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) . (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 . 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 . 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 . 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.