5 Pearls on Hyponatremia Diagnostics

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Pearl 1 - General Approach

• Hyponatremia is a significant clinical problem:
  • MC electrolyte disorder, occurring in up to 30% of hospitalized patients
  • May result from:
    • Underlying medical conditions such as heart failure, liver failure, renal insufficiency, GI losses and SIADH 
    • Medications such as loop, thiazide, K-sparing diuretics, RAS-acting agents, ADH-stimulating drugs
  • Mild chronic hyponatremia associated with more frequent falls, which may be related to gait and attention impairments which have also been observed.
• Understand what each diagnostic test adds vs. rote dependence on algorithm
•  H&P – may be helpful, but don’t ignore other objective data that contradicts!
  • History:
    • Quickly assess for red flags (confusion, seizures) → immediate intervention, ICU admission
    • Ask about dietary history, fluid/EtOH intake, new meds, endocrine ROS, relevant comorbidities
  • Physical Examination:
    •  Volume status is theoretically helpful as diagnostic algorithms hinge on it, but error prone
• Our approach focuses on understanding what each diagnostic test adds vs. rote dependence on algorithm
  • More helpful given that most hyponatremia in the hospital is multifactorial
  • Ask yourself where your patient with hyponatremia is on “Cartesian space” with:
    • ADH secretion, as indirectly measured by UOsm relative to
    • Effective arterial blood volume (EABV), as estimated based on clinical examination and measurement of urine sodium
• What if we encounter a patient after intervention, and without complete labs?
  • Still obtain appropriate serum and urine studies as you can assess response to interventions (urine output, change in urine concentration and serum sodium) and the patient’s current ADH/EABV state

Pearl 2 – Serum Osmolality (Nl value 280-285 mOsm/kg)

• We expect patients with true hyponatremia to have a low osmolality (<275 mOsm/kg)
  • This makes sense because sodium is the most significant contributor to osmolality SOsm= 2 [Na⁺] + [Glu]/18 + [BUN]/2.8
• Serum osmolality can be thought of as a “quality check” to verify the hypothesis that low sodium is accompanied by low osmolality, as it should be.
  • If osmolality is normal assess if the patient has high triglycerides or a paraproteinemia (ex. Multiple myeloma, recent IVIG administration)
    • Such cases referred to as “pseudohyponatremia” – laboratory artifact that results on assumption that aqueous component of blood is 93%, with 7% serum particles (high lipids or extra protein changes this ratio)
    • Serum osmolality isn’t subject to this error (whole blood sample)
    • This type of “hyponatremia” is not of clinical significance
• If osmolality is elevated (usually >280-285), or if normal osmolality without elevated proteins/lipids, go looking for extra osmoles, either measured or unmeasured!
  • Measured: Severe hyperglycemia, BUN, (depending on equation) EtOH
  • Unmeasured: Toxic alcohols, iodinated contrast, sucrose
• Serum osmolality assessment prompts us to consider effective and ineffective osmoles at play:
  • Effective osmoles (sodium, glucose, potassium) do not cross the plasma membrane, and therefore cause shifts in water movement (have tonicity)
    • Ineffective osmoles (ethanol, urea, lactate) cross the plasma membrane more readily, and therefore do not cause shifts in water movement (do not have tonicity)
• Sodium and other effective osmoles, such as glucose do not cross the plasma membrane readily, and therefore cause shifts in water movement.
  • Most of the clinical complications that arise as a result of hyponatremia (and its correction) are driven by the fact that sodium is an effective osmole – it impacts tonicity, and therefore cell size.
• Serum osmolarity is not a serially measured lab!
  • Measure it once unless you are following clearance of an unmeasured osmole (such as a toxic alcohol) or if there is a significant sodium change that is difficult to contextualize.

Pearl 3 – Urine Osmolality is a window into ADH activity

• Urine osmolality (UOsm) is the nearest to a direct measure of ADH activity as we have in clinical practice (although copeptin has promise as a surrogate for ADH)

o   Range of possible urine osmolality in healthy kidneys is broad (50-1200 mOsm/kg)

o   ADH secretion results in resorption of free water in collecting duct, resulting in high urine Osm; ADH suppression results in low urine Osm

•  If ADH is not active, dilute urine results (UOsm <100-200). Low urine osmolality on presentation is indicative of:
  • Too little solute to keep up with reasonable fluid intake (tea-toast syndrome) 
  • Too much fluid to keep up with reasonable solute intake (primary polydipsia)
    • This is observed in up to 20% of psychiatric inpatients, and may be underestimated due to am lab testing
  • Some combination of low solute and high intake of hypo-osmolar fluid (beer potomania)
  • Can also occur in the setting of acute illness, where many patients will push large volumes of hypotonic fluids (i.e. sports drinks) in the setting of GI losses
• The story of hyponatremia is often the story of ADH activity; one study found that non-osmotic ADH release is present in 97% of patients with hyponatremia
  • ADH activity is reflected by UOsm >200-300 in patients with hyponatremia
  • ADH on? Next step is to figure out whether because of decreased EABV, increased osmolality, or independent of physiologic stimulus (see pearl 4 below)
• Remember that renal insufficiency impacts our ability to maximally dilute urine
  • Hyponatremia may develop as a result of acute or chronic renal failure for this reason
  • Renal insufficiency limits our ability to interpret UOsm as a direct window into ADH activity
• Change in UOsm (and urine output) can be assessed serially to determine response to treatment
  • If urine osmolality gently declines with volume resuscitation, this indicates that your intervention has resulted in suppression of ADH (proving hypothesis)
  • Heads up! If UOP and UOsm change dramatically in response to an intervention, this may be an early indicator a patient is correcting too quickly

Pearl 4 – Urine sodium, FeNa, FeUrea reveal RAAS activity

• UOsm gives us a window into ADH activity at a given time – it does not tell us why ADH is activated.
  •  Physiologic or “appropriate” ADH activity can occur in the following circumstances:
    •  Hyperosmolarity (readily apparent when serum Osm >285 mOsm/kg)
    • Low sensed effective arterial blood volume (may be hypovolemic or hypervolemic)
  • ADH activity that is not stimulated by one of the above mechanisms is by definition inappropriate (may occur in SIADH, adrenal insufficiency, hypothyroidism)
• Urine sodium is a window into activity of renin-angiotensin-aldosterone activity, which is more sensitive than ADH to low EABV states
  • Low EABV (hypovolemic or hypervolemic) → RAAS activation → UNa <20 mEq/L
  • SIADH → no RAAS activation → UNa >40
•  In patients with intermediate UNa (20-40 mEq/L), FeNa (and especially FeNa + FeUrea) is more sensitive for reflecting low EABV
  • FeNa <1% indicates RAAS is active, low EABV
  • Validated in oliguric patients, less reliable in patients putting out large quantity of dilute urine
• Caveats to UNa & FeNa use
  • Use of diuretics (thiazide or loop) increases UNa, in which case FeUrea <55% is a reasonable surrogate (and FeNa <0.5% + FeUrea < 55% better than either alone)
  • CKD impairs Na reabsorption, making UNa less helpful in this population
  • UNa will be low in patients with low Na diets (rare in US)

Pearl 5 – Urine uric acid is a tiebreaker for distinguishing between SIADH and other causes of hyponatremia

• Expected characteristics of uric acid in SIADH:
  • Serum uric acid → low <4 mg/dL
  • Urine uric acid → high
  • FeUricAcid → high >12%
• FeUricAcid may be a more helpful diagnostic test when trying to distinguish between causes of hyponatremia with low EABV and normal/elevated EABV (UCr X SUricAcid / SCr x UUricAcid x 100)
  • Patients with saline-responsive hyponatremia (increase Na by 5 mmol/L with 2L NS) have significantly lower FeUricAcid compared with saline non-responders (P<0.01)

Contributors

Shreya Trivedi, MD - Editor, Host

Martin Fried, MD - Editor, Host

Timothy Rowe, MD - Editor, Host

Jeffery William, MD - Guest Expert

John Hwang, MD - Guest Expert

Sean Burke, MD - Editor

Clem Lee, MD - Editor

Reviewers

Helbert Rondon, MD, MS, FACP, FASN, FNKF

Larissa Kruger Gomes, MD

None of the individuals in control of content for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

Release Date: February 10, 2021

Expiration Date: February 10, 2024

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