Polyuria–polydipsia syndrome characterized by hypotonic polyuria (excessive urination) and compensatory polydipsia (excessive drinking of water).
Less than 10% of DI is hereditary. X-linked nephrogenic DI (NDI) accounts for 90% of cases of congenital NDI
Etiopathogenesis
Associated with inadequate arginine vasopressin (AVP) or antidiuretic hormone (ADH) secretion or renal response to AVP, resulting in hypotonic polyuria and a compensatory/underlying polydipsia.
Pathophysiology of DI: Diabetes insipidus (DI) is a form of polyuria–polydipsia syndrome, which is caused by various acquired or hereditary lesions or disorders. Central DI results from inadequate production and/or secretion of arginine vasopressin (AVP)
in the hypothalamic–neurohypophyseal system in response to osmotic stimulation. Acquired central DI is caused by disruption of the neurohypophysis, whereas hereditary central DI is due to mutations in AVP. Nephrogenic DI is the result of an inadequate response of the kidneys to AVP, either acquired (as an adverse effect of various drugs or due to electrolyte disorders) or hereditary (due to mutations in the genes encoding arginine vasopressin receptor 2 (AVPR2) or the water channel aquaporin 2 (AQP2)). In primary polydipsia, excessive fluid intake that leads to polyuria occurs, even when AVP secretion and an appropriate antidiuretic renal response are present. In gestational DI, increased activity of arginine vasopressinase during pregnancy reduces the levels of AVP, leading to a presentation similar to that of central DI. | Christ-Crain, M., Bichet, D.G., Fenske, W.K. et al. Diabetes insipidus. Nat Rev Dis Primers 5, 54 (2019). https://doi.org/10.1038/s41572-019-0103-2
All four forms of polyuria–polydipsia syndrome result in a water diuresis due to an inability to maximally concentrate urine
Etiology of polyuria–polydipsia syndrome | Christ-Crain, M., Bichet, D.G., Fenske, W.K. et al. Diabetes insipidus. Nat Rev Dis Primers 5, 54 (2019). https://doi.org/10.1038/s41572-019-0103-2
Central DI (hypothalamic/neurogenic DI) (M/C form):
Results from inadequate secretion and usually deficient synthesis of arginine vasopressin (AVP) in the hypothalamic–neurohypophyseal system in response to osmotic stimulation
Usuyally secondary to surgery or head injury which causes traumatic injury to the hypothalamus or posterior pituitary gland and destruction/degeneration of neurons originating in the supraoptic and paraventricular nuclei of the hypothalamus
Pathogenetic mechanisms in acquired central DI: In the triphasic response, the first phase of central diabetes insipidus (DI) occurs after pituitary stalk damage that severs the connections between the cell bodies (in the hypothalamus) and axons (in the posterior pituitary gland) of the arginine vasopressin (AVP)-producing magnocellular neurons, which prevents stimulated secretion of AVP (step 1). This is followed in several days by the second phase, syndrome of inappropriate antidiuretic hormone secretion (SIADH), which is caused by uncontrolled release of AVP
from the degenerating nerve terminals in the posterior pituitary gland into the bloodstream (step 2). After all stored AVP in the posterior pituitary gland has been released, the third phase of DI occurs if the cell bodies of >80–90% of the AVP- producing neurons in the hypothalamus undergo retrograde degeneration (step 3). Similar pathogenetic mechanisms underlie autoimmune and inflammatory aetiologies of central DI that result in destruction of axons and cell bodies of AVP- producing neurons, and rapid enlargement of anterior pituitary lesions (for example, metastatic lesions and pituitary apoplexy) that compress the axons of AVP- producing neurons. | Loh, J. A. & Verbalis, J. G. Disorders of water and salt metabolism associated with pituitary disease. Endocrinol. Metab. Clin. North Am. 37, 213–234 (2008).
Nephrogenic DI:
Result of an inadequate response of the kidneys to AVP, either due to mutations in AVP receptor 2 (AVPR2) or aquaporin 2 (AQP2) (hereditary nephrogenic DI) or as an adverse effect of various drugs, most commonly lithium, or due to electrolyte disorders, such as hypercalcaemia or hypo-kalaemia (acquired nephrogenic DI).
Children usually present with the inherited form whereas adults present with the acquired form of NDI. In most cases (90%), inherited NDI is an X-linked condition caused by a loss-of-function mutation in the V2R gene.
Pathogenetic mechanisms in nephrogenic DI: a) Mechanism of arginine vasopressin (AVP)-stimulated osmotic water permeability in principal cells of the collecting duct. AVP binding to the G protein-coupled receptor AVP receptor 2 (AVPR2) results in increased production of cAMP by adenylyl cyclase 6, thereby activating protein kinase A and inducing phosphorylation of target proteins, including the water channel aquaporin 2 (AQP2). These phosphorylations promote fusion of AQP2-containing vesicles with the apical plasma membrane of the principal cells, and thereby increased AQP2 levels, resulting in increased water uptake from the urine. The basolateral plasma membrane expresses AQP3 and AQP4, making it constitutively water- permeable. b) Mechanisms of nephrogenic diabetes insipidus (DI) caused by lithium, hypokalaemia and hypercalcaemia or hypercalciuria. Entry of lithium into the principal cell inhibits glycogen synthase kinase 3β (GSK3β), reducing expression of AQP2 (which forms tetramers). Hypokalaemia and hypercalcaemia or hypercalciuria cause autophagy-mediated degradation of monomeric AQP2 and UTA1. Hypercalciuria may activate the calcium-sensing receptor (CaSR), which increases intracellular Ca2+ levels and enhances basal autophagy by one or more mechanisms. Autophagy is initiated by the formation of phagophores, which engulf AQP2, UTA1 and other cytoplasmic proteins (including junctional and cytoskeletal proteins), as well as dysfunctional organelles (such as damaged mitochondria). Phagophores elongate and close to generate double-membrane autophagosomes, which then fuse with lysosomes to form single- membrane autolysosomes, thereby delivering cargo for degradation. As a result, decreased abundance of AQP2 and UTA1 leads to impaired urinary concentrating ability. | Part a: Bockenhauer, D. & Bichet, D. G. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat. Rev. Nephrol. 11, 576–588 (2015). This article is a detailed review of nephrogenic DI, including the importance of early genetic testing and clinical management. | Part b: Khositseth, S. et al. Hypercalcemia induces targeted autophagic degradation of aquaporin-2 at the onset of nephrogenic diabetes insipidus. Kidney Int. 91, 1070–1087 (2017).
Gestational DI
Results from the enzymatic breakdown of endogenous AVP by increased placental vasopressinase levels in pregnancy.
Models of pathogenesis in primary polydipsia in schizophrenia and gestational DI: a) Primary polydipsia.
Findings pertain to schizophrenia patients with primary polydipsia with and without the psychosis intermittent hyponatraemia–polydipsia syndrome (PIP). The figure highlights the initial unexplained observations suggesting that the life-threatening water imbalance in patients with PIP was directly linked to their psychotic disorder, as well as subsequent studies that provide plausible pathophysiological mechanisms arising from disruption of recognized mammalian neural functions. The structural and functional findings support the view that the more- disrupted neuroendocrine function in patients with PIP than in non–PIP polydipsic patients is due to more- extensive pathological changes in the anterior lateral hippocampus, whereas non–polydipsic patients have structural changes on the anterior medial surface which do not interfere with their normal hippocampus- mediated compensatory neuroendocrine responses to chronic psychological stress. b) Gestational diabetes insipidus (DI) is caused by increased degradation of arginine vasopressin (AVP) by placental vasopressinase, which results in a presentation resembling that in central DI. Placental vasopressinase is produced by placental trophoblasts and is detectable by 10 weeks of gestation. Circulating vasopressinase levels increase about 300-fold over the following weeks, peaking in the third trimester, remain higher during labour and delivery and return to undetectable levels around the second week postpartum. AH, anterior hippocampus. | Christ-Crain, M., Bichet, D.G., Fenske, W.K. et al. Diabetes insipidus. Nat Rev Dis Primers 5, 54 (2019). https://doi.org/10.1038/s41572-019-0103-2
Presentation
Onset of CDI can be abrupt (due to insult to the body) or gradual (due to tumor or idiopathic causes). The age of onset and the severity of the disease can differ among patients who have congenital disease.
Polyuria: Excessive urination
Compared with other forms of DI, patients with central DI more often describe nocturia and a sudden onset of symptoms, as urinary concentration can often be maintained fairly well until the residual neuronal capacity of the hypothalamus to synthesize AVP falls below 10–15% of normal capacity, after which urine output increases dramatically
Polyuria: > 50 ml/kg body-wt/24 h | osmolality <300 mOsm/L)
Compensatory polydipsia:
Most patients with an intact hypothalamic thirst centre maintain their fluid balance by drinking water. But patient who are unable to access free water as seen in neonates and elderly present with clinical features of hypernatremia and dehydration
Excessive drinking: > 3 l/day
Other symptoms:
Dizziness, weakness, nocturia, fatigue
Signs of dehydration: Fever, dry skin and mucus membranes, weight loss, poor skin turgor
Congenital DI:
Severe dehydration, vomiting, constipation, fever, irritability, sleep disturbances, retardation of growth, and failure to thrive
Mental retardation (caused by repeated and unrecognized dehydration)
Diagnosis
Modified algorithm for differential diagnosis of polyuria–polydipsia syndrome: In a first step, polyuria must be confirmed, otherwise polyuria–polydipsia syndrome is excluded and genitourinary (GU) evaluation is needed. In case of polyuria and a urinary osmolality <800 mOsm/kg, serum sodium and plasma osmolality are measured. If these levels are inthe normal range, further differentiation is done using either a classical water deprivation test or a copeptin- based algorithm (if copeptin measurement is available). | DI, diabetes insipidus. | Gubbi, S.,
Hannah- Shmouni, F., Koch, C.A. & Verbalis, J.G. in Endotext (eds. Feingold, K.R . et al.). https://www.ncbi.nlm.nih.gov/books/NBK537591/ or at Endotext.org.
Water deprivation test “Hare-Hickey test” and desmopressin (DDAVP) trial:
Indirect assessment of AVP activity by measurement of the urine concentration capacity during a prolonged period of dehydration and again after a subsequent injection of an exogenous synthetic AVP analogue, desmopressin
During water deprivation, hourly measurements of body weight and urine osmolality are made, until 2–3 samples vary by <30 mOsm/kg (or <10%), or until the patient loses 5% of his/her body weight. Serum ADH is then measured and ADH/desmopressin (5 units) is injected. Urine osmolality is measured 30–60 min after this. The test is discontinued if the patient loses >5% of his/her body weight and/or plasma Na+ exceeds 143 mEq/L and/or urine osmolality increases to normal. Response to the administration of desmopressin distinguishes between CDI and NDI.
Different patterns to water restriction and desmopressin administration will help to discriminate between the different causes of polyuria | Saifan, C., Nasr, R., Mehta, S., Sharma Acharya, P., Perrera, I., Faddoul, G., Nalluri, N., Kesavan, M., Azzi, Y., & El-Sayegh, S. (2013). Diabetes insipidus: a challenging diagnosis with new drug therapies. ISRN nephrology, 2013, 797620. https://doi.org/10.5402/2013/797620
Graphical representation of the water deprivation test. | Image courtesy: Sriram Gubbi, NIDDK, NIH. | Gubbi S, Hannah-Shmouni F, Koch CA, et al. Diagnostic Testing for Diabetes Insipidus. [Updated 2019 Feb 10]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537591/
Hypertonic saline infusion:
Alternative to water restriction test
Plasma AVP and serum Na levels in response to hypertonic saline injection. In normal subjects, plasma AVP levels increase in proportion to increases in serum Na levels. In CDI patients, the response of AVP is abolished. Note that serum Na levels are around 140 mEq/L in normal subjects but around 145 mEq/L in CDI patients before hypertonic saline injection. | Arima, H., Azuma, Y., Morishita, Y., & Hagiwara, D. (2016). Central diabetes insipidus. Nagoya journal of medical science, 78(4), 349–358. https://doi.org/10.18999/nagjms.78.4.349
Baseline copeptin levels:
Copeptin, the C- terminal segment of the AVP prohormone, is an easy- to-measure AVP surrogate that is very stable ex vivo. As the serum copeptin level reflects the osmosensitive circulating AVP concentration, it is a promising biomarker for differential diagnosis of polyuria–polydipsia syndrome.
Central DI (partial and complete): <4.9 pmol/L (after hypertonic saline infusion)
Nephrogenic DI (partial and complete): Baseline copeptin value of >21.4 pmol/L
Complete central DI: <2.6 pmol/L
Post-transcription processing of vasopressin and related peptides: The pre-pro-vasopressin is a peptide consisting of 164 amino acids. This pre-pro-hormone is then converted to pro-vasopressin after the removal of the signal peptide and N-linked glycosylation of copeptin. Further processing of pro-vasopressin gives rise to the individual peptides: arginine vasopressin (AVP), neurophysin II (NP II), and copeptin. | Image courtesy: Sriram Gubbi, NIDDK, NIH. | Gubbi S, Hannah-Shmouni F, Koch CA, et al. Diagnostic Testing for Diabetes Insipidus. [Updated 2019 Feb 10]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537591/
MRI:
MRI Appearance of Posterior Pituitary in Hypothalamic/Cranial DI | Ball S. Diabetes Insipidus. [Updated 2018 Jun 13]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279011/
Differential diagnosis:
Primary polydipsia (PP): Characterized by excessive fluid intake that leads to polyuria, despite intact AVP secretion and an appropriate ADH renal response.
Mild cases of DI may not even need treatment and sufficient water intake may suffice. The removal of aggravating factors (e.g.,: reductions in glucocorticoids that directly cause free water clearance) improves polyuria.
DDAVP (1-deamino-8-arginine vasopressin):
DRUG OF CHOICE for the long-term management of central DI. It is a synthetic, long-acting vasopressin analog with minimal pressor activity but has nearly two-fold antidiuretic potency of arginine vasopressin.
Other drugs:
Summary of drugs used for the treatment of diabetes insipidus | Kalra, S., Zargar, A. H., Jain, S. M., Sethi, B., Chowdhury, S., Singh, A. K., Thomas, N., Unnikrishnan, A. G., Thakkar, P. B., & Malve, H. (2016). Diabetes insipidus: The other diabetes. Indian journal of endocrinology and metabolism, 20(1), 9–21. https://doi.org/10.4103/2230-8210.172273
Nephrogenic DI:
Treatment involves pharmacological management with salt restriction
Diabetes insipidus (DI) is a disorder characterized by excretion of large amounts of hypotonic urine. Central DI results from a deficiency of the hormone arginine vasopressin (AVP) in the pituitary gland or the hypothalamus, whereas nephrogenic DI results from resistance to AVP in the kidneys. Central and nephrogenic DI are usually acquired, but genetic causes must be evaluated, especially if symptoms occur in early childhood. | Diabetes insipidus. Nat Rev Dis Primers 5, 55 (2019). https://doi.org/10.1038/s41572-019-0114-z
