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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. Select etiologies of NDI: Table 1.
A broad approach to polyuria should be undertaken when considering the diagnosis of NDI in any patient. This should involve collecting a careful history looking at various etiologies of central and nephrogenic diabetes insipidus.
NDI is suspected if there is a failure of response to water restriction and desmopressin in raising urine osmolarity or reducing plasma sodium concentration. However, patients strongly suspected of having NDI (children with very dilute urine, patients on chronic lithium therapy) should not undergo water restriction and can rather have direct administration of desmopressin followed by a response assessment. 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-salt diet and 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-salt 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 their increase.
In patients in whom the therapy discussed above is unsuccessful, we suggest a trial of desmopressin.
Vasopressin V2-receptor gene mutations (X-linked),a AQP2 gene mutations (autosomal dominant/autosomal recessive)
– Systemic disorders: hypercalcemia,a amyloidosis, Sjögren syndrome, polycystic kidney disease, sickle cell disease
– Drugs: lithium,a cidofovir, foscarnet, amphotericin B
– Other: hypokalemia, pregnancy
a The most common causes.