Copeptin Test Can Detect Diabetes Insipidus vs Other Polyuria

A blood test for copeptin, a precursor of antidiuretic hormone (ADH, vasopressin), differentiates between "harmless" polydipsia-polyuria and diabetes insipidus more quickly and accurately than a traditional water-deprivation test, researchers report.

Measuring plasma levels of copeptin after a 2-hour saline infusion was more accurate than being deprived of fluids for 16 hours. The latter is a technically cumbersome test to administer, and the results are often inaccurate, not to mention the fact that patients find it extremely unpleasant and stressful.

The study, by Wiebke Kristin Fenske, MD, PhD, from the University of Leipzig, Germany, and colleagues, was published online August 2 in the New England Journal of Medicine.

"The water deprivation test is...more or less flipping a coin [to come] to the right diagnosis for patients consulting us with symptoms of polyuria-polydipsia," Fenske told Medscape Medical News in a conference call along with senior author Mirjam Christ-Crain, MD, PhD, University Hospital Basel, Switzerland.

"In the past, unfortunately, we had nothing better than the water deprivation test," to make the differential diagnosis, she added, "simply because the [antidiuretic] hormone, which we assume is insufficiently produced by the body, cannot be reliably measured in the circulation."

"Although diabetes insipidus is a rare disease, primary polydipsia is not as rare as we [may] think," Christ-Crain noted. Patients are very thirsty and drink much more than 3 or 4 L/day, and then may wake in the night to drink more water or go to the bathroom.

Now, "there is a new test which allows us to diagnose the underlying disease of the symptoms polyuria and polydipsia. [The test is] highly reliably, with an overall diagnostic accuracy of 96% or 97% compared to our previous worldwide diagnostic standard, the water deprivation test, which yielded an overall diagnostic accuracy of about [77% or 73%]," Fenske said.

"This is very important," Christ-Crain added, "because the wrong diagnosis results in the wrong treatment, which can be very dangerous for patients."

The therapy of the two conditions is fundamentally different. Diabetes insipidus must be treated with the hormone vasopressin; whereas, patients with primary polydipsia require behavioral therapy to reduce their habitual drinking.

So the wrong therapy can have grave consequences "if you don't have diabetes insipidus," but are given the treatment for it, synthetic desmopressin, that "can lead to water intoxication, which can be life threatening," Christ-Crain explained.

The reverse is also true. "If you have diabetes insipidus and you don't get the [correct] treatment, then the risk is that you have severe hypernatremia and dehydration, and this is also life-threatening."

Harmless Copious Water Intake or Hormone Disorder?

Vasopressin production increases in diseases related to stress, such as an acute myocardial infarction, Fenske noted, and it is difficult to measure, whereas its precursor copeptin is much easier to assess.

As previously reported by Medscape Medical News, the Biomarkers in Cardiology 8 (BIC-8) trial found that patients who had suspected acute coronary syndrome but negative troponin and copeptin tests could be safely discharged from hospital without further testing. The copeptin assay has a CE mark in Europe for this use.

Vasopressin also regulates the water and salt content in the body.

In conditions where patients have excessive thirst and excessive fluid intake they may have diabetes insipidus — and lack vasopressin — or they may have developed a habit of drinking excessive fluids or have a mental illness.

To investigate whether copeptin might aid in this differential diagnosis, researchers recruited 156 patients with hypotonic polyuria at 11 centers in Germany, Switzerland, and Brazil.

Patients' final diagnosis was determined at study end by two independent endocrinology experts based on a patient's medical history, clinical symptoms, water-deprivation test results, laboratory and imaging data, and response to therapy after 3 months.

About half of the patients were diagnosed with primary polydipsia (57%), most of the remainder (41%) had central (neurogenic) diabetes insipidus (deficient vasopressin because of a damaged hypothalamus or pituitary gland or genetics), and a few (2%) had nephrogenic diabetes insipidus (deficient kidney response to vasopressin).

Of the patients with central diabetes insipidus, 61% had complete and 39% had partial disease.

Overall, two thirds of the patients were women. Patients with a diagnosis of primary polydipsia were a median age of 32 years, and the other patients were a median age of 45 years.

Overall, patients drank 5 to 6 L/day of fluids (91% water) and excreted 5 L/day of urine.

Almost all (92%) patients with diabetes insipidus got up to drink water at night, also reported by 62% of the other patients.

Patients underwent three tests:

water deprivation (fluids were restricted for 17 hours);
plasma copeptin stimulated by water deprivation; and
plasma copeptin stimulated by a hypertonic saline infusion (copeptin was measured when plasma sodium had reached 150 mmol/L).

The copeptin assay was an automated immunofluorescence assay (BRAHMS KRYPTOR Copeptin proAVP, Thermo Scientific Biomarkers).

Copeptin Test Has Higher Diagnostic Accuracy

Overall, the hypertonic saline-stimulated copeptin test had a higher diagnostic accuracy than the water deprivation test (96.5% vs 76.6%).

Moreover, in patients with only partial diabetes insipidus, the hypertonic saline-stimulated copeptin test was still more accurate than the water deprivation test (95.2% vs 73.3%).

On the other hand, adding a copeptin test to a water deprivation test was "completely useless," Christ-Crain noted.

This prospective study, the authors conclude, "validated hypertonic saline–stimulated copeptin measurement as a diagnostic method that appeared to be superior to the indirect water-deprivation test in distinguishing central diabetes insipidus from primary polydipsia."

"In both our centers involved in the study, the [copeptin] test is part of our clinical routine now," Fenske said.

The test is available and will likely become part of clinical routine practice in Europe in the next 3 or 4 years, she predicts.

In the United States, the assay is not FDA-approved for distinguishing diabetes insipidus from polydipsia-polyuria, but it can be obtained and used in research studies.

The study was supported by grants from the Swiss National Foundation; University Hospital Basel, Switzerland; Federal Ministry of Education and Research, Germany; and Deutsche Forschungsgemeinschaft. Laboratory measurement of copeptin was funded by Thermo Fisher Scientific. Disclosures for the authors are listed with the article.

N Engl J Med. 2018;379:428-439. Abstract

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