Diabetes Insipidus

DI^1,2

• DI is characterized by polyuria (more than 50 mL/kg), dilute urine (osmolality less than 300 mOsm/L), and increased thirst, with fluid intake up to 20 L/day. If left untreated, DI causes hypovolemia, dehydration, and electrolyte imbalances. Infants may demonstrate failure to thrive and rapid dehydration during illness, and may develop short stature and dilation of the ureters and bladder when left untreated.
• DI presents in two primary forms: central (AVP-D) and nephrogenic (AVP-R) (Figure 1)
  • Central DI is characterized by a failure to concentrate urine due to an absence or insufficient production of ADH at the level of the central nervous system.
  • Nephrogenic DI is characterized by failure to concentrate urine due to diminished or a lack of effect of ADH at the level of the kidneys.
• There are two less common forms of DI: dipsogenic DI, which is caused by excessive thirst due to a low osmotic threshold, and gestational DI, which is caused by increased placental vasopressinase during pregnancy.
• ADH is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and transported to the posterior pituitary by the hypothalamo-neurohypophyseal tract.
• ADH is released by the posterior pituitary and regulates the osmolarity of body fluids. In the kidney, ADH opens aquaporins in the distal and collecting tubules (in a cyclic adenosine monophosphate-dependent mechanism), resulting in increased water resorption.

Laboratory Findings

• Urine osmolality less than 300 mOsmol/kg
• Urinary specific gravity <1.005
• Serum sodium more than 145 mEq/L
• Serum osmolality more than 300 mOsm/kg
• Plasma volume can be euvolemic (if allowed free access to fluids)

Central DI, also known as AVP-D^1-3

• Central DI is characterized by a lack of or insufficient production of ADH at the level of the posterior pituitary gland. The most common causes are:
  • Idiopathic (~30%)
  • Intracranial tumors (malignant or benign), of brain or pituitary gland (~25%)
  • Postoperative from cranial surgery (~20%)
  • Head Trauma (~16%)
• Desmopressin (DDAVP – a synthetic analogue of vasopressin) will increase urine osmolality more than 50%. Copeptin, which is derived from the same precursor as vasopressin, can also be measured in adults, and will be less than 4.9 pmol/L following osmotic stimulation (water deprivation and 3% saline infusion).

Nephrogenic DI, also known as AVP-R^1-3

• In nephrogenic DI, the body may produce a normal amount of ADH at the level of the central nervous system, but ADH is unable to exert its intended action at the level of the renal tubules. This can result either from resistance at the site of ADH activity itself or from failure of the countercurrent mechanism (e.g., medullary injury).
• The most common causes are:
  • Hereditary nephrogenic DI in children
  • V1 (AVPR1) and V2 (AVPR2) receptor aberrancies; AVPR2 gene on X chromosome. ~90% of cases of hereditary NDI are related to the AVPR2 gene.
  • Chronic lithium ingestion
  • In ~20% of patients on chronic lithium therapy
  • Hypercalcemia in adults
  • Typically in the setting of persistent plasma calcium concentration more than 11 mg/dL
• Other causes:
  • Aquaporin-2 gene mutation
  • Severe hypokalemia
  • Disorders affecting the kidneys (e.g., sickle cell disease/trait, autosomal dominant polycystic kidney disease, medullary cystic kidney disease, renal amyloidosis)
  • Other drugs (e.g., foscarnet, clozapine, amphotericin B, orlistat)
  • Although rare, a 2020 review noted perioperative DI attributed to several anesthetic agents – most commonly dexmedetomidine, followed by sevoflurane, ketamine, and propofol.⁴
• DDAVP will increase urine osmolality less than 50%. Copeptin will be more than 21.4 pmol/L.

Management

Nephrogenic DI Management¹

• Patients with central and nephrogenic DI should have free access to drinking water to maintain hydration.
• Reversible causes of nephrogenic DI should be addressed and, if possible, the offending agent should be discontinued.
• Urine output can be reduced by a low-salt, low-protein diet, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs). Patients are commonly treated with a thiazide diuretic in combination with either amiloride or indomethacin. The increased renal sodium excretion results in extracellular volume contraction and lowered glomerular filtration rate with an accompanying increase in proximal tubular sodium and water reabsorption. NSAIDs inhibit prostaglandin synthesis, which has an antagonistic effect on ADH.
• In patients who are unable to respond to increased thirst (e.g., infants and very young children), water should be offered every 2 hours.
• Fluid replacement should be tailored carefully to the etiology of hypovolemia in nephrogenic DI patients. Replacement fluids with an osmolality higher than that of urine can cause hypernatremia. When patients present with emergent dehydration (e.g., due to diarrhea or vomiting), salt-containing solutions like 0.9% NaCl should be avoided. Hypotonic fluid infusions are preferred with a rate that matches physiological demand. If hypotonic fluids are given at a rate higher than the urine output, then hyponatremia can result. Isotonic fluids are recommended for acute fluid resuscitation in hypovolemic shock.⁵
• Although DDAVP is not the primary treatment for nephrogenic DI, it can sometimes be part of the treatment plan.

Central DI Management^2,3

• Unless there is a hypothalamic lesion/injury causing hypodipsia, patients with central DI are generally able to replace urinary water losses with oral intake.
• The primary therapy is DDAVP or vasopressin to control polyuria. However, water retention can cause hyponatremia; therefore, sodium levels must be closely monitored, particularly if concurrent illness, such as diarrhea or vomiting, is present.
• Other additional treatment options include thiazide diuretics, dietary changes, and NSAIDs.