the renal response to ADH or ADH secretion.
Nephrogenic DI can be hereditary or acquired. In adults, a concentrating defect severe enough to produce polyuria due to nephrogenic DI is most often due to chronic lithium use or hypercalcemia, and less frequently to other conditions that impair tubular function, such as Sjögren's syndrome . Release of ureteral obstruction is often associated with a diuresis, but this is short lived and does not require specific therapy other than maintenance fluids. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus" and "Clinical manifestations and diagnosis of urinary tract obstruction and hydronephrosis", section on 'Prognosis and recovery of renal function'.)
Hereditary nephrogenic DI, which is largely an X-linked disease, may also be seen by internists since early recognition and treatment in infancy has led to survival to adulthood [2,3]. In addition, affected women may be carriers with few or no symptoms until pregnancy or other stress.
In infants with hereditary nephrogenic DI, treatment is aimed at minimizing the polyuria and avoiding hypernatremia and volume depletion. In adults, therapy is usually aimed at correcting the underlying disorder or discontinuing an offending drug. In hypercalcemic patients, for example, normalization of the plasma calcium concentration usually leads to amelioration of polyuria. By contrast, lithium-induced nephrogenic DI may be irreversible if the patient already has severe tubular injury and a marked concentrating defect . (See "Renal toxicity of lithium".)
The approach to the treatment of polyuria in patients with nephrogenic DI will be reviewed here. The causes of nephrogenic DI, the diagnostic approach to polyuria, and the treatment of central DI are discussed separately. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus" and "Diagnosis of polyuria and diabetes insipidus" and "Treatment of central diabetes insipidus".)
- Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.754,782.
- Fujiwara TM, Bichet DG. Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol 2005; 16:2836.
- Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat Rev Nephrol 2015; 11:576.
- Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 1987; 10:329.
- Ulinski T, Grapin C, Forin V, et al. Severe bladder dysfunction in a family with ADH receptor gene mutation responsible for X-linked nephrogenic diabetes insipidus. Nephrol Dial Transplant 2004; 19:2928.
- Shalev H, Romanovsky I, Knoers NV, et al. Bladder function impairment in aquaporin-2 defective nephrogenic diabetes insipidus. Nephrol Dial Transplant 2004; 19:608.
- Uribarri J, Kaskas M. Hereditary nephrogenic diabetes insipidus and bilateral nonobstructive hydronephrosis. Nephron 1993; 65:346.
- Streitz JM Jr, Streitz JM. Polyuric urinary tract dilatation with renal damage. J Urol 1988; 139:784.
- Zender HO, Ruedin P, Moser F, et al. Traumatic rupture of the urinary tract in a patient presenting nephrogenic diabetes insipidus associated with hydronephrosis and chronic renal failure: case report and review of the literature. Clin Nephrol 1992; 38:196.
- Higuchi A, Kawamura T, Nakai H, Hasegawa Y. Infrequent voiding in nephrogenic diabetes insipidus as a cause of renal failure. Pediatr Int 2002; 44:540.
- Caletti MG, Balestracci A, Di Pinto D. Pre- and post-treatment urinary tract findings in children with nephrogenic diabetes insipidus. Pediatr Nephrol 2014; 29:487.
- Bockenhauer D. Diabetes insipidus. In: Comprehensive Pediatric Nephrology, 1st ed, Geary DF, Schaefer F. (Eds), Mosby Elsevier, Philadelphia 2008. p.489.
- Wesche D, Deen PM, Knoers NV. Congenital nephrogenic diabetes insipidus: the current state of affairs. Pediatr Nephrol 2012; 27:2183.
- 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.
- Earley LE, Orloff J. THE MECHANISM OF ANTIDIURESIS ASSOCIATED WITH THE ADMINISTRATION OF HYDROCHLOROTHIAZIDE TO PATIENTS WITH VASOPRESSIN-RESISTANT DIABETES INSIPIDUS. J Clin Invest 1962; 41:1988.
- Libber S, Harrison H, Spector D. Treatment of nephrogenic diabetes insipidus with prostaglandin synthesis inhibitors. J Pediatr 1986; 108:305.
- Monnens L, Jonkman A, Thomas C. Response to indomethacin and hydrochlorothiazide in nephrogenic diabetes insipidus. Clin Sci (Lond) 1984; 66:709.
- Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med 1985; 312:408.
- Knoers N, Monnens LA. Amiloride-hydrochlorothiazide versus indomethacin-hydrochlorothiazide in the treatment of nephrogenic diabetes insipidus. J Pediatr 1990; 117:499.
- Bedford JJ, Weggery S, Ellis G, et al. Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. Clin J Am Soc Nephrol 2008; 3:1324.
- Christensen BM, Zuber AM, Loffing J, et al. alphaENaC-mediated lithium absorption promotes nephrogenic diabetes insipidus. J Am Soc Nephrol 2011; 22:253.
- Kortenoeven ML, Li Y, Shaw S, et al. Amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant nephrogenic diabetes insipidus. Kidney Int 2009; 76:44.
- Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009; 5:270.
- O'Brien WT, Harper AD, Jové F, et al. Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 2004; 24:6791.
- Alsady M, Baumgarten R, Deen PM, de Groot T. Lithium in the Kidney: Friend and Foe? J Am Soc Nephrol 2016; 27:1587.
- Berl T, Raz A, Wald H, et al. Prostaglandin synthesis inhibition and the action of vasopressin: studies in man and rat. Am J Physiol 1977; 232:F529.
- Stokes JB. Integrated actions of renal medullary prostaglandins in the control of water excretion. Am J Physiol 1981; 240:F471.
- Allen HM, Jackson RL, Winchester MD, et al. Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus. Arch Intern Med 1989; 149:1123.
- Miller M, Dalakos T, Moses AM, et al. Recognition of partial defects in antidiuretic hormone secretion. Ann Intern Med 1970; 73:721.
- Zerbe RL, Robertson GL. A comparison of plasma vasopressin measurements with a standard indirect test in the differential diagnosis of polyuria. N Engl J Med 1981; 305:1539.
- Stasior DS, Kikeri D, Duel B, Seifter JL. Nephrogenic diabetes insipidus responsive to indomethacin plus dDAVP. N Engl J Med 1991; 324:850.
- 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.
- Bernier V, Morello JP, Zarruk A, et al. Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 2006; 17:232.
- 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.
- Jean-Alphonse F, Perkovska S, Frantz MC, et al. Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 2009; 20:2190.
- Sasaki S. Nephrogenic diabetes insipidus: update of genetic and clinical aspects. Nephrol Dial Transplant 2004; 19:1351.
- Yang B, Zhao D, Verkman AS. Hsp90 inhibitor partially corrects nephrogenic diabetes insipidus in a conditional knock-in mouse model of aquaporin-2 mutation. FASEB J 2009; 23:503.
- Olesen ET, Rützler MR, Moeller HB, et al. Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus. Proc Natl Acad Sci U S A 2011; 108:12949.
- Gao M, Cao R, Du S, et al. Disruption of prostaglandin E2 receptor EP4 impairs urinary concentration via decreasing aquaporin 2 in renal collecting ducts. Proc Natl Acad Sci U S A 2015; 112:8397.
- 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.
- Assadi F, Sharbaf FG. Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus. Am J Nephrol 2015; 42:65.
- Special considerations in hereditary disease
- Special considerations in patients requiring intravenous fluids
- Decreased dietary solute
- Nonsteroidal anti-inflammatory drugs
- Exogenous ADH
- Experimental approaches
- - V2 receptor chaperones
- - V2 receptor bypass
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS
- Initial therapy
- Hereditary disease