Diabetes insipidus and other polyuric syndromes

Chapter 51 Diabetes insipidus and other polyuric syndromes



Diabetes insipidus (DI: literal translation, ‘tasteless siphon’) refers to a syndrome characterised by pathological polyuria, excessive thirst and polydipsia. Polyuria is arbitrarily defined as a urine loss of > 3 l/day in an adult of normal mass. The urine produced in DI is inappropriately dilute, having both low specific gravity and low osmolality in the face of a high or normal plasma osmolality.


Three subtypes of DI are recognised:





A separate disorder is occasionally classified as a fourth form of DI – primary polydipsia (also called psychogenic or neurogenic polydipsia or polydipsic DI). This is caused by excessive water ingestion, usually due to psychological disturbance but occasionally associated with a lesion of the hypothalamus. In the context of hospital inpatients, a similar iatrogenic condition is created by overenthusiastic administration of intravenous solutions of dextrose 5% or hypotonic saline. Whilst water overload will reduce plasma osmolality and reduce the ability of the kidney to concentrate urine maximally, the diuresis of hypo-osmolar urine seen with water overload is not pathological but physiological and appropriate. In this instance, plasma osmolality is low or in the low-normal range and the body is attempting to restore plasma osmolality to normality by reducing water reabsorption in the kidneys and inducing a water diuresis.


In critically ill patients, polyuria may be the sole part of the DI syndrome apparent to the clinician. Patients are seldom in control of their own fluid intake and are frequently unable to report thirst. The recognition of DI is important as failure to recognise and treat the syndrome appropriately will result in severe dehydration and hyperosmolality with a significant risk of morbidity and mortality. As there are many causes of polyuria in the critically ill (Table 51.1), it is important to adopt a systematic approach to the clinical assessment, investigations, diagnosis and management of such patients.


Table 51.1 Causes of polyuria































































Water diuresis
Pathological
Diabetes insipidus: cranial, nephrogenic, gestational
Physiological
Psychogenic polydipsia (excess drinking is pathological but the diuresis is not)
Iatrogenic – excessive administration of hypotonic solutions, e.g. 5% dextrose solution, 0.45% saline, 0.18% saline 4% dextrose solutions
Solute diuresis
Pathological
Fanconi’s syndrome
Renal tubular acidosis
Glomerulonephritis
Hyperaldosteronism
Anorexia nervosa
Migraines
Paroxysmal tachycardia (via increased atrial natriuretic peptide release)
Poisons/drugs:
Ethanol
Methanol
Ethylene glycol
Mannitol
Loop diuretics
Thiazide diuretics
Hyperglycaemia
Physiological
Resolving sepsis (redistribution of fluid into the vascular compartment from the third space)
Iatrogenic – excessive administration of isotonic or hypertonic solutions, e.g.
0.9% saline
Hypertonic saline
Hartmann’s solution
Gelofusin

The classification as a solute or water diuresis is not always absolute; the table provides a convenient structure but a diuresis should be considered in terms of the individual patient and both physical and biochemical examinations. A diuresis may frequently represent the clearance of both an excess of water and solute, such as is usually the case following the resolution of septic shock with multiorgan failure.



BACKGROUND PHYSIOLOGY AND ANATOMY









OSMORECEPTORS AND OTHER INPUTS TO THE SUPRAOPTIC AND PARAVENTRICULAR NUCLEI


Detection of osmolality occurs largely at osmo- (Na+) receptors sited around the anterior aspect of the third ventricle of the brain. These are sensitive to plasma osmolality and cerebrospinal fluid sodium concentration. Hypertonic saline is a more potent stimulus than equi-isotonic equiososmolar solutions of other solutes.4 These osmoreceptors link to the cells of the paraventricular nuclei (PVN) and supraoptic nuclei (SON), the sites of ADH synthesis. The axons of the cells in the PVN and SON form part of the pituitary stalk linking the hypothalamus to the pituitary gland in which they terminate. A smaller proportion of the axons terminate in the median eminence where they release ADH and oxytocin, which is transported to the anterior lobe of the pituitary by portal vessels. The ADH and oxytocin so released cause release of adrenocorticotrophic hormone (ACTH) and prolactin respectively; the ADH acts synergistically with corticotrophin-releasing factor (CRF) but is also believed to have ACTH secretagogue properties in its own right.5,6


Direct inputs from the sympathetic nervous system to the PVN and SON can stimulate ADH release via α-adrenoreceptors. Other central osmoreceptors lie outside the blood–brain barrier in the subfornical organ and come into contact with plasma. It is believed that ANP and angiotensin II7 act via these receptors to inhibit or elicit ADH synthesis and ADH release and to modify the sensation of thirst. Additional osmoreceptors in the mouth, stomach and liver are believed to play a role in the anticipation of an osmolal load following ingestion of food and can pre-emptively stimulate ADH synthesis in the hypothalamus.


As the baroreceptor and osmoreceptor inputs to the PVN and SON are distinct, it is possible to lose the normal ADH response to hyperosmolality but maintain a normal ADH response to hypovolaemia.8 Additionally, in animal experiments, when hypotension increases the basal plasma ADH concentration, there is a simultaneous resetting of the osmomolality–plasma ADH response curve in an attempt to preserve osmoregulatory function from the new higher baseline.9 If this did not occur, the ADH response to hypotension would always result in the development of a hypo-osmolal state in addition to causing vasoconstriction.


The normal response of osmoreceptors to changing plasma osmolality in terms of ADH is illustrated in Figure 51.2. At plasma osmolalities of < 275 mosmol/kg, the osmoreceptors remain hyperpolarised and virtually no ADH release occurs via them. At osmolalities > 295 mosmol/kg, the osmoreceptors are maximally depolarised and plasma concentrations of ADH of > 5 pg/ml are attained. Other inputs and influences upon ADH release are summarised in Figure 51.3 and Table 51.2.




Table 51.2 Factors influencing antidiuretic hormone (ADH) release











































Increased ADH release with:
Hyperosmolality
Hypovolaemia
Hypotension
Hypoxia
Hypothyroidism
Hyperthermia
Positive-pressure ventilation
Pain
Emotional stress
Exercise
Nausea
Nicotine
Trauma/surgery
Decreased ADH release with:
Hypo-osmolality
Hypervolaemia
Hypertension
Ethanol
Cranial diabetes insipidus


ANTIDIURETIC HORMONE/ARGININE VASOPRESSIN (AVP)


ADH (8-arginine vasopressin) is a nine-amino-acid peptide which differs from oxytocin at only two residues but shares the disulphide bond between the first and sixth ones. This similar structure and conformation results in some cross-reactivity at receptors and in function.10 It is synthesised in the SON and PVN, bound to neuorophysin, transferred through axons to the posterior pituitary gland and stored in granules prior to release. Synthesis to replace any released stores is a rapid process (1–2 hours from synthesis to storage) and patients with damage to the pituitary can achieve near-normal plasma concentrations of ADH, in terms of osmoregulatory function, via release of newly synthesised ADH via the axons terminating in the median eminence. However, the higher plasma concentrations associated with hypovolaemia cannot be achieved. Normal osmoregulatory plasma ADH concentrations are in the range of 1–8 pg/ml but rise as high as 40 pg/ml in hypovolaemic patients under the influence of the sympathetic nervous system, baroreceptor responses and angiotensin II.


Once released from the pituitary, ADH has a plasma half-life of around 10–35 minutes.11 It is metabolised by hepatic and renal vasopressinases and around 10% of the active hormone is excreted unchanged in the urine.



ACTIONS OF ADH


ADH has antidiuretic, vasopressor, haemostatic and ACTH secretagogue actions. Additionally, it has roles in memory, water permeability of the blood–brain barrier, nociception, splenic contraction and thermoregulation. These actions are mediated through V1, V2 and V3 receptors. It also has actions on the uterus and mammary tissue mediated through oxytocin receptors. Cardiac inotropic effects are reported to be mediated through purinergic P2 receptors but this remains controversial.12



Antidiuresis


ADH binds to V2 receptors on the basal membranes of the principal cells of the collecting duct and distal tubule. The activated receptor induces production of cyclic adenosine monophosphate (cAMP) by adenylate cylase and this in turn activates protein kinases which effect the integration into the luminal membrane of vesicles containing aquaporin-2 highly selective water channels. The production of prostaglandin E2 (PGE2) inhibits cAMP production. PGE2 synthesis is stimulated by the action of ADH on V1 receptors on the luminal membrane of the collecting duct.13 Thus, a form of autoregulatory limitation of the antidiuretic effect of ADH may exist. Hypokalaemia, lithium and hypercalcaemia also anatagonise the renal actions of ADH.


ADH also increases the urinary concentrating ability of the kidney by increasing the expression of urea transport proteins in the collecting duct and reducing renal medullary blood flow (V1-mediated), facilitating an increase in medullary interstitial hypertonicity. This hypertonicity additionally depends upon intact functioning of the ascending loop of Henle where sodium and chloride are reabsorbed without absorption of water at the same time. Interference with this process reduces the osmolal gradient between the collecting duct and the interstitium and reduces water absorption even in the presence of ADH and functioning aquaporin-2.


In low dose, administration of exogenous ADH may paradoxically cause a diuresis in patients with septic shock.14 Whether this is due to increased renal perfusion pressure and raised glomerular filtration rate (GFR) is unclear.




Coagulation


ADH increases circulating levels of tissue plasminogen activator, factor VIII and von Willebrand factor.19 These effects may be mediated by V2 receptors but this remains controversial. At high but physiological concentrations it can act as a platelet-aggregating agent.20,21 Platelet aggregation is mediated through activation of platelet V1 receptors.22 ADH and its analogue DDAVP are used as first-line treatments in patients with von Willebrand’s disease, and may be used in bleeding associated with renal failure and platelet dysfunction.




VOLUME RECEPTORS


Volume homeostasis takes precedence over sodium homeostasis and so rises and falls in sodium will occur in order to preserve the circulating volume. In euvolaemic patients sodium homeostasis is maintained. Sodium concentration is detected by both the osmoreceptors of the subfornical organ outside the blood–brain barrier and also by the juxtaglomerular apparatus which secretes renin in response to reduced GFR and a lower sodium load in the tubule.23


The predominant determinants of sodium balance, however, are the high-pressure baroreceptors in the pulmonary veins, left atrium, carotid sinus and aortic arch.24 Reduced stretch of these receptors increases sympathetic nervous system activity and activation of the renin–angiotensin–aldosterone system, resulting in reduced sodium excretion (via reduced GFR) and increased reabsorption of sodium in the proximal and distal convoluted tubules. Additionally, release of ADH can be stimulated, resulting in concomitant water retention. Conversely, stretch of the baroreceptors will result in a fall in sodium retention through reduced activity of the sympathetic nervous and renin–angiotensin–aldosterone systems. Stretch additionally results in the release of ANP and a natriuresis through reduced sodium reabsorption in the distal convoluted tubule and collecting duct. ADH release is reduced by the fall in sympathetic nervous tone from the baroreceptors. ADH secretion may also be inhibited by the action of ANP on cerebral osmoreceptors lying outside the blood–brain barrier.25


The role of low-pressure baroreceptors in the systemic venous circulation and right atrium is less clearly defined. When venodilatation occurs, as is seen in sepsis, or when there is a reduction in cardiac output, reduced baroreceptor signalling in the high-pressure system will result in both sodium and water retention, as outlined previously. This will expand the extracellular fluid compartment and potentially cause tissue oedema. As sepsis resolves, venous tone is restored, capillary leak reduces, an increase in the loading of the high-pressure baroreceptors results and a natriuresis takes place. Patients may become transiently polyuric as they clear the excess salt and water accumulated whilst shocked. During this physiological diuresis, plasma osmolality remains tightly within the normal range, provided that renal concentrating mechanisms have not been injured during the septic episode or by drug administration.



CRANIAL DIABETES INSIPIDUS




ACQUIRED CDI


Acquired CDI may be transient or permanent and can arise due to an absolute (complete) or relative (incomplete) lack of ADH. Complete central DI is usually associated with lesions above the level of the median eminence in the SON or PVN or of the neurohypophyseal stalk whereby the production of ADH in the hypothalamus is terminated.26 Permanent central DI tends to be associated with transecting, obliterating or chronic inflammatory lesions, whereas transient DI is more likely to be associated with acute inflammatory or oedematous lesions with some recovery of ADH secretion occurring as the inflammation or oedema resolves. An exception to this is the transient DI seen following excision or destruction of the posterior pituitary; ADH produced in the hypothalamus can still be released into the systemic circulation from capillaries in the median eminence.


In the past the majority of acquired non-traumatic CDI was categorised as idiopathic but it has become apparent that the majority of these cases are associated with abnormality of the inferior hypophyseal arterial system27 or autoimmune reactivity against ADH-producing cells.28 These findings may indicate causality or association.


When the normal release of ADH into the circulation in response to rising plasma osomolality is reduced or absent, inappropriately high urine volumes are passed and the urine osmolality becomes inappropriately low for the state of water depletion being suffered by the patient. Where ADH is entirely absent from the circulation, over 20 litres of very dilute urine (25–200 mosomol/kg) per day may be produced. If patients are unable to drink freely (most ICU patients) or their thirst mechanisms are impaired, profound dehydration will result very rapidly unless appropriate interventions are made by the physician.


Where ADH deficiency is relative rather than absolute, it is possible for the patient to concentrate the urine partially and values of 500–800 mosmol/kg would not be atypical. However, these osmolalities are inappropriately low relative to the plasma osmolality. In partial ADH deficiency volumes of urine as low as 3 l/day may be evidenced. These are still inappropriately high when assessed in terms of the solute excretion of the patient but are more difficult to recognise as being due to DI as there are many other causes of diureses of this magnitude. Additionally, extrinsic stimulants of ADH release (see Table 51.2) may have an antidiuretic effect, further complicating the diagnosis.


The plasma osmolality measured in central DI is usually in the higher regions of the normal range or very slightly supranormal. It is remarkably constant in those with free access to water and intact thirst mechanisms as they will drink huge quantities of water to regulate and maintain their water balance. Hyperosmolality or hypernatraemia suggest impaired sensation of thirst or inability to access water (see water deprivation test later) and can also be seen if patients are administered large quantities of isotonic saline or Hartmann’s solution to replace their hypotonic urine losses. If unrecognised and untreated, hyperosmolality and hypernatraemia may result in death.


CDI is usually associated with reduced production of ADH or damage to the normal release mechanisms of ADH. However, there can be dysfunction of the osmolality-sensing mechanism at receptor or intracellular signalling levels whilst actual ADH production and storage are normal. It is possible to have a normal release of ADH in response to baroreceptor detection of hypotension but subnormal release in response to hyperosmolality. This has been described in association with chronic hypernatraemia.29


The main recognised causes of central DI are listed in Table 51.3. A particularly common cause of DI seen in the ICU is traumatic or postsurgical brain injury. Transsphenoidal surgery for treatment of suprasellar tumours can result in DI in 10–70% of patients; the frequency parallels the magnitude of the tumour being removed. Additionally, transcranial surgery may cause the development of DI in the absence of a fall in plasma ADH. This is postulated to be due to the release of a hypothalamic ADH precursor which acts as a competitive antagonist of both ADH and synthetic analogues. The presence of a competitive antagonist effectively creates an endocrinologice picture similar to NDI with normal or high plasma ADH levels but an inappropriate diuresis of dilute urine.


Table 51.3 Causes of cranial diabetes insipidus



























































Acquired
Idiopathic
Autoimmune
Tumours (especially suprasellar, lung, breast, lymphoma and leukaemia)
Surgery (especially transsphenoidal surgery)
Traumatic head injury (strongly associated with base-of-skull fracture*)
Hypoxic brain injury
Brainstem death
Electrolyte disturbance – profound hyponatraemia
Radiotherapy
Drugs – amiodarone, lithium (lithium more likely to cause nephrogenic diabetes insipidus)
Inflammatory/infectious diseases
Sickle-cell disease
Tuberculosis
Abscesses
Encephalitis
Meningitis
Sarcoidosis (may also cause nephrogenic diabetes insipidus)
Wegener’s granulomatosis
Histiocytosis X
Vascular disease
Ischaemic or haemorrhagic strokes
Aneurysmal bleeds (especially anterior communicating artery subarachnoid haemorrhage)
Sheehan’s syndrome
Pituitary apoplexy
Congenital
Autosomal-dominant mutations of antidiuretic hormone expression (despite the dominant expression of the gene, the onset of clinical diabetes insipidus may take up to 30 years to develop)
Wolfram syndrome – autosomal-recessive condition characterised by diabetes insipidus, diabetes mellitus, optic atrophy and deafness

* Doczi T, Tarjanyi J, Kiss J. Syndrome of inappropriate antidiuretic syndrome after head injury. Neurosurgery 1982; 10: 685–8.


Repaske DR, Medlej R, Gulteken EK et al. Heterogeneity in clinical manifestation of autosomal dominant neurohypophyseal diabetes insipidus caused by a mutation encoding Ala1-Val in the signal peptide of the arginine vasopressin/neurophysin II/copeptin precursor. J Clin Endocrinol Metab 1997; 82: 51–6.


Following surgery or traumatic brain injury, several different patterns of polyuria can be seen: immediate permanent or transient polyuria, initial normal or low urine production followed by transient or permanent polyuria, or initial low followed by normal urine output. Additionally, a classical triphasic pattern of urine output may be observed with:


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Jul 7, 2016 | Posted by in CRITICAL CARE | Comments Off on Diabetes insipidus and other polyuric syndromes

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