Robertson GL. Diabetes insipidus: Differential diagnosis and management. Best Pract Res Clin Endocrinol Metab. 2016 Mar;30(2):205-18. doi: 10.1016/j.beem.2016.02.007. Epub 2016 Feb 18. Review. PMID: 27156759.
Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat Rev Nephrol. 2015 Oct;11(10):576-88. doi: 10.1038/nrneph.2015.89. Epub 2015 Jun 16. Review. PMID: 26077742.
Emma F, Nesterova G, Langman C, et al. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014 Sep;29 Suppl 4:iv87-94. doi: 10.1093/ndt/gfu090. PMID: 25165189; PMCID: PMC4158338.
Both T, Zietse R, Hoorn EJ, et al. Everything you need to know about distal renal tubular acidosis in autoimmune disease. Rheumatol Int. 2014 Aug;34(8):1037-45. doi: 10.1007/s00296-014-2993-3. Epub 2014 Mar 29. Review. PMID: 24682397; PMCID: PMC4107275.
Haque SK, Ariceta G, Batlle D. Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies. Nephrol Dial Transplant. 2012 Dec;27(12):4273-87. doi: 10.1093/ndt/gfs493. Review. PMID: 23235953; PMCID: PMC3616759.
Reddy P. Clinical approach to renal tubular acidosis in adult patients. Int J Clin Pract. 2011 Mar;65(3):350-60. doi: 10.1111/j.1742-1241.2009.02311.x. Review. PMID: 21314872.
Landau D. Potassium-related inherited tubulopathies. Cell Mol Life Sci. 2006 Sep;63(17):1962-8. Review. PMID: 16810456.
Rodríguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol. 2002 Aug;13(8):2160-70. Review. PMID: 12138150.
Shaer AJ. Inherited primary renal tubular hypokalemic alkalosis: a review of Gitelman and Bartter syndromes. Am J Med Sci. 2001 Dec;322(6):316-32. Review. PMID: 11780689.
Definition and EtiologyTop
Nephrogenic diabetes insipidus (NDI) refers to the inability to appropriately concentrate urine that results from resistance to circulating antidiuretic hormone (ADH). This can be due to a defect at the site of action of ADH, interference with the countercurrent mechanism, or decreased sodium chloride reabsorption at the level of the thick ascending limb of the loop of Henle.
The etiology of NDI can be divided into hereditary and acquired causes. Hereditary causes are more common in children, whereas acquired causes are more common in adults. Selected etiologies of NDI: Table 11.9-5.
There are many causes of polyuria aside from diabetes insipidus (DI). Polyuria must also be differentiated from urinary frequency, which may present similarly. A broad approach to polyuria should be undertaken when considering the diagnosis of DI in any patient. This should involve collecting a careful history looking at various etiologies of central and nephrogenic diabetes insipidus.
DI is confirmed if there is a failure of water restriction to raise urine osmolality, whereas NDI, if there is a minimal increase in urine osmolality to desmopressin. However, in patients strongly suspected of having severe DI, it may be unsafe to undergo prolonged water restriction and it may need to occur in a monitored setting. Alternatively, they may have an infusion of hypertonic saline to obtain the same elevated serum sodium level as can be achieved with water deprivation. A suboptimal response to desmopressin, represented by minor or no elevation in urine osmolality, is the hallmark of complete NDI. A small (<45%) elevation in urine osmolality in response to desmopressin occurs in partial NDI.
Secondary etiology should be corrected when identified and offending medications should be stopped, if feasible. All patients should receive advice to stay on a low-solute (low salt and low protein) diet to limit polyuria and to perform double voiding to prevent bladder distension. Special recommendations for children with NDI are beyond the scope of this chapter.
If the patient is unable to control polyuria with a low-solute diet, a nonsteroidal anti-inflammatory drug or thiazide diuretic can be tried. The effect of thiazide diuretics is likely due to the increase in proximal sodium and water reabsorption, which is induced by hypovolemia. This diminishes water delivery to the ADH-sensitive sites in the collecting tubules, reducing urine output. Amiloride can be also attempted if inadequate response is achieved with initial therapies; this can be particularly helpful in patients with NDI in whom lithium cannot be discontinued. However, we advise careful and frequent monitoring of lithium levels, as this approach may result in increased lithium levels.
In patients in whom the therapy discussed above is unsuccessful, we suggest a trial of desmopressin, as many patients have partial NDI and show some response to desmopressin.
Vasopressin V2-receptor gene mutations (X-linked)a, AQP2 gene mutations (autosomal dominant/autosomal recessive)
– Systemic disorders: hypercalcemiaa, amyloidosis, Sjögren syndrome, polycystic kidney disease, sickle cell disease
– Drugs: lithiuma, cidofovir, foscarnet, amphotericin B
– Other: hypokalemia, pregnancy
a The most common causes.