At A Glance

The features of Nephrogenic Diabetes Insipidus (DI) include:


inappropriately dilute urine

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hypernatremia and hyperosmolality, if water restricted

increased plasma vasopressin, despite dilute urine

no response to exogenous vasopressin

DI is the inability to concentrate urine because of lack of action of vasopressin. DI may be a consequence of vasopressin deficiency (Central DI) or inability of nephrons to respond to adequate concentrations of vasopressin (Nephrogenic DI). In DI, dehydration and increased serum osmolality and sodium occur only if the individual has restricted access to water.

DI , in general, will present with complaints of polyuria, nocturia, and thirst. The patient will not be dehydrated if he or she has free access to water. Serum electrolytes and renal and liver function may be within normal limits. Urine osmolality will typically be low (<300 mosmols/kg H2O) and a 24-hour urine volume will be elevated greater than 50 ml per kg of body weight. A 70 kg patient may have a daily urine volume exceeding 3500 mls. Serum osmolality and serum sodium may be normal, provided the patient does not become dehydrated. If water is restricted, these latter measurements will increase.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

A fluid deprivation test is the restriction of all oral intake in a carefully-controlled environment. The patient is typically weighed after the excretion of each liter of urine. Serum sodium, osmolality, and urine osmolality are determined regularly. Over the course of the test, if DI is indeed present, the patient will continue to excrete copious volumes of urine and serum sodium and osmolality will increase, whereas urine osmolality will remain paradoxically low. At this stage, the blood urea nitrogen (BUN) may be elevated, consistent with dehydration. The test is terminated once the patient has lost 3-5% of their body weight.(Table 1)

Table 1.
Initial Urine Osmolality (mosmols/kg H2O) H2O Deprivation Test Desmopressin Injection
>300 – solute diuresis (e.g., diabetes mellitus) In DI, urine osmolality remains inappropriately low with a urine-to-plasma osmolality of <1.0. Central DI:
Urine osmolality rises significantly by >50%, often to values exceeding 700 mosmols/kg H2O.
<300 – water diuresis (e.g., diabetes insipidus) In primary polydipsia, urine osmolality rises with water restriction. Nephrogenic DI:
No response

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

A clue to the general cause of the DI may be found in the patient’s medication history. Nephrogenic DI may be produced by lithium, foscarnet, clozapine, or demeclocycline, among others. Lithium can produce DI in up to 40% of patients, and it is the most common adverse effect of lithium.

What Lab Results Are Absolutely Confirmatory?

At the end of the fluid deprivation, blood is drawn for determination of plasma antidiuretic hormone (ADH or vasopressin). After this, the patient is administered 2 mcg of desmopressin (also called DDAVP, usually given at 0.03 mcg/kg), a synthetic analog of vasopressin. Urine osmolality is determined 2 hours later. In nephrogenic DI, the polyuria will persist after administration of desmopressin and there will be no significant alteration in the urine osmolality, which will remain inappropriately low.

Endogenous plasma vasopressin will be very elevated at all stages, especially at the end of the water deprivation study. The very high vasopressin combined with the lack of response (in terms of urine concentrating ability) to exogenous synthetic vasopressin establishes the diagnosis of a nephrogenic DI.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Nephrogenic DI may be congenital, so a detailed history of the condition is invaluable. Congenital DI may be due to X-linked mutations in the gene encoding the vasopressin V2 receptor (90% of cases) or, less commonly, autosomally-transmitted mutations in aquaporin 2.

Acquired nephrogenic DI may result from medications, hypokalemia, hypercalcemia, polycystic kidney disease, or infarcts.

If a patient has partial or incomplete central DI or partial nephrogenic DI, fluid deprivation might result in a modest concentration of the urine, producing an effect similar to that encountered in primary polydipsia. Responses of urine osmolality to injected desmopressin may not be helpful because of overlap in the range of the responses. In this instance, there is utility in enhancing the serum osmolality by infusing hypertonic saline during the fluid restriction until the osmolality rises above 300 mosmol/kg H2O. The volume loss combined with hyperosmolality will further stimulate vasopressin secretion in a normal individual. Determination of plasma vasopressin as a function of serum osmolality can better distinguish partial DI states and primary polydipsia.