Renal Sodium and Water Regulation

Background Concepts

Fluid compartments

To understand renal sodium and water regulation, it is important to understand how water is normally distributed in the body.

Total body water (TBW):

• A percentage of lean body weight
• TBW accounts for: 
  • 60% of lean weight in men
  • 50% of lean weight in women

Intracellular fluid (ICF):

• All fluid enclosed within cells by their plasma membranes
• ⅔ of TBW

Extracellular fluid (ECF): 

• All fluid outside the cells
• ⅓ of TBW
• Divided into 2 sub-compartments: 
  • Intravascular fluid:
    • The fluid component of blood (also known as plasma)
    • ¼ of the ECF
    • Approximately 8% of the TBW (⅓ x ¼)
  • Interstitial fluid:
    • The fluid that surrounds cells that are not within the blood
    • ¾ of the ECF
    • Approximately 25% of the TBW (⅓ x ¾)

Osmolality

Plasma osmolality refers to the combined concentration of all solutes in the blood.

• Determinants of plasma osmolality:
  • Mostly determined by serum Na⁺ (sNa⁺)
  • Glucose and BUN contribute, but to a much smaller degree when in the normal range.
  • All other solutes contribute only a negligible amount → not included in formula
• Equation: Plasma osmolality = (2 x sNa⁺) + (glucose/18) + (BUN/2.8)
• Normal range: 275–295 mOsm/kg H₂O
• Regulation:
  • Osmoreceptors in the hypothalamus sense osmolality.
  • Important for water regulation

Tonicity

Plasma tonicity refers to the concentration of only the osmotically active solutes in blood and is often referred to as effective osmolality.

• Osmotically active solutes:
  • Do not equilibrate across a semipermeable membrane (these solutes cannot move freely across cell membranes)
  • Difference in concentrations on each side of membrane → creates an osmotic force
  • These solutes are called “effective osmoles.”
• Non-osmotically active solutes:
  • Do equilibrate across a semipermeable membrane (these solutes can move freely across cell membranes)
  • Equal concentrations on each side of membrane → no osmotic force
  • These solutes are called “ineffective osmoles.”
• Equation: effective plasma osmolality = (2 x sNa⁺) + (glucose/18)
  • Na⁺ and glucose are effective osmoles:
    • Plasma tonicity is mostly determined by sNa⁺.
    • Normal glucose concentrations do not contribute much to tonicity.
  • Urea (e.g., BUN) is an ineffective osmole → not considered for the tonicity equation 
  • Other effective osmoles contribute only a negligible amount → not included in the formula
• Regulation:
  • Osmoreceptors in the kidney sense tonicity.
  • Important for Na⁺ regulation
• Tonicity determines how water shifts between the body’s fluid compartments.
• Compared to normal plasma, a fluid may be:
  • Hypertonic: containing more osmotically active solutes in the fluid 
  • Isotonic: containing the same amount of osmotically active solutes in the fluid
  • Hypotonic: less osmotically active solutes in the fluid
• Tonicity can be discordant with plasma osmolality:
  • Renal failure → elevated BUN → ↑ plasma osmolality but normal tonicity
  • Ethanol intoxication (ineffective osmole) → ↑ plasma osmolality but normal tonicity

Disorders of water balance

• Total Na⁺ in the body determines the ECF volume:
  • Hypovolemia: volume is depleted → ↓ total body Na⁺
  • Hypervolemia: volume overloaded → ↑ total body Na⁺
  • Assessed on physical exam, and not sNa⁺ levels
• Disorders of water balance are characterized by abnormalities in the concentration of sNa⁺:
  • Hyponatremia: too much water
  • Hypernatremia: too little water
  • Both disorders can exist at any level of total body Na⁺.

Renal Sodium and Water Handling

A nephron is the functional unit of the kidney through which fluid and solutes, including Na⁺, are filtered, reabsorbed, and secreted.

Glomerulus and proximal tubule

• Glomerulus: Water and Na⁺ are freely filtered.
• Proximal tubule:
  • Approximately ⅔ of filtered water and Na⁺ are reabsorbed.
  • Tubular fluid is isotonic to plasma.

Thick ascending limb of the loop of Henle (TAL)

• Location of the sodium-potassium-chloride cotransporter 2 (NKCC2 cotransporter)
  • Na⁺, K⁺, and Cl^– are reabsorbed.
  • TAL is not permeable to water.
  • Water does not follow solutes (Na⁺, K⁺, Cl^–) into the medulla.
  • Generates an osmotic gradient between the tubular fluid and renal medulla 
• Tubular fluid is hypotonic to plasma.
• Known as a “diluting segment” (urine is diluted)

Distal convoluted tubule (DCT)

• Location of thiazide-sensitive NaCl cotransporter
  • Na⁺ and Cl^– are reabsorbed.
  • DCT is not permeable to water.
  • Water does not follow solutes (Na⁺, Cl^–) into the medulla.
  • Generates an even stronger osmotic gradient between the tubular fluid and renal medulla 
• Tubular fluid is even more hypotonic to plasma at this point.
• Another “diluting segment”

Collecting duct

• The segment primarily responsible for maintaining plasma osmolality by concentrating or diluting the urine
• Contains the aquaporin channels:
  • Allow water to move from the tubular fluid into renal medulla by diffusion
  • Renal medulla is hypertonic due to solute reabsorption in the diluting segments (TAL and DCT).
• Antidiuretic hormone (ADH) stimulates the production and insertion of aquaporins
  • ↑ ADH levels → ↑ aquaporins → ↑ water reabsorption → concentrated urine
  • ↓ ADH levels → ↓ aquaporins → ↓ water reabsorption → dilute urine

Sodium Regulation

Overview

The body regulates Na⁺ balance by sensing changes in the effective circulating volume (ECV), which is also known as the effective arterial blood volume (EABV).

• The ECV is the portion of the intravascular volume that is found on the arterial side only.
• Changes in Na⁺ balance result in changes in the ECV.
• Changes in the ECV are relayed to the kidney primarily through:
  • The RAAS 
  • Natriuretic peptides

Renin-angiotensin-aldosterone system

The RAAS is stimulated by a low ECV:

• Juxtaglomerular apparatus and carotid sinus/aortic arch baroreceptors trigger renin release from kidneys when ECV is ↓
• Renin (kidneys) → converts angiotensinogen (liver) to angiotensin I 
• ACE (lungs) → converts angiotensin I to angiotensin II
• Angiotensin II:
  • Causes vasoconstriction
  • Stimulates aldosterone release (from the adrenal cortex)

Effects of aldosterone:

• Stimulates production of the following proteins within the principal cells in the collecting ducts:
  • Na⁺/K⁺-ATPase on the basolateral side
  • Epithelial sodium channels (ENaC) on the lumen side: allow Na⁺ reabsorption from the lumen into the principal cells
  • Renal outer medullary potassium (ROMK) channels on the lumen side: allow excretion of K⁺ into the urine
• Stimulates Na⁺ reabsorption from the renal tubules
  • Water follows the Na⁺.
  • Creates a negative electrical gradient across the lumen promoting the secretion of K⁺ and H⁺ into the urine
• End result of ↑ aldosterone: 
  • ↑ Serum Na⁺ (↓ urinary excretion of Na⁺)
  • ↑ BP (↑ water reabsorption from the kidneys)
  • ↓ Serum K⁺ (↑ urinary excretion of K⁺)
  • ↑ Serum pH (↑ urinary excretion of H⁺)

Natriuretic peptides

• Natriuretic peptides include:
  • Atrial natriuretic peptide (ANP)
  • BNP
• Regulation: 
  • Cardiac baroreceptors sense an ↑ in ECV
  • Trigger the release of natriuretic peptides from the atria and ventricles
• Functions of the natriuretic peptides:
  • Stimulate urinary Na⁺ excretion (known as “natriuresis”)
  • Water follows the Na⁺.
  • ANP also has counterregulatory actions to inhibit the RAAS.

Summary

Changes in ECV are sensed by the juxtaglomerular apparatus, carotid-sinus and aortic-arch baroreceptors, and cardiac baroreceptors.

• ↑ Na⁺ causes ↑ ECV (↑ stretch), which results in:
  • ↓ Renin release
  • ↑ Natriuretic peptide release
  • End result: ↑ Na⁺ and water excretion
• ↓ Na⁺ causes ↓ ECV (↓ stretch), which results in:
  • ↑ Renin release
  • ↓ Natriuretic peptide release
  • End result: ↑ Na⁺ and water retention

Water Regulation

Overview

• To excrete water, the urine is diluted, which requires:
  • Solute and fluid delivery to the kidney
  • Functioning diluting segments
  • Suppressed ADH
• To retain free water, the urine is concentrated, which requires:
  • ↑ Solute reabsorption in the thick ascending loop
  • Presence of ADH
  • Ability of collecting ducts to respond to ADH by inserting aquaporin channels
• ADH can be released in response to osmotic and non-osmotic regulation.

Osmotic ADH regulation

Water regulation is primarily controlled by osmoreceptors in the hypothalamus, which maintain plasma osmolality very tightly. Very small changes in plasma osmolality result in changes in ADH release and the sensation of thirst.

• Osmoreceptors:
  • Located in the hypothalamus
  • Detect changes in plasma osmolality (caused by changes in water balance)
• ↑ Plasma osmolality sensed by the hypothalamus triggers:
  • ADH release from the posterior pituitary
  • Thirst
• ADH binds to:
  • V₂ receptors on the basolateral membrane of collecting duct cells → stimulate insertion of aquaporin channels into the apical membrane
  • V_1A receptors in vasculature → cause vasoconstriction
• Overall effect: 
  • ↑ Plasma osmolality → ↑ ADH → ↑ aquaporins → ↑ water reabsorption
  • ↓ Plasma osmolality → ↓ ADH → ↓ aquaporins → ↑ water excretion
• Normal ADH levels:
  • Usually minimal when plasma osmolality is in the normal range
  • ADH secretion increases linearly when plasma osmolality is elevated.

Non-osmotic ADH release

Very large decreases in the ECV can independently cause ADH release in an attempt to preserve volume.

• Can occur even if plasma tonicity is not elevated 
• Occurs only in extreme settings, where ECV losses are high enough to cause hypotension:
  • Acute severe bleeding
  • Severe diarrhea
• Constitutes a salvage mechanism: 
  • The body reabsorbs as much water as possible to support the BP when other mechanisms (e.g., RAAS) are not sufficient.
  • ↓ Volume will supersede a ↓ in osmolality: If the volume is low enough, ADH will be released even if the patient is already hypoosmotic. 
• ↓ ECV is sensed by:
  • Macula densa cells 
  • Renal afferent arterioles
  • Atrial and carotid sinus baroreceptors
• ↓ ECV triggers:
  • Activation of the RAAS
  • Norepinephrine release
  • ANP Suppression
  • ADH release
• End effect:
  • Vasoconstriction
  • ↑ Volume

Clinical Relevance

• Hypernatremia: elevated sNa⁺ concentration, defined as Na⁺ levels > 145 mmol/L. The pathophysiology most commonly involves a lack of access to water (e.g., altered mental status, dementia, mechanically ventilated patient). Another important etiology is diabetes insipidus (DI). Mild hypernatremia is characterized by an increased sensation of thirst, whereas more severe hypernatremia can result in altered mental status. The etiology of hypernatremia is often easy to determine based on clinical history. Treatment primarily involves replacement of the free water deficit.
• DI: a cause of hypernatremia due to increased urinary losses of water. Diabetes insipidus can be either central, due to decreased release of ADH, or nephrogenic, due to renal resistance to ADH. Without effective ADH, water cannot be effectively absorbed in the collecting ducts, leading to impaired urinary concentration and inappropriately dilute urine. Patients will present with polyuria, nocturia, polydipsia, hypernatremia, and increased osmolality. Management may include desmopressin (for central DI), a low-Na⁺/low-protein diet, diuretics, and NSAIDs.
• Hyponatremia: decreased sNa⁺ concentration, defined as Na⁺ levels < 135 mmol/L. The pathophysiology is more varied than hypernatremia, but most commonly involves a dilution of the total body Na⁺ due to an increase in the total body water. The clinical presentation varies greatly from asymptomatic to subtle cognitive deficits to seizures and death. Treatment is guided by acuity and severity of symptoms, and usually involves a combination of oral fluid restriction and hypertonic IV fluids. Overly rapid correction of hyponatremia can lead to an irreversible neurological complication known as the osmotic demyelination syndrome.
• Hypervolemia: an increase in ECF volume that occurs due to an increase in total body Na⁺. Clinical presentation includes hypertension, pulmonary edema, ascites, pitting edema in the lower extremities, and weight gain. Common etiologies include congestive heart failure, cirrhosis, and renal failure. In these diseases, the mechanisms of Na⁺ regulation are disturbed and the increased total body Na⁺ is not excreted. Treatment is with loop diuretics, which results in increased urinary Na⁺ and water losses.
• Hypovolemia: a decrease in ECF volume that occurs due to a decrease in total body Na⁺. Clinical presentation includes hypotension, decreased skin turgor, dry mucous membranes, orthostatic vital signs, and weight loss. Common etiologies include diarrhea, diuretic use, bleeding, poor oral intake, and 3rd spacing of fluids. Treatment includes administration of isotonic IV fluids, such as 0.9% NaCl or packed RBCs.