These findings “validated hypertonic saline-stimulated copeptin measurement as a diagnostic method that appeared to be superior to the indirect [water deprivation] test in distinguishing central [DI] from primary polydipsia,” the researchers concluded.3
Endocrinology Advisor spoke with the following experts to learn more about diagnostic challenges and treatment considerations pertaining to DI: Caitlin White, MD, assistant professor of clinical medicine in the division of endocrinology, diabetes, and metabolism in the Perelman School of Medicine at the University of Pennsylvania, and Leann Olansky, MD, an endocrinologist at the Cleveland Clinic.
Endocrinology Advisor: What are some of the diagnostic challenges associated with DI?
Dr White: When approaching a patient with polyuria, it is often easier to identify patients with a solute- or medication-induced diuresis. It is more difficult to distinguish between DI and primary polydipsia. A water deprivation test is typically needed in this circumstance. It is important to identify patients with very large volume polyuria beforehand because they become severely dehydrated if asked to restrict water. For this reason, these patients should only undergo water deprivation testing in a closely monitored setting. They should not be asked to start water restriction overnight before the water deprivation test, as is sometimes done for patients with less severe polyuria.
Dr Olansky: The diagnostic challenges in diagnosing DI are that increased urination and increased thirst are not always attributable to DI. Diabetes mellitus can also present with these symptoms, as can primary polydipsia. These conditions can be distinguished from DI by common laboratory tests of urine and blood.
If these symptoms occur because of diabetes mellitus, the blood and urine will show rather high glucose levels. If they occur in cases of primary polydipsia, the urine will be dilute as with DI. However, serum levels of sodium, blood urea nitrogen, and creatinine will all be low compared with values seen in DI, where the serum is concentrated and those electrolytes are high-normal or clearly high.
The 2 conditions that are hardest to distinguish are central (hypothalamic) DI and nephrogenic DI. The first is caused by a deficiency of vasopressin, and the second occurs from an inability of the kidney cells to respond to the hormone. The classic test to confirm DI is a water deprivation test where urine output and concentration and serum sodium are monitored hourly without water intake by the patient. Once the urine concentration stabilizes, the subject is injected with an AVP analog. If the urine gets more concentrated, the problem is a lack of the hormone and the DI is central. On the other hand, if the urine does not concentrate, the problem is nephrogenic DI.
Endocrinology Advisor: What are the treatment strategies for this disorder, and what are some common treatment challenges?
Dr White: Patients with central DI can be treated with desmopressin, which is available in oral, intranasal, and subcutaneous/intravenous formulations. When initiating treatment, it is typically recommended to start with a low dose at bedtime to control nocturia first. Then, the dose can be gradually increased, and a daytime dose can be added if needed.
A major limitation of desmopressin is that excessive doses can cause hyponatremia. For this reason, it is important to monitor serum sodium approximately 1 week after any dose increase and whenever patients have symptoms suggesting hyponatremia, such as headache, nausea, or confusion.
The main principle of treatment is to use adequate desmopressin to mitigate polyuria symptoms, but not so much that it leads to hyponatremia.
Patients with nephrogenic DI may be treated with a combination of low solute diet, thiazide diuretics, amiloride, and nonsteroidal anti-inflammatory drugs such as indomethacin.
Dr Olansky: If the patient has central DI, we use that analog of vasopressin/desmopressin. This can be taken orally about every 8 to 12 hours. If the patient has a normal thirst, the dose is adjusted to give a reasonable amount of urine, but if thirst is abnormal, the patient needs to consume a specific amount of water/day and take a specific dose of desmopressin. If the patient has nephrogenic DI, the patient is managed with a low-sodium diet, and sometimes with a diuretic to limit urine output and therefore limit water loss.
Endocrinology Advisor: What are some of the remaining needs in this area in terms of research or otherwise?
Dr White: Most patients with DI have an intact thirst mechanism, and this helps protect them from hyponatremia and hypernatremia. Patients with central DI who also have an impairment in thirst are prone to severe hyponatremia and hypernatremia, particularly if their desmopressin dose is either excessive or insufficient, respectively. There is very limited availability of point-of-care sodium testing. Wider accessibility of this technology for both patients and clinicians could dramatically improve the quality of life for these patients.
Dr Olansky: I do not think there is much research in this area. Maybe we will one day have gene replacement therapy for the genetic forms of nephrogenic DI.
Endocrinology Advisor: What else should clinicians know about this disorder?
Dr White: Patients with DI should be instructed to obtain a medical alert identifying them as having this condition. They should be educated to alert all of their medical providers that they have DI, especially during any hospitalization or surgery. Care should be taken to closely monitor serum sodium during periods of fasting or intravenous fluid administration, such as typically occurs perioperatively.
Dr Olansky: Clinicians should suspect DI if the patient is having polyuria and the serum sodium level is high or high normal.
1. Garrahy A, Moran C, Thompson CJ. Diagnosis and management of central diabetes insipidus in adults. Clin Endocrinol (Oxf). 2019;90(1):23-30.
2. Pivonello R, De Bellis A, Faggiano A, et al. Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology. J Clin Endocrinol Metab. 2003;88(4):1629-1636.
3. Fenske W, Refardt J, Chifu I, et al. A copeptin-based approach in the diagnosis of diabetes insipidus. N Engl J Med. 2018;379(5):428-439.
4. Winzeler B, Zweifel C, Nigro N, et al. Postoperative copeptin concentration predicts diabetes insipidus after pituitary surgery. J Clin Endocrinol Metab. 2015;100(6):2275-2282.
5. Christ-Crain M, Morgenthaler NG, Fenske W. Copeptin as a biomarker and a diagnostic tool in the evaluation of patients with polyuria-polydipsia and hyponatremia. Best Pract Res Clin Endocrinol Metab. 2016;30(2):235-247.
6. Timper K, Fenske W, Kühn F, et al. Diagnostic accuracy of copeptin in the differential diagnosis of the polyuria-polydipsia syndrome: a prospective multicenter study. J Clin Endocrinol Metab. 2015;100(6):2268-2274.