In an alcoholic, rapid intravenous fluid correction of hyponatremia with saline may result in central pontine myelinolysis (see Fig. 25-28), an irreversible demyelinating disorder. However, as a general rule, all intravenous replacement of sodium-containing fluids should be given slowly over the first 24 hours regardless of the cause of the underlying serum sodium imbalance.

Central pontine myelinolysis: rapid correction of hyponatremia with saline

c. Gain of pure water

(1) Net gain in only water (TBNa⁺/↑↑TBW)

(2) Decreased POsm and serum Na⁺

(3) Expansion of ECF and ICF volumes

(4) Normal skin turgor

Hypotonic gain of water: TBNa⁺/↑↑TBW; SIADH

(5) Examples—syndrome of inappropriate secretion of antidiuretic hormone (syndrome of inappropriate antidiuretic hormone [SIADH], e.g., small cell carcinoma of the lung), compulsive water drinking

d. Hypotonic gain of Na⁺

(1) Net gain in H₂O in excess of Na⁺ (↑TBNa⁺/↑↑TBW)

(2) Decreased POsm and serum Na⁺

(3) Expansion of the ECF and ICF volumes

(4) Caused by pitting edema states with Starling pressure alterations

(a) Right-sided heart failure with increase in venous hydrostatic pressure

(b) Cirrhosis and nephrotic syndrome with decrease in plasma oncotic pressure

Hypotonic gain water + Na⁺: ↑TBNa⁺/↑↑TBW

Pitting edema states: right-side heart failure, cirrhosis, nephrotic syndrome; cardiac output decreased

In these pitting edema states, the cardiac output is decreased, which causes the release of catecholamines, activation of the renin-angiotensin-aldosterone system, stimulation of ADH release, and increased renal retention of Na⁺. The kidney reabsorbs a slightly hypotonic, Na⁺– containing fluid (↑TBNa⁺/↑↑TBW). Because these pitting edema states have alterations in Starling pressures, the Na⁺-containing fluid is redirected into the interstitial space, causing pitting edema and body cavity effusions. Unfortunately, the cardiac output remains decreased, until the cause of the decreased cardiac output is corrected.

4. Hypertonic fluid disorders (Table 4-2)

Table 4-2 Hypertonic Disorders

Hypertonic disorder: hypernatremia or hyperglycemia; ICF contraction

a. Increased POsm is most often due to hypernatremia or hyperglycemia.

(1) Osmotic gradient is present.

(2) Water shifts from the ICF (contracts) to the ECF.

b. Hypotonic loss of Na⁺

(1) Net loss of H₂O in excess of Na⁺ (↓TBNa⁺/↓↓TBW)

(2) POsm and serum Na⁺ increased

(3) Contraction of the ECF and ICF volumes

(4) Signs of volume depletion

Hypotonic loss Na⁺ + water: ↓TBNa⁺/↓↓TBW; osmotic diuresis, sweating

(5) Examples—sweating, osmotic diuresis (e.g., glucosuria)

c. Loss of pure water

(1) Net loss of only H₂O (TBNa⁺/↓↓TBW)

(2) POsm and serum Na⁺ increased

(3) Contraction of the ECF and ICF volumes

• ECF contraction is mild, because there has been no loss of Na⁺.

(4) Normal skin turgor

(5) Examples

Hypotonic loss of water: TBNa⁺/↓↓TBW; diabetes insipidus; insensible water loss

(a) Diabetes insipidus, due to loss of antidiuretic hormone (ADH) or refractoriness to ADH

(b) Insensible water loss (e.g., fever)

• Water evaporates from the warm skin surface.

d. Hypertonic gain of Na⁺

(1) Net gain in Na⁺ in excess of H₂O (↑↑TBNa⁺/↑TBW)

(2) POsm and serum Na⁺ increase.

(3) ECF volume expands and ICF volume contracts.

(4) Pitting edema and body cavity effusions may be present.

Hypertonic gain: ↑↑TBNa⁺/↑TBW; excess NaHCO₃, infusion Na⁺-containing antibiotic

(5) Examples include infusion of NaHCO₃ or Na⁺-containing antibiotics.

e. Hypertonic state due to hyperglycemia

• Examples—diabetic ketoacidosis (DKA), hyperosmolar nonketotic coma

(1) Water shifts from the ICF to the ECF compartment.

(a) Dilutional effect on serum Na⁺ causes hyponatremia.

(b) Increased POsm (due to hyperglycemia) and hyponatremia (dilutional)

(c) Water does not remain in the ECF, because glucose in urine acts as an osmotic diuretic causing loss of water and Na⁺.

(2) Signs of volume depletion

• Glucosuria produces a hypotonic loss of water and Na⁺ (osmotic diuresis), causing signs of volume depletion.

Diabetic ketoacidosis: hypertonic state with dilutional hyponatremia; osmotic diuresis

C. Volume control (Box 4-1)

D. Correlation of nephron cotransporters and pumps with electrolyte disorders

1. Proximal renal tubule

BOX 4-1 Volume Control

Protection of the intravascular volume is paramount to normal survival. Maintenance of the extracellular fluid (ECF) volume involves the integration of factors that (1) control thirst (e.g., increased POsm and angiotensin II [ATII]), (2) activate the renin-angiotensin-aldosterone (RAA) system (e.g., reduced renal blood flow, sympathetic nervous system stimulation), (3) stimulate the baroreceptors in the arterial circulation (e.g., decreased effective arterial blood volume), (4) increase free water reabsorption to concentrate the urine (e.g., antidiuretic hormone), and (5) increase renal reabsorption of Na⁺ and water.

Effective Arterial Blood Volume

Effective arterial blood volume (EABV) is a conceptual term that refers to that portion of the ECF that is in the vascular space. In most instances, it correlates directly with the ECF volume and TBNa⁺ status of the individual (i.e., ↓ EABV // ↓ ECF/↓ TBNa⁺ or ↑ EABV // ↑ ECF/↑TBNa⁺). However, in edema states, where there is an alteration in Starling pressures (e.g., right-sided heart failure), the redistribution of fluid (a transudate) from the intravascular compartment into the interstitial fluid compartment increases the total ECF volume at the expense of reducing the venous return of blood to the right side of the heart, reducing cardiac output, and reducing EABV (↓ EABV // ↑ ECF/ ↑ TBNa⁺). Hence, an increase in total ECF volume does not always correlate with an increase in the EABV.

Baroreceptors and the Renin-Angiotensin-Aldosterone System

Control of the EABV is monitored by the pressure impacting upon the high pressure arterial baroreceptors located in the aortic arch and carotid sinus, and the flow of blood to the renal arteries. When the baroreceptors are activated by a decreased EABV, signals are sent to the medulla to increase sympathetic tone leading to release of catecholamines resulting in vasoconstriction of peripheral resistance arterioles (increases diastolic blood pressure), venoconstriction (increases venous return to the heart), increases heart rate (chronotropic effect), and increases cardiac contractility (inotropic effect). Signals are also sent to the supraoptic and paraventricular nuclei in the hypothalamus to synthesize and release antidiuretic hormone (ADH, vasopressin), the latter from nerve endings located in the posterior pituitary. ADH enhances the reabsorption of free water (fH₂O; water without electrolytes) from the collecting tubules in the kidneys and is a potent vasoconstrictor of the peripheral resistance vessels. Finally, the RAA system is activated owing to reduced blood flow to the juxtaglomerular (JG) apparatus located in the afferent arterioles and by direct sympathetic stimulation of the JG apparatus with subsequent release of the enzyme renin. Renin initiates the following reaction sequence: it cleaves renin substrate (angiotensinogen) into angiotensin I (ATI), which is converted by pulmonary angiotensin converting enzyme (ACE) into angiotensin II (ATII). ATII has a fourfold function:

1. Vasoconstriction of peripheral resistance arterioles

2. Stimulation of aldosterone synthesis and release from the zona glomerulosa (increases Na⁺ reabsorption in exchange for potassium ions [K⁺] and hydrogen ions [H⁺])

3. Direct stimulation of the thirst center in the brain

4. Enhances activity of H⁺/Na⁺ cotransporter in the proximal renal tubule

All of these events are an attempt to increase the EABV before medical intervention.

In contradistinction, when there is an increase in EABV, there are many counterregulatory mechanisms that come into play to eliminate the excess fluid prior to medical intervention. An increase in EABV is associated with a corresponding increase in cardiac output. This stretches the arterial baroreceptors, which triggers cessation of sympathetic outflow from the medulla. This, in turn, leads to inhibition of ADH synthesis and release, vasodilation of peripheral resistance arterioles, decreased cardiac contraction, inhibition of the RAA system, and decreased renal retention of Na⁺ and water. Other counterregulatory factors also come into play including atrial natriuretic peptide (ANP), prostaglandin E₂, and brain natriuretic peptide (BNP). ANP is released from the left and right atria in response to atrial distention (e.g., left- and/or right-sided heart failure). ANP has multiple functions including (1) suppression of ADH release, (2) inhibition of the effect of ATII on stimulating thirst and aldosterone secretion, (3) vasodilation of the peripheral resistance vessels, (4) direct inhibition of Na⁺ reabsorption in the kidneys (diuretic effect), and (5) suppression of renin release. Prostaglandin E₂ (1) inhibits ADH, (2) blocks Na⁺ reabsorption in the kidneys, and (3) is a potent intrarenal vasodilator that offsets the vasoconstrictive effects of ATII and the catecholamines. BNP increases in the blood when the right and/or left ventricles are volume overloaded (e.g., left- and/or right-sided heart failure).

Renal Mechanisms in Volume Regulation

The response of the kidney to volume alterations is closely integrated with many of the events previously described. The reabsorption of solutes from the proximal tubules is dependent on the filtration fraction (FF) in the glomerulus in concert with Starling pressures that are operative in the peritubular capillaries. The FF is the fraction of the renal plasma flow (RPF) that is filtered across the glomerular capillaries into the tubular lumen. It is calculated by dividing the glomerular filtration rate (GFR) by the RPF (FF = GFR ÷ RPF). Normally, the FF is ∼︀20%, with the remaining 80% of the RPF entering the efferent arterioles, which divide to form the intricate peritubular capillary microcirculation. Because prostaglandin E₂, a vasodilator, controls the afferent arteriolar blood flow into the glomerulus and ATII, a vasoconstrictor, monitors the efferent arteriolar blood flow leaving the glomerulus, the FF is significantly affected by alterations in their concentrations. Starling pressures in the peritubular capillaries determine how much of the fluid from the proximal tubule is reabsorbed back into the ECF compartment. A low peritubular capillary hydrostatic pressure (P_H) coupled with a high oncotic pressure (P_O) is responsible for enhancing the reabsorption of solutes from the tubular lumen into the tubular cell out into the lateral intercellular space, and into the peritubular capillary (B). This occurs when the EABV is decreased (e.g., ECF volume depletion, or hypovolemia). A high P_H coupled with a low P_O results in the loss of solutes in the urine in conditions when the EABV is increased (A; e.g., ECF volume overload, or hypervolemia). When hypovolemia is present in the ECF, the EABV is reduced and the FF is increased (↑FF = ↓GFR ÷ ↓↓RPF), hence increasing the filtered load of Na⁺ and other solutes. The P_H is decreased and the P_O is increased, resulting in the reabsorption of the filtered Na⁺ plus other solutes into the ECF compartment (e.g., urea) in isosmotic proportions. The above mechanism is so effective that a random urine Na⁺ (UNa⁺) measurement is usually < 20 mEq/L and is often 0 when hypovolemia is extreme. In the presence of an increased EABV, or hypervolemia, the FF is decreased (↓FF = ↑GFR ÷ ↑↑RPF), the filtered load of Na⁺ and other solutes is decreased, the P_H is increased and the P_O is decreased, hence favoring loss of the filtered Na⁺ plus other solutes (e.g., urea, uric acid) in the urine (random UNa⁺ > 20 mEq/L).

From Goljan EF: Star Series: Pathology. Philadelphia, WB Saunders, 1998, p 77, Fig. 5-2.

Proximal tubule: reabsorb Na⁺, reclaim HCO₃⁻

a. Primary site for Na⁺ reabsorption

(1) Na⁺ reabsorption is increased when cardiac output is decreased.

(a) ↓ EABV→ ↑ FF → P_O > P_H

(b) Examples—congestive heart failure, cirrhosis, hypovolemia

(2) Na⁺ reabsorption is decreased when cardiac output is increased.

↓ EABV → ↑ FF → P_O > P_H

(a) ↑ EABV→ ↓ FF → P_H > P_O

(b) Examples—mineralocorticoid excess, isotonic gain in fluid

↑ EABV → ↓ FF → P_H > P_O

b. Primary site for reclamation of bicarbonate (HCO₃⁻; Fig. 4-5)

• Mechanism for reabsorbing some of the filtered HCO₃⁻ back into the blood

(1) Hydrogen ions (H⁺) in tubular cells are exchanged for Na⁺ in the urine.

(2) H⁺ combines with filtered HCO₃⁻ to form H₂CO₃ in the brush border of the proximal tubules.

(3) Carbonic anhydrase (c.a.) dissociates H₂CO₃ to H₂O and CO₂

• CO₂ and H₂O are reabsorbed into proximal renal tubular cells.

(4) H₂CO₃ is re-formed in the proximal renal tubular cells.

• H₂CO₃ dissociates into H⁺ and HCO₃⁻.

(5) HCO₃⁻ is reabsorbed into the blood.

(6) An Na⁺/K⁺-ATPase pump moves Na⁺ into the blood.

c. Clinical effect of lowering renal threshold for reclaiming HCO₃⁻

(1) Example—normal threshold is lowered from the normal of 24 mEq/L to 15 mEq/L.

(2) This results in loss of more of the filtered HCO₃⁻ than normal.

(a) Urine pH > 5.5 (alkalinizing effect of increased HCO₃⁻)

(b) Urine loss of HCO₃⁻ occurs until serum HCO₃⁻ matches the renal threshold.

4-5 Reclamation of bicarbonate in the proximal tubule. See text for description. c.a., carbonic anhydrase.

(From Goljan EF, Sloka KI: Rapid Review Laboratory Testing in Clinical Medicine. St. Louis, Mosby Elsevier, 2008, p 32, Fig. 2-5.)

Carbonic anhydrase inhibitor: causes proximal renal tubular acidosis

Carbonic anhydrase inhibitors (e.g., acetazolamide) lower the renal threshold for reclaiming HCO₃⁻. HCO₃⁻ combines with Na⁺ to form NaHCO₃, which is excreted, hence acting as a proximal tubule diuretic. Loss of HCO₃⁻ produces metabolic acidosis (see later).

d. Clinical effect of raising renal threshold for reclaiming HCO₃⁻

(1) Example—volume depletion associated with vomiting

(2) Increased threshold means that proportionately more of the filtered HCO₃⁻ is reclaimed.

• Increased reclamation of HCO₃⁻ is the most important factor contributing to the increase in serum HCO₃⁻ that defines metabolic alkalosis (see later).

Heavy metal poisoning: produces Fanconi syndrome

In heavy metal poisoning with lead or mercury, the proximal tubule cells undergo coagulation necrosis, which produces a nephrotoxic acute tubular necrosis (refer to Chapter 19). All of the normal proximal renal tubule functions are destroyed resulting in a loss of sodium (hyponatremia), glucose (hypoglycemia), uric acid (hypouricemia), phosphorus (hypophosphatemia), amino acids, bicarbonate (type II proximal renal tubular acidosis), and urea in the urine. This is called the Fanconi syndrome.

2. Thick ascending limb (TAL; medullary segment)

a. Primary function is to generate free water (fH₂O)

• Secondary function is to reabsorb calcium (Ca²⁺)

b. Generation of fH₂O primarily occurs in the active Na⁺-K⁺-2 Cl⁻ symporter (Fig. 4-6)

c. Water proximal to the symporter is obligated (o).

(1) Water is normally bound to Na⁺ (oNa⁺), K⁺ (oK⁺), and Cl⁻ (oCl⁻).

(2) Obligated water must accompany every Na⁺, K⁺, or Cl⁻ excreted in urine.

(3) Obligated water cannot be reabsorbed by ADH, only fH₂O.