Diabetes insipidus

Introduction

• Pathological polyuria, excessive thirst and polydipsia
• Polyuria = >3L/day
• Urine is inappropriately dilute with low specific gravity and low osmolality despite normal or high plasma osmolality
• Three subtypes
• Nephrogenic – Insensitivity of kidneys to ADH
• Central – Reduced or absent ADH release
• Gestational – Increased placental production of vasopressinase
• In the critically ill, polyuria is usually the only clue to diagnosis

Pathophysiology

• In 75kg male, there is obligatory loss of 800mmol of solute (300mmol urea and 500mmol of cations/anions
• Maximum concentrating ability of kidneys is 1200mosm/kg; consequently a minimum of 666mL of urine is required per day to excrete osmotically active solutes
• Insensible water losses equate to 10mL/kg/day (higher with fever)
• Urinary osmolality – 500-700mOsm/kg 
• Given obligatory solute load to be excreted is relatively constant, the urine osmolality falls in response to increased water intake and rises in response to dehydration
• Minimum osmolality achievable in humans is 25mOsm/kg

• Water diuresis = Total solute in urine excreted per day is within normal range but osmolality of urine is low
• Osmotic/solute diuresis = Total solute passed per day is higher than normal, and urine passed is usually iso-osmolar with plasma if hypervolaemic OR hyperosmolar if patient is hypo- or euvolaemic
• ADH
• Acts at principal cells to increase aquaporin-2 channel membrane localisation to increase water reabsorption
• Also increases urinary concentrating ability by increasing expression of urea transport proteins in the collecting duct and reduced renal medullary blood flow

Water diuresis

• Pathological
• Diabetes insipidus
• Physiological
• Psychogenic polydipsia
• Iatrogenic

Solute diuresis

• Pathological
• Fanconi’s, RTA, GN, hyperaldosteronism, anorexia nervosa, migraines, paroxysmal SVT (ANP release), ethanol, methanol, ethylene glycol, mannitol, loop diuretics/ thiazides, hyperglycaemia
• Physiological
• Resolving sepsis/third-spacing
• Iatrogenic – N/Saline, Hartmann’s, Hypertonic saline

Differentiating

• Urine solute excretion in 24 hours
• >600-900mosm/day = solute diuresis
• Spot urine osmolality >300 suggests solute diuresis

Plasma and urine osmolality

• If high plasma osmolality (>295mosm/L), urine osmolality should be high

(1000-1200mosmol/kg)

• Urine osmolalities less than this suggest renal concentrating impairment (DI) or medications that reduce renal interstitial hypertonicity e.g. loop diuretics
• If urine osmolality <150 in this setting = DI (provided no gross solute or fluid overload)
• If polyuric, high plasma osmolality and high urine osmolality achieved, this implies osmotic diuresis
• If osmolar gap >10 = toxic alcohols/mannitol/sorbitol
• If osmolar gap <10 = hyperglycaemia, hyperkalaemia, hypernatraemia

Neurogenic DI

• Congenital
  • Rare and usually autosomal dominant
  • May present up to middle age
  • Acquired
  • May be transient or absolute
  • If entirely absent, can lead to up to 20L of very dilute urine production per day (25-200mOsm/kg)
  • If partially absent, can still concentrate urine to 500-800mOsm/kg (but still inappropriately low compared to plasma osmolality)
  • Plasma hyperosmolality and hypernatraemia suggest impaired thirst mechanisms or access to fluids or large volume isotonic fluid administration to replace hypotonic losses
• Acquired
  • Autoimmune, tumours, surgery, BOS fracture, hypoxic brain death, radiotherapy, amiodarone, lithium (although more commonly nephrogenic), sickle cell, TB, meningoencephalitis, stroke, aneurysmal bleed ACom), Sheehan’s, pituitary apoplexy

• Treatment
  • Manage associate anterior pituitary dysfunction
  • Detect and manage hypernatraemia
  • Replace any deficit in total body water
  • Underlying deficiency of ADH must be addressed
  • Anterior pituitary dysfunction
    • Hydrocortisone 100mg if suspected. May worsen polyuria but will improve cardiovascular stability
  • Hypernatraemia
    • If euvolaemic, provide DDAVP or AVP, fluid restrict and replace previous hour’s urine output with appropriate fluid to ensure Na does not drop >0.5mmol/hr
    • Avoid any fall >5mmol in 24 hours ! Dehydration and hypovolaemia
    • If shocked and hypernatraemic – resuscitate with N/saline with frequent reassessments of plasma sodium
    • If >155, consider N/saline + hypertonic saline to avoid abrupt drop in plasma Na

Nephrogenic DI

• Congenital
  • X-linked recessive
  • Traps V2 receptor intracellularly
  • Early diagnosis and management are essential to avoid hypernatraemia and dehydration in infants/children
• Acquired
  • Lithium is most common
  • 20% of patients on chronic lithium therapy suffer polyuria
  • Taken up into principal cells via sodium channels and inhibits adenylate cyclase to inhibit effect of ADH
  • Also reduces interstitial medullary hypertonicity
  • Hypercalcaemia, hypokalaemia, post-obstructive and hypoproteinaemia are other causes of acquired nephrogenic DI

• Treatment
  • Stop any drug
  • Correct hypokalaemia, hypercalcaemia and hypoproteinaemia
  • Reduce solute load if possible (reduces volume of urine required to clear)
  • Reduce salt intake (<100mmol/day)
  • Reduce protein intake (but still providing minimum daily requirements)
  • Closely monitor fluid balance and ensure appropriate replacement
  • Thiazides
    • Cause solute loss > water and a drop in intravascular volume which leads to RAS stimulation and a fall in GFR and ANP
    • Less solute reaches collecting duct principal cells and urine volume falls
  • Amiloride
    • Causes further slight drop in urine volume and combats the hypokalaemia seen with thiazides
    • Blocks sodium channels through which lithium reaches intracellular principal cells
  • ADH
    • If not absolute, supplemental ADH can be effective
  • NSAIDs
    • Reduces renal PGE2 to reduce GFR and urine flow

Last Updated on October 8, 2021 by Andrew Crofton