Diagnosis & Treatment

Diagnosis of NDI

Nephrogenic diabetes insipidus (NDI) is only one of four types of diabetes insipidus (DI), for which all patients exhibit extreme thirst (polydipsia) and excessive urination (polyuria) as symptoms. Distinguishing among the different types of DI can be straightforward under some conditions, and under other conditions requires additional tests. Factors taken into consideration during diagnosis include:

1. urinary concentration (Urine contains both a solute aspect – salts, minerals, sugars, and a solvent aspect – the body water minus the solutes. Urine concentration is measured in terms of the ratio of osmotically active particles to body water.),
2. plasma concentration (the ratio of plasma solutes to plasma solvent),
3. measurement of the level of the antidiuretic hormone, arginine vasopressin (AVP) in the plasma, and
4. urine volume.

If a person shows the classic symptoms of DI, polyuria and polydipsia, clinicians will test the patient’s blood  and urine to measure their relative concentration of osmotically active particles. If a person has complete NDI, he or she will have normal to elevated plasma concentrations of AVP and low levels of osmotically active particles in the urine.

Often the patient will be given a water deprivation test to confirm an NDI diagnosis and to help distinguish what type of NDI the patient has. The patient is carefully monitored during the test to make sure their body weight and plasma osmolality stay within safe ranges. The patient goes without water for no more than 5 or 6 hours during which time his or her plasma concentrations and urine volume are measured. If the patient has complete NDI, that is, if he or she has a full resistance to the antidiuretic action of AVP, then it is likely that immediately following the water deprivation period when the patient is significantly dehydrated, he or she will show high levels of osmotically active particles in the blood and low levels of osmotically active particles in the urine. At the end of the water fast, the patient’s response to an infusion of a synthetic analog of AVP called desmopressin acetate(DDAVP) is measured. If the patient shows a more highly concentrated urine in response to DDAVP, he or she may have a different form of diabetes insipidus called pituitary diabetes insipidus (also called central or neurogenic diabetes insipidus). If the patient does not respond to DDAVP, he or she may have NDI.

Administering DDAVP, then measuring the responses that take place outside the kidney such as heart rate, diastolic blood pressure and facial flushing is one way clinicians have of distinguishing between NDI caused by mutant V2R genes and NDI caused by mutant AQP2 genes. The patient with NDI caused by mutant AQP2 genes will show responses to DDAVP that take place outside the kidney. The patient whose NDI is the result of mutated V2R genes will not.

However, as Gary Robertson of Northwestern University Medical School in Chicago, Illinois, USA states in his article Diabetes Insipidus (Robertson), a patient may have a partial form of any one of the types of DI. For example, he or she may have only partial resistance to AVP. In these cases, diagnosis is more challenging. A significant proportion of patients who have either the acquired or the inherited forms of NDI do concentrate their urine very well during standard fluid deprivation tests because they have only partial resistance to the antidiuretic effects of vasopressin.

If the patient evidences urinary concentration after water deprivation there are three remaining diagnostic possibilities.  The patient may have either partial neurogenic, partial nephrogenic, or a type of DI called dipsogenic DI. In this case the change in urine osmolality produced by administering AVP or DDAVP is of no value in differentiating among them. Clinicians will measure the patient’s plasma AVP, plasma osmolality and urine osmolality before and during a standard water deprivation test, and then plot a graph showing the relation among the three variables to help with the diagnosis.

Treatment of NDI

There is as yet no cure for inherited NDI, though researchers are hopeful that their study of the genetic basis of the disorder will lead to some form of genetic therapy that will cure it. Currently, NDI is managed by:

1. ensuring ready access to water,
2. following a low-sodium (and sometimes low-protein) diet, and
3. using thiazide diuretics, alone or in combination with a prostaglandin inhibitor or a potassium-sparing diuretic, to reduce the volume of urine output.

Thiazide diuretics can reduce an NDI patient’s polyuria, but they may also deplete the body’s stores of potassium. This depletion can cause other symptoms and may be dangerous. When taking thiazide diuretics, the patient’s potassium levels must be monitored. To maintain sufficient potassium in the body, the addition of potassium supplements or amiloride (but not both) to the treatment regime may be required.

Walter Rosenthal and Alexander Oksche of the Forschungsinstitut für Molekulare Pharmakologie in Berlin, Germany state in The Molecular Basis of Nephrogenic Diabetes Insipidus that combining a thiazide (such as hydrochlorothiazide) with a potassium-sparing diuretic (such as amiloride) may be more effective than using a thiazide alone. Sometimes thiazides are used in combination with the prostaglandin inhibitor, indomethacin.  Elevated levels of Prostaglandin E2 (PGE2) have been reported in NDI patients, and PGE2 in the kidney interferes with the activity of AVP. Indomethacin inhibits the synthesis of prostaglandin in the kidney, thus reducing polyuria in cases of both inherited and acquired NDI. However, Rosenthal and Oksche mention that the combination of thiazides and amiloride may be preferable because they have less potential side effects than a combination of indomethacin and thiazide. Indomethacin, a nonsteroidal anti-inflammatory agent, often causes headaches and dizziness, or an increased risk of gastrointestinal disorders. Also, if administered in the first year of life, indomethacin increases the risk of kidney disease.

Thiazide diuretics should be used with care in cases of lithium-induced NDI as they reduce the degree to which the kidney can excrete lithium, thereby setting the stage for a toxic build-up of lithium. Amiloride is more widely used in these cases as it inhibits the accumulation of lithium while blunting lithium’s  inhibiting action on water reabsorption. In The Management of Diabetes Insipidus in Adults, Dr. Irwin Singer of the Veterans Affairs Medical Center in Miami, Florida, USA, et al., notes that while thiazides rob the body of potassium, amiloride inhibits excretion of potassiumin the urine. Dr. Patricia Adams from Smiley’s Clinic in Minneapolis, Minnesota, USA states in Evaluation and Management of Diabetes Insipidus that thiazide diuretics and amiloride deplete total body salt, which allows the kidneys to more readily absorb water. However, this improved water absorption is negated by a diet heavy in salt, so low-sodium diets such as that recommended in Low Sodium Diet Basics by Cristine Trahms and Beth Ogata of the University of Washington in Seattle, Washington, USA are prescribed for NDI patients.