Polyuria-polydipsia syndrome: a diagnostic challenge.

The main determinants for the maintenance of water homeostasis are the hormone arginine vasopressin (AVP) and thirst. Disturbances in these regulatory mechanisms can lead to polyuria-polydipsia syndrome, which comprises of three different conditions: central diabetes insipidus (DI) due to insufficient secretion of AVP, nephrogenic DI caused by renal insensitivity to AVP action and primary polydipsia due to excessive fluid intake and consequent physiological suppression of AVP. It is crucial to determine the exact diagnosis because treatment strategies vary substantially. To differentiate between the causes of the polyuria-polydipsia syndrome, a water deprivation test combined with desmopressin administration is the diagnostic 'gold standard'. Thereby, AVP activity is indirectly evaluated through the measurement of urine osmolality after prolonged dehydration. However, this test has several limitations and may fail to distinguish precisely between patients with primary polydipsia and mild forms of central and nephrogenic DI. The direct measurement of AVP during the water deprivation test, which was reported in the 1980s, has not been widely adopted due to availability, assay issues and diagnostic performance. Recently, copeptin, the c-terminal portion of the larger precursor peptide of AVP, has been evaluated in the setting of polyuria-polydipsia syndrome and appears to be a useful candidate biomarker for the differential diagnosis. A standardised method for the water deprivation test is presented as part of a joint initiative of the Endocrine Society of Australia, the Australasian Association of Clinical Biochemists and the Royal College of Pathologists of Australasia to harmonise dynamic endocrine tests across Australia.

Diagnostic value of the water deprivation test in the polyuria-polydipsia syndrome.

OBJECTIVE: Diabetes insipidus (DI) and primary polydipsia (PP) are characterised by polyuria and polydipsia. It is crucial to differentiate between these two disorders since the treatment is different. The aim of this study was to evaluate the diagnostic value of the short and an extended variant of the water deprivation test (WDT) and of measuring urinary vasopressin (AVP) in patients with polyuria and polydipsia. DESIGN: A retrospective, single-centre study based on WDTs performed between 2004 and 2014 including 104 consecutive patients with the polyuria-polydipsia syndrome. During a strict water deprivation, weight, urinary osmolality, urinary vasopressin and specific gravity were collected until one of the following was reached: i) >3% weight reduction, ii) Urinary specific gravity >1.020 or, urinary osmolality >800 mOsm/L, iii) Intolerable adverse symptoms such as excessive thirst. RESULTS: Out of 104 patients (67 women, 37 men), 21 (20%) were diagnosed with DI and 83 (80%) with PP. The median (interquartile range; range) test duration was 14 hours (10-16; 3-36) in patients with DI and 18 hours (14-24; 7-48) in patients with PP (P=0.011). Of those diagnosed with PP, 22 (26%) did not reach urinary specific gravity >1.020 nor urine osmolality >800 mOsm/L. Urine AVP did not overlap between patients with PP and patients with central DI. CONCLUSIONS: The short WDT is of limited value in the diagnostic work-up of polydipsia and polyuria and a partial DI may have been missed in every fourth patient diagnosed with PP. Urinary AVP has excellent potential in discriminating PP from central DI.

[A practical algorithm for polydipsia in children]. / Een praktisch algoritme voor polydipsie bij kinderen.

There is a lack of consent on a clinical diagnostic work-up for children with polydipsia. This can result in a delay in diagnosis in some children and unnecessary investigations in others. We describe three children who presented with polydipsia. Two of them were diagnosed with psychogenic polydipsia and one with central diabetes insipidus. We discuss the differential diagnosis and relevant clinical signs before going on to propose a clinical diagnostic algorithm that can be used in children with polydipsia. A systematic diagnostic work up for children with polydipsia helps to differentiate between those in whom polydipsia is unlikely to have a somatic cause and those where a water deprivation-test is indicated. A water deprivation test in children is an invasive procedure and should be performed by a paediatric endocrinologist or nephrologist.

Inhibition of natriuresis in median eminence polydipsia: effects after intake of diets with different osmolalities and after hypertonic NaCl administration.

Lesions in the hypothalamic median eminence (ME) induce polydipsia and polyuria in male rats. A first experiment was designed to examine the effect of salt consumption (standard 0.25 percent Na+ vs. low-salt 0.04 percent Na+ diet) on the fluid-electrolytic balance (plasma sodium, urinary sodium excretion, urine osmolality) and water intake of ME polydipsic animals. In the first 6 h post-surgery, the natriuretic response was higher in ME-lesioned animals than in control groups. At 24 h post-surgery, however, less sodium was excreted by ME rats fed with a standard salt diet (ME/SS), despite showing no decrease in salt intake, and they evidenced an increase in plasma sodium concentration and water intake. Urine osmolality was significantly higher in control animals than in either ME-lesioned group. In experiment 2, hypertonic NaCl administration (2 ml/2M) increased the polydipsic behavior of ME-lesioned but not control rats (day 2). Animals deprived of food/salt showed a significant reduction (on day 2) in the initial (day 1) polydipsia, which increased on day 3 when the animals had access to a standard-salt diet. These results suggest that the reduced natriuretic response and the consequent sodium retention observed in ME animals may exacerbate the hydromineral imbalance of this polydipsic syndrome.

Central diabetes insipidus associated with impaired renal aquaporin-1 expression in mice lacking liver X receptor ß.

The present study demonstrates a key role for the oxysterol receptor liver X receptor ß (LXRß) in the etiology of diabetes insipidus (DI). Given free access to water, LXRß(-/-) but not LXRα(-/-) mice exhibited polyuria (abnormal daily excretion of highly diluted urine) and polydipsia (increased water intake), both features of diabetes insipidus. LXRß(-/-) mice responded to 24-h dehydration with a decreased urine volume and increased urine osmolality. To determine whether the DI was of central or nephrogenic origin, we examined the responsiveness of the kidney to arginine vasopressin (AVP). An i.p. injection of AVP to LXRß(-/-) mice revealed a partial kidney response: There was no effect on urine volume, but there was a significant increase of urine osmolality, suggesting that DI may be caused by a defect in central production of AVP. In the brain of WT mice LXRß was expressed in the nuclei of magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus. In LXRß(-/-) mice the expression of AVP was markedly decreased in the magnocellular neurons as well as in urine collected over a 24-h period. The persistent high urine volume after AVP administration was traced to a reduction in aquaporin-1 expression in the kidney of LXRß(-/-) mice. The LXR agonist (GW3965) in WT mice elicited an increase in urine osmolality, suggesting that LXRß is a key receptor in controlling water balance with targets in both the brain and kidney, and it could be a therapeutic target in disorders of water balance.

Physiological function of the angiotensin AT1a receptor in bone remodeling.

In order to determine whether the renin-angiotensin system (RAS) has any physiologic function in bone metabolism, mice lacking the gene encoding the major angiotensin II receptor isoform, AT1a, were studied using micro CT scanning, histomorphometric, and biochemical techniques. Three-dimensional (3D) micro CT analysis of the tibial metaphysis revealed that both male and female AT1a knockout mice exhibited an increased trabecular bone volume along with increased trabecular number and connectivity. Histomorphometric analysis of the tibial metaphysis indicated that the parameters of bone formation as well as resorption were increased, which was also supported by elevated serum osteocalcin and carboxy-terminal collagen crosslink (CTX) concentrations in the AT1a-deficient mice. Osteoclastogenesis and osteoblastogenesis assays in ex vivo cultures, however, did not reveal any intrinsic alterations in the differentiation potential of AT1a-deficient cells. Quantitative RT-PCR using RNA isolated from the tibia and femur revealed that the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) ratio and the expression of stromal cell-derived factor (SDF)1α were increased, whereas that of SOST was decreased in AT1a-deficient bone, which may account for the increased bone resorption and formation, respectively. AT1a-deficient mice also displayed a lean phenotype with reduced serum leptin levels. They maintained high bone mass with advancing age, and were protected from bone loss induced by ovariectomy. Collectively, the data suggest that RAS has a physiologic function in bone remodeling, and that signaling through AT1a negatively regulates bone turnover and bone mass.