B. Regulation of Ion and Water Balance

What percentage of normal body weight is water?

About 55% to 60% of normal body weight is water.

What are the two sources of body water gain?

1) Water produced from the oxidation of organic nutrients

2) Water ingested in liquids and food

What are the four main sites of water loss from the body?

1) Skin

2) Respiratory airways

3) Gastrointestinal tract

4) Urinary tract

(A fifth potential source is menstrual flow in women)

What is insensible water loss?

The continuous loss of water by evaporation from the skin and respiratory passageways that occurs without the person's awareness.

What is the range of possible urinary water excretion per day?

Approximately 0.4 L/day to 25 L/day, depending on hydration status.

What is the average daily sodium consumption in the United States?

3.4 g/day (equivalent to 8.5 g of sodium chloride)

What is the recommended maximum daily sodium intake according to the Institute of Medicine?

No more than 2.3 g of sodium per day (approximately 5.8 g or 1 teaspoon of table salt)

Where does most sodium and water loss normally occur?

Through the kidneys (urinary excretion)

What happens to sodium and water loss during severe sweating, vomiting, or diarrhea?

Sodium and water loss via the skin and gastrointestinal tract increases markedly.

What percentage of filtered sodium and water is normally reabsorbed?

More than 99% of filtered sodium and water is reabsorbed.

Where does the bulk of sodium and water reabsorption (about two-thirds) occur?

In the proximal tubule.

Where is the major hormonal control of sodium and water reabsorption exerted?

On the distal convoluted tubules and collecting ducts.

What are the two generalizations about sodium and water reabsorption mechanisms?

1) Sodium reabsorption is an active process occurring in all tubular segments except the descending limb of the loop of Henle

2) Water reabsorption is by osmosis (passive) and is dependent upon sodium reabsorption

What is the essential feature underlying sodium reabsorption throughout the tubule?

The primary active transport of sodium out of the cells and into the interstitial fluid via Na+/K+-ATPase pumps in the basolateral membrane.

How does sodium enter proximal tubule cells across the apical membrane?

By cotransport with organic molecules (like glucose) or by countertransport with H+.

What is the main function of the ascending limb of the loop of Henle?

To reabsorb NaCl but not water.

What special transporter is found in the ascending limb of the loop of Henle?

The Na-K-2Cl cotransporter (NKCC).

How does sodium enter cortical collecting duct cells across the apical membrane?

Primarily by diffusion through sodium channels.

How is water reabsorption coupled to sodium reabsorption?

As sodium and other solutes are reabsorbed, water follows passively by osmosis (if the apical membrane is permeable to water).

What is required for water movement across tubular epithelium?

The epithelium must be permeable to water, which depends largely on the presence of water channels called aquaporins in the plasma membranes.

Which segments of the tubule have water permeability under physiological control?

The cortical and medullary collecting ducts are the only tubular segments with controlled water permeability.

What hormone controls water permeability in the collecting ducts?

Vasopressin (also known as antidiuretic hormone or ADH).

What are aquaporins?

Water channels in the plasma membrane that allow water to move across epithelial cells.

Which specific aquaporin is regulated by vasopressin in the collecting ducts?

AQP2 (Aquaporin-2)

How does vasopressin increase water permeability in collecting duct cells?

Vasopressin binds to receptors on the basolateral membrane, increases cAMP production, activates protein kinase A, which leads to increased insertion of AQP2 water channels into the apical membrane.

What happens in the presence of high plasma vasopressin concentration?

The water permeability of collecting ducts increases dramatically, passive water reabsorption is maximal, and final urine volume is small (less than 1% of filtered water).

What happens when vasopressin is absent or low?

The water permeability of collecting ducts is extremely low, little water is reabsorbed, and a large volume of water is excreted as urine (water diuresis).

What is diuresis?

Diuresis simply means a large urine flow from any cause.

What's the difference between water diuresis and osmotic diuresis?

Water diuresis: increased urine flow without increased solute excretion (due to low vasopressin)

Osmotic diuresis: increased urine flow resulting from a primary increase in solute excretion

What is diabetes insipidus and what causes it?

A disease characterized by constant water diuresis (up to 25 L/day). It's caused by either:

1. Central diabetes insipidus: failure to synthesize or release vasopressin

2. Nephrogenic diabetes insipidus: inability of kidneys to respond to vasopressin

What's an example of osmotic diuresis in a disease state?

In uncontrolled diabetes mellitus, glucose that escapes reabsorption (due to high filtered load) retains water in the lumen, causing it to be excreted along with the glucose.

What's the relationship between solute loss and water loss in the urine?

Any loss of solute in the urine must be accompanied by water loss (osmotic diuresis), but water diuresis is not necessarily accompanied by equivalent solute loss.

What is the maximum urinary concentration the human kidney can produce?

1400 mOsmol/L, which is almost five times the osmolarity of plasma (285-300 mOsmol/L).

What is obligatory water loss?

The minimal volume of urine required to excrete the daily solute load.

It's calculated as: daily solute excretion (mOsmol/day) ÷ maximum urine concentration (mOsmol/L).

Example: 600 mOsmol/day ÷ 1400 mOsmol/L = 0.444 L/day.

Where does urinary concentration primarily take place?

In the medullary collecting ducts, where water diffuses out of the ducts into the hyperosmotic interstitial fluid of the medulla in the presence of vasopressin.

What is a countercurrent flow?

The opposing flows in the two limbs of the loop of Henle, where fluid flows down the descending limb and then up the ascending limb.

What are the 5 key factors that make the medullary interstitial fluid hyperosmotic?

1) The countercurrent anatomy of the loop of Henle of juxtamedullary nephrons

2) Reabsorption of NaCl in the ascending limbs of those loops

3) Impermeability to water of those ascending limbs

4) Trapping of urea in the medulla

5) Hairpin loops of vasa recta to minimize washout of the hyperosmotic medulla

What is the osmolarity of fluid entering the descending limb of the loop of Henle from the proximal tubule?

300 mOsmol/L (same as plasma) because the proximal tubule reabsorbs Na+ and water in the same proportions

How does the ascending limb contribute to the countercurrent multiplier system?

The ascending limb actively reabsorbs Na+ and Cl- but is relatively impermeable to water.

This creates a concentration gradient where the interstitial fluid becomes hyperosmotic compared to the fluid in the ascending limb.

How does the descending limb differ from the ascending limb in terms of permeability?

The descending limb does not reabsorb sodium chloride and is highly permeable to water, whereas the ascending limb reabsorbs sodium chloride and is relatively impermeable to water.

What happens to the osmolarity of fluid as it flows through the loop of Henle?

The osmolarity increases as fluid descends deeper into the medulla (can reach up to 1400 mOsmol/L at the bend), then decreases as it ascends, becoming hypoosmotic (about 100 mOsmol/L) when it reaches the distal convoluted tubule.

What is the effect of vasopressin on the collecting ducts?

Vasopressin increases tubular permeability to water in both the cortical and medullary collecting ducts by increasing the insertion of aquaporin water channels.

How does vasopressin affect the osmolarity of urine?

With high vasopressin, water diffuses out of the collecting ducts into the hyperosmotic medulla, resulting in concentrated (hyperosmotic) urine.

With low vasopressin, collecting ducts are relatively impermeable to water, resulting in dilute (hypoosmotic) urine.

Does vasopressin directly influence water reabsorption in parts of the tubule before the collecting ducts?

No, vasopressin does not directly influence water reabsorption in the parts of the tubule prior to the collecting ducts.

What happens to fluid osmolarity in the cortical collecting duct when vasopressin is high?

Water reabsorption occurs by diffusion from the hypoosmotic fluid until it becomes isoosmotic (300 mOsmol/L) to the cortical interstitial fluid.

What are vasa recta and how do they help maintain the medullary concentration gradient?

Vasa recta are blood vessels in the medulla that form hairpin loops running parallel to the loops of Henle.

Their structure allows solutes that diffuse into the vessels during the descending portion to diffuse back out during the ascending portion, minimizing washout of the concentration gradient.

How does urea contribute to the hyperosmotic medullary interstitium?

Urea undergoes recycling through reabsorption, secretion, and reabsorption again, which traps it in the medullary interstitium.

As an osmotically active molecule, urea increases the osmolarity of the interstitium.

What percentage of filtered urea is reabsorbed in the proximal tubule?

Approximately 50% of the filtered urea is reabsorbed in the proximal tubule.

How does vasopressin affect urea handling in the kidneys?

Vasopressin increases the permeability of the inner medullary collecting ducts to urea, which enhances urea reabsorption and contributes to the high medullary interstitial urea concentration.

Why is the peak osmolarity in the loop of Henle lower in the absence of vasopressin?

Without vasopressin, urea reabsorption from the medullary collecting ducts decreases, reducing urea concentration in the medulla.

Since urea comprises about half of the solutes in the medulla, the maximum osmolarity at the bottom of the loop of Henle decreases.

What percentage of water reabsorption is not controlled by vasopressin?

About 60-70% of water reabsorption occurs isosmotically in the proximal tubule and is not controlled by vasopressin.

What happens to tubular fluid osmolarity in the latter half of the loop of Henle?

Tubular fluid osmolarity decreases in the latter half of the loop of Henle due to selective reabsorption of solutes from the water-impermeable segments.

What determines the volume and concentration of urine under any set of conditions?

Vasopressin is the ultimate determinant of urine volume and concentration. High vasopressin leads to antidiuresis (small volume, concentrated urine), while low vasopressin leads to diuresis (large volume, dilute urine).

What happens during water diuresis (low vasopressin)?

The collecting ducts are relatively impermeable to water, resulting in minimal water reabsorption, large urine volume, and hypoosmotic urine.

What happens during antidiuresis (maximum vasopressin)?

Most water is reabsorbed in the collecting ducts, leading to very small urine volume and hypertonic urine.

What is the fundamental equation for sodium excretion?

Na⁺ excreted = Na⁺ filtered – Na⁺ reabsorbed

How precisely do healthy kidneys maintain total-body sodium?

Total-body sodium normally varies by only a few percentage points despite wide ranges of sodium intake and occasional large losses via skin and GI tract.

What happens to Na⁺ excretion when total-body sodium decreases?

Na⁺ excretion decreases because Na⁺ reabsorption increases.

Are there receptors that directly detect total amount of sodium in the body?

No. Surprisingly, there are no important receptors capable of detecting the total amount of sodium in the body.

What receptors initiate the responses controlling Na⁺ reabsorption?

Cardiovascular baroreceptors (such as the carotid sinus) and sensors in the kidneys that monitor the filtered load of Na⁺.

Why does total-body sodium affect cardiovascular pressures?

Na⁺ is the major extracellular solute (~90%), so changes in total-body sodium result in similar changes in extracellular volume, including plasma volume, which affects cardiovascular pressures.

Explain the chain linking total-body sodium to cardiovascular pressures

Low total-body sodium → low plasma volume → decrease in cardiovascular pressures → baroreceptor activation → reflexes affecting renal arterioles and tubules → decreased GFR and increased Na⁺ reabsorption → decreased Na⁺ excretion → Na⁺ retention → prevention of further decreases in plasma volume and pressures.

What is the main direct cause of decreased GFR during sodium loss?

Decreased net glomerular filtration pressure.

What are two ways net glomerular filtration pressure decreases during sodium loss?

1) Decreased arterial pressure in the kidneys

2) Reflex vasoconstriction of the renal arterioles

Which hormones participate in the renal vasoconstrictor response during sodium loss?

Angiotensin II and vasopressin

Which is more important for long-term regulation of Na⁺ excretion?

Control of Na⁺ reabsorption is more important than control of GFR.

What hormone is the major factor determining the rate of tubular Na⁺ reabsorption?

Aldosterone

Where in the nephron does aldosterone stimulate Na⁺ reabsorption?

The distal convoluted tubule and the cortical collecting ducts

How much filtered Na⁺ can be excreted when aldosterone is very low?

Approximately 2% of filtered Na⁺ (equivalent to 35g of sodium chloride per day)

Why does aldosterone act more slowly than vasopressin?

Aldosterone is a steroid that induces changes in gene expression and protein synthesis, while vasopressin is a peptide that acts quickly.

What is the sequence of the renin-angiotensin system?

Renin (from juxtaglomerular cells) → splits angiotensinogen (from liver) → angiotensin I → converted by ACE to angiotensin II → stimulates aldosterone secretion

What is the rate-limiting factor in angiotensin II formation?

The plasma renin concentration

What are the three distinct inputs that cause increased renin secretion during sodium depletion?

1) Renal sympathetic nerves

2) Intrarenal baroreceptors in afferent arterioles

3) The macula densa

How does the macula densa sense changes in sodium balance?

It senses the amount of Na⁺ in the tubular fluid flowing past it. Decreased Na⁺ delivery causes release of paracrine factors that stimulate nearby JG cells to release renin.

Besides affecting sodium balance, how else does angiotensin II influence arterial pressure?

Angiotensin II is a potent constrictor of arterioles in many parts of the body, which increases peripheral resistance and arterial pressure.

What is the mechanism of ACE inhibitors like lisinopril?

They reduce angiotensin II production by inhibiting angiotensin-converting enzyme.

How do angiotensin II receptor blockers like losartan work?

They prevent angiotensin II from binding to its receptor on target tissue

What is the mechanism of action for eplerenone?

It blocks the binding of aldosterone to its receptor in the kidney.

What do direct renin inhibitors do?

They decrease the production of angiotensin I.

What does the effectiveness of these different drug classes in treating hypertension suggest?

It suggests that many forms of hypertension can be attributed to the failure of the kidneys to adequately excrete Na⁺ and water.

Where is ANP synthesized and secreted?

Cells in the cardiac atria

What are the effects of ANP on sodium excretion?

ANP inhibits Na⁺ reabsorption in several tubular segments, increases GFR, and directly inhibits aldosterone secretion—all leading to increased Na⁺ excretion.

What stimulates increased ANP secretion?

Increased atrial distension due to expansion of plasma volume that accompanies an increase in body sodium.

What is pressure natriuresis?

The process where an increase in arterial pressure inhibits Na⁺ reabsorption and thereby increases Na⁺ (and water) excretion.

What are the two mechanisms by which increased blood pressure decreases Na⁺ reabsorption?

1) It inhibits the activity of the renin-angiotensin-aldosterone system 2) It acts locally on the tubules to inhibit Na⁺ reabsorption

What is one hypothesis for the development of hypertension?

Some people develop hypertension because their kidneys do not excrete enough Na⁺ in response to a normal arterial pressure, leading to sodium retention, plasma volume expansion, and increased arterial pressure.

What determines water excretion in the kidneys?

Water excretion is the difference between the volume of water filtered (the GFR) and the volume reabsorbed.

What is the most important factor for determining how much water is excreted?

The rate of water reabsorption.

Which hormone is primarily responsible for regulating water reabsorption?

Vasopressin (also known as antidiuretic hormone or ADH).

Where is vasopressin produced?

In a discrete group of hypothalamic neurons whose axons terminate on capillaries in the posterior pituitary.

How does water distribution in the body differ from sodium distribution?

Water distributes throughout all body fluid compartments (with about two-thirds entering intracellular compartments), while sodium stays primarily in the extracellular compartment.c

What is the major effect of water gain or loss out of proportion to Na+ gain or loss?

A change in the osmolarity of the body fluids.

Which receptors initiate reflexes controlling vasopressin secretion in response to changes in water balance?

Osmoreceptors in the hypothalamus that respond to changes in osmolarity.

What happens to vasopressin secretion when you drink 2L of water?

The excess water decreases body fluid osmolarity, which inhibits vasopressin secretion via hypothalamic osmoreceptors.

When vasopressin secretion is inhibited, what happens to the collecting ducts and urine production?

The water permeability of collecting ducts decreases dramatically, water reabsorption is greatly reduced, and a large volume of hypoosmotic urine is excreted.

What happens to vasopressin secretion during water deprivation?

Vasopressin secretion is reflexively increased via the osmoreceptors.

How do the kidneys help reduce body fluid osmolarity during water deprivation?

By increasing water reabsorption in the collecting ducts and excreting a small volume of highly concentrated urine, the kidneys retain relatively more water than solute.

Besides osmoreceptors, what other important receptors control vasopressin secretion?

Baroreceptors in the cardiovascular system.

What happens to vasopressin secretion when extracellular fluid volume decreases?

A decreased extracellular fluid volume triggers an increase in vasopressin secretion.

How do baroreceptors respond to decreased cardiovascular pressures?

They decrease their rate of firing, which results in fewer impulses transmitted to the hypothalamus, leading to increased vasopressin secretion.