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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. 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 Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys 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 Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys when ECV is ↓
• Renin ( kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys) → converts angiotensinogen ( liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver) to angiotensin I 
• ACE ( lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. 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 Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. 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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. 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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus
  • Detect changes in plasma osmolality (caused by changes in water balance)
• ↑ Plasma osmolality sensed by the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. 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 Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension:
  • Acute severe bleeding
  • Severe diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. 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 Diabetes Insipidus Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus (DI). Mild hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia is characterized by an increased sensation of thirst, whereas more severe hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia can result in altered mental status. The etiology of hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia is often easy to determine based on clinical history. Treatment primarily involves replacement of the free water deficit.
• DI: a cause of hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. 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 Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. 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 Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. 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 Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. 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 IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids. Overly rapid correction of hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. 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 Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites, pitting edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema in the lower extremities, and weight gain. Common etiologies include congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. 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 Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. 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 Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, decreased skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin turgor, dry mucous membranes, orthostatic vital signs, and weight loss. Common etiologies include diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, diuretic use, bleeding, poor oral intake, and 3rd spacing of fluids. Treatment includes administration of isotonic IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids, such as 0.9% NaCl or packed RBCs.