EJE AWARD 2019: New diagnostic approaches for patients with polyuria polydipsia syndrome

Abstract

Diabetes insipidus (DI), be it from central or nephrogenic origin, must be differentiated from secondary forms of hypotonic polyuria such as primary polydipsia. Differentiation is crucial since wrong treatment can have deleterious consequences. Since decades, the gold standard for differentiation has been the water deprivation test, which has limitations leading to an overall unsatisfying diagnostic accuracy. Furthermore, it is cumbersome for patients with a long test duration. Clinical signs and symptoms and MRI characteristics overlap between patients with DI and primary polydipsia. The direct test including vasopressin (AVP) measurement upon osmotic stimulation was meant to overcome these limitations, but failed to enter clinical practice mainly due to technical constraints of the AVP assay. Copeptin is secreted in equimolar amount to AVP but can easily be measured with a sandwich immunoassay. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation and has led to a 'revival' of the direct test in the differential diagnosis of DI. We have shown that a baseline copeptin, without prior thirsting, unequivocally identifies patients with nephrogenic DI. In contrast, for the differentiation between central DI 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 superior to the water deprivation test. Close sodium monitoring during the test is a prerequisite. Further new test methods are currently evaluated and might provide an even simpler way of differential diagnosis in the future.

Figure 1

Structure of pre-provasopressin. The prohormone is packaged into neurosecretory granules of magnocellular neurons. During axonal transport of the granules from the hypothalamus to the posterior pituitary, enzymatic cleavage of the prohormone generates the final products: AVP, neurophysin and the COOH-terminal glycoprotein copeptin. Modified from (30) with permission.

Figure 2

Correlation of arginine vasopressin (AVP) and copeptin (A) and correlation of AVP and copeptin with plasma osmolality (B). Plasma AVP and copeptin concentrations measured during water load and hypertonic saline tests are shown as scatter plot. rS denotes Spearman’s rank correlation coefficients. Modified from (37, 39) with permission.

Figure 3

Stimulated copeptin levels in response to the hypertonic saline infusion and water deprivation test in patients with polyuria polydipsia syndrome. Shown are stimulated copeptin levels in response to the hypertonic saline infusion test (HIS) and water deprivation test (WDT) in patients with polyuria polydipsia syndrome that was caused by complete central diabetes insipidus (DI) or partial central diabetes insipidus as compared with primary polydipsia. The horizontal line in each box represents the median, the lower and upper boundaries of the boxes the interquartile range, the ends of the whisker lines the minimum and maximum values within 1.5 times the interquartile range and the dots outliers. Modified from (11) with permission.

Figure 4

New algorithm for the differential diagnosis of polyuria polydipsia syndrome. Modified from (2).

Figure 5

Copeptin levels upon pituitary surgery. A copeptin cut-off level of <2.5 pmol/L, measured within the first 12 h after surgery, had a positive predictive value for development of postoperative diabetes insipidus of 81% and a specificity of 97%; while a level >30 pmol/L excluded it with a negative predictive value of 95% and a sensitivity of 94%. Modified from (69) with permission.