Diabetes Insipidus and SIADH — Central vs Nephrogenic DI, Water Deprivation Test and Management

Diabetes insipidus (DI) is a clinical syndrome of passing abnormally large volumes of dilute (hypotonic) urine — the 'insipidus' refers to urine devoid of dissolved solutes — together with thirst. It results from insufficient arginine vasopressin (AVP, ADH) secretion or from a poor renal response to it. Polyuria is defined as urine output above 3 L/day in adults (or 2 L/m² in children); nocturia and polydipsia are the usual complaints.

Newer literature has renamed the two forms: central DI is 'AVP deficiency' (AVP-D) and nephrogenic DI is 'AVP resistance' (AVP-R). The reason for the rename is that using 'diabetes' for both this and diabetes mellitus has confused patients and carers. In older textbooks and in most exam options you will still see the classic names, so know both.

ADH is synthesised in the hypothalamus as a precursor and stored in and released from the posterior pituitary. Its main job is osmoregulation: a rise in plasma osmolality stimulates AVP release (and thirst), and a large fall in effective blood volume can also shift ADH towards volume regulation. In the kidney, AVP binds V2 receptors on the basolateral membrane of principal cells in the late distal tubule and collecting duct. A G protein couples the receptor to cAMP generation, which inserts aquaporin-2 (AQP2) water channels into the apical membrane so that water is reabsorbed and urine is concentrated.

• Too little ADH, or a receptor that cannot respond → water is not reabsorbed → large volumes of dilute urine → DI.
• Too much ADH → water is retained → concentrated urine and a diluted plasma → SIADH.
• The posterior pituitary can synthesise far more AVP than the body needs, so 80% to 90% of the hypothalamic neurons must be destroyed before polyuria appears.

In central DI the posterior pituitary does not release enough AVP in response to osmotic stimulation and falling blood pressure. The causes cluster into acquired, idiopathic and genetic.

Adipsic DI develops when the same lesion also damages the hypothalamic osmoreceptors that drive thirst. The patient does not feel thirsty, so moderate to severe hypernatraemia develops and mortality is high. After neurosurgery, most polyuria is not DI: it is usually excess fluid given during surgery or an osmotic diuresis from mannitol or glucocorticoid-induced hyperglycaemia.

In nephrogenic DI the AVP level is adequate but the kidney does not respond. In children the commonest cause is the hereditary form; in adults chronic lithium use and hypercalcaemia predominate.

• X-linked: about 90% of hereditary nephrogenic DI is due to mutations in the AVPR2 gene (V2 receptor), located at Xq28.
• Lithium: about 20% of patients on chronic lithium develop polyuria. Lithium enters principal cells through the epithelial sodium channel (ENaC) and impairs the signalling that inserts AQP2.
• Metabolic: hypercalcaemia and hypokalaemia.
• Other drugs: demeclocycline, cidofovir, foscarnet, amphotericin B, ofloxacin, ifosfamide and orlistat. Drug-induced AVP resistance is typically at least partly reversible.
• Chronic kidney disease (vascular, inflammatory or neoplastic) and polycystic kidney disease are other acquired causes.

Gestational DI occurs in about 1 in 30,000 pregnancies. A placental enzyme, cysteine aminopeptidase (vasopressinase), degrades AVP; its level is up to 300 times higher in pregnancy and higher still in twins. Hormone levels are often normal, suggesting that pregnancy unmasks a subtle underlying deficiency. Desmopressin (DDAVP) is considered safe in pregnancy.

Primary polydipsia is excessive water intake that suppresses AVP, producing hypotonic polyuria. It is the main alternative diagnosis. Dipsogenic DI is a low hypothalamic thirst threshold, and these patients are prone to water overload and have very low AVP. Hypothalamic disease (sarcoidosis, tuberculosis, trauma, tumours), and psychiatric disorders or their treatment (anticholinergic dry mouth) can lower the thirst threshold.

Diagnosis follows an algorithm: (1) confirm hypotonic polyuria, (2) classify the polyuria–polydipsia syndrome, (3) find the cause. Step 1 separates water diuresis from osmotic diuresis (for example hyperglycaemia). A 24-hour urine output below 2.5 L is reassuring, and a urine osmolality above 800 mOsm/kg indicates adequate AVP and renal response, ruling out DI.

In step 2 the water deprivation test (a 7-hour test is usually adequate; primary polydipsia may need longer) rests on a simple principle. Dehydration raises plasma osmolality, which in a normal person (or in primary polydipsia) releases AVP and concentrates the urine. In DI of either type the urine stays dilute despite rising plasma osmolality. Desmopressin is then given to distinguish the two forms.

Measuring AVP directly is cumbersome (rapid clearance and a turnaround of 3 to 7 days). Copeptin, the C-terminal part of pro-vasopressin co-secreted with AVP, is far more stable and easier to measure. A hypertonic saline (3%) infusion test with copeptin is increasingly recommended in place of the water deprivation test. In step 3, central DI needs MRI of the sella and suprasellar region to look for the cause, while nephrogenic DI needs a drug review and checks for hypercalcaemia and hypokalaemia.

A thiazide helps in nephrogenic DI by causing mild volume contraction: less water is delivered to the collecting duct, where ADH acts, and endogenous aldosterone rises. NSAIDs inhibit prostaglandin synthesis, which normally opposes ADH. Patients on desmopressin must be monitored for hyponatraemia because water retention can cause brain injury; teach them to report nausea, vomiting, lethargy, headache, confusion or seizures.

SIADH is unsuppressed ADH release (from the pituitary or a non-pituitary source) or continued ADH action on its receptors. It was first described by William Schwartz and Frederic Bartter in two patients with lung cancer. The result is water retention with euvolaemic hyponatraemia and inappropriately concentrated urine.

• Malignancy: small-cell lung cancer is the commonest tumour causing ectopic ADH; also extrapulmonary small-cell carcinoma, head and neck cancers and olfactory neuroblastoma.
• Drugs: carbamazepine, oxcarbazepine, chlorpropamide, cyclophosphamide and SSRIs. Carbamazepine and oxcarbazepine act partly by increasing sensitivity to ADH.
• CNS and pulmonary disease, and surgery are other recognised causes.

Correction speed matters. For SIADH the rise should not exceed about 8 mEq/L per 24 hours (or 0.5 to 1 mEq/L per hour) because faster correction risks osmotic demyelination. Traditional guidance for hyponatraemia in general was a maximum of 10 to 12 mEq/L in 24 hours. For hypernatraemia, including DI, the goal is to lower sodium by not more than 10 to 12 mEq/L in 24 hours. For the full sodium approach, see sodium disorders.

Related reading: body fluid compartments, the counter-current mechanism and pituitary tumours.