Central diabetes insipidus (CDI) is characterized by hypotonic polyuria due to impairment of AVP secretion from the posterior pituitary. In clinical practice, it needs to be distinguished from renal resistance to the antidiuretic effects of AVP (nephrogenic DI), and abnormalities of thirst appreciation (primary polydipsia). As nephrogenic diabetes insipidus is rare in adults, unless they are treated with lithium salts, the practical challenge is how to differentiate between CDI and clinical disorders of excess thirst. The differential diagnosis is usually straight forward, but the recommended gold standard test, the water deprivation test, is not without interpretative pitfalls. The addition of the measurement of plasma AVP concentrations improves diagnostic accuracy, but the radioimmunoassay for AVP is technically difficult, and is only available in a few specialized centres. More recently, the measurement of plasma copeptin concentrations has been claimed to provide a reliable alternative to measurement of plasma AVP, without the sampling handling challenges. In addition, the measurement of thirst ratings can help the differentiation between CDI and primary polydipsia. Once the diagnosis of CDI is biochemically certain, investigations to determine the cause of AVP deficiency are needed. In this review, we will outline the diagnostic approach to polyuria, revisit the caveats of the water deprivation test and review recent data on value of adding AVP/copeptin measurement. We will also discuss treatment strategies for CDI, with analysis of potential complications of treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cen.13866

Diagnosis and management of central diabetes insipidus in adults

Arginine-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a prospective diagnostic study

Arginine Vasopressin (AVP) and copeptin derive from the same precursor molecule. Due to the equimolar secretion, copeptin responds as rapidly as AVP to osmotic, hemodynamic and unspecific stress-related stimuli and both peptides show a very strong correlation. The physiological functions of AVP are homeostasis of fluid balance, vascular tonus and regulation of the endocrine stress response. In contrast, the exact function of copeptin remains unknown. Since copeptin, in contrast to AVP, can easily be measured with a sandwich immunoassay, its main function so far that it indirectly indicates the amount of AVP in the circulation. Copeptin has emerged as a useful measure in different diseases. On one hand, through its characteristics as a marker of stress, it provides a unique measure of the individual stress burden. As such, it is a prognostic marker in different acute diseases such as ischemic stroke or myocardial infarction. On the other side, it has emerged as a promising marker in the diagnosis of AVP-dependent fluid disorders. Copeptin reliably differentiates various entities of the polyuria polydipsia syndrome; baseline levels >20 pmol/L without prior fluid deprivation identify patients with nephrogenic diabetes insipidus, whereas levels measured upon osmotic stimulation with hypertonic saline or upon non-osmotic stimulation with arginine differentiate primary polydipsia from central diabetes insipidus. In patients with hyponatremia, low levels of copeptin together with low urine osmolality identify patients with primary polydipsia, but copeptin levels overlap in all other causes of hyponatremia, limiting its diagnostic use in hyponatremia. Copeptin has also been put forward as predictive marker for autosomal dominant polycystic kidney disease and for diabetes mellitus, but more studies are needed to confirm these findings.

Vasopressin and Copeptin in Health and Disease

Copeptin is secreted in an equimolar amount to arginine vasopressin (AVP) but can easily be measured in plasma or serum with a sandwich immunoassay. The main stimuli for copeptin are similar to AVP, that is an increase in osmolality and a decrease in arterial blood volume and pressure. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation. Copeptin has, therefore, been evaluated as diagnostic biomarker in vasopressin-dependent disorders of body fluid homeostasis. Disorders of body fluid homeostasis are common and can be divided into hyper- and hypoosmolar circumstances: the classical hyperosmolar disorder is diabetes insipidus, while the most common hypoosmolar disorder is the syndrome of inappropriate antidiuresis (SIAD). Copeptin measurement has led to a "revival" of the direct test in the differential diagnosis of diabetes insipidus. Baseline copeptin levels, without prior thirsting, unequivocally identify patients with nephrogenic diabetes insipidus. In contrast, for the difficult differentiation between central diabetes insipidus and primary polydipsia, a stimulated copeptin level of 4.9 pmol/L upon hypertonic saline infusion differentiates these two entities with a high diagnostic accuracy and is clearly superior to the classical water deprivation test. On the contrary, in the SIAD, copeptin measurement is of only little diagnostic value. Copeptin levels widely overlap in patients with hyponatraemia and emphasize the heterogeneity of the disease. Additionally, a variety of factors lead to unspecific copeptin elevations in the acute setting further complicating its interpretation. The broad use of copeptin as diagnostic marker in hyponatraemia and specifically to detect cancer-related disease in SIADH patients can, therefore, not be recommended.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cen.13991

Copeptin and its role in the diagnosis of diabetes insipidus and the syndrome of inappropriate antidiuresis.

Central diabetes insipidus (CDI) is a clinical syndrome which results from loss or impaired function of vasopressinergic neurones in the hypothalamus/posterior pituitary, resulting in impaired synthesis and/or secretion of arginine vasopressin (AVP). AVP deficiency leads to the inability to concentrate urine and excessive renal water losses, resulting in a clinical syndrome of hypotonic polyuria with compensatory thirst. CDI is caused by diverse aetiologies, although it typically develops due to neoplastic, traumatic or autoimmune destruction of AVP synthesizing/secreting neurones. This review focuses on the diagnosis and management of CDI, providing insights into the physiological disturbances underpinning the syndrome. Recent developments in diagnostic techniques, particularly the development of the copeptin assay, have improved accuracy and acceptability of the diagnostic approach to the hypotonic polyuria syndrome. We discuss the management of CDI with particular emphasis on management of fluid intake and pharmacological replacement of AVP. Specific clinical syndromes such as adipsic diabetes insipidus and diabetes insipidus in pregnancy as well as management of the perioperative patient with diabetes insipidus are also discussed.

Diagnosis and Management of Central Diabetes Insipidus in Adults.

Background The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the resul...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1803760

A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus.

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A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus.