Renal Physiology: Control of Plasma Osmolarity

Control of Plasma Osmolarity

Learning Objectives

By the end of this lecture, you will be able to:

• Describe the process of countercurrent mechanism – loop of Henle

• Explain the mechanism of countercurrent exchange – vasa recta

• Describe the actions of Antidiuretic hormone (vasopressin) secretion, syndrome of inappropriate ADH secretion, NSIAD and Diabetes insipidus

• Explain the role of urea

Importance of Maintaining Plasma Osmolarity

The osmolarity of extracellular fluids must be kept constant because:

• If plasma osmolarity is too low: net water movement into cells, causing them to swell, compromising cellular function. This can lead to cell lysis and disrupt overall tissue homeostasis.

• If plasma osmolarity is too high: net water movement out of cells, causing them to shrink, also compromising cellular function. Cellular dehydration impairs metabolic processes and can cause cell death.

• The kidneys maintain plasma osmolarity within narrow limits (285-295 mosmoles/litre).

• A 1% deviation either way is sufficient to trigger a corrective response, achieved by increasing water loss or retention by the kidneys. This intricate control is essential for maintaining cell volume and function.

Water Reabsorption and Excretion

• Normally, 180 L of plasma is filtered through glomeruli per day.

• Only 1-1.5 L is excreted as urine per day. This highlights the kidney's crucial role in reabsorbing the majority of the filtered fluid.

• The same solute load can be excreted in varying urine volumes and concentrations:

  • 500 ml with a concentration of 1200-1400 mosm/L

  • 23.3 L/day with a concentration of 30 mosm/L

• ADH (anti-diuretic hormone) regulates water output by acting mainly on Collecting ducts. It increases water reabsorption, leading to more concentrated urine.

Water Reabsorption

Most of the water is reabsorbed passively by osmotic forces.

A. Obligatory Reabsorption: (87%)

• Occurs secondary to solutes reabsorption (e.g., $Na^+$).

• Does not affect urine concentration.

  • 1- Proximal convoluted tubules (PCT): 65% of water is reabsorbed through Aquaporin-1 (AQP1) channels, secondary to actively absorbed solutes e.g. $Na$, $Cl$, glucose and amino acids. This process is vital for reabsorbing essential nutrients and maintaining fluid balance.

  • 2- Loop of Henle: 15% of water is reabsorbed at the descending limb only. The descending limb's permeability to water allows for significant water reabsorption.

  • 3- Early distal convoluted tubules (DCT): (5-7 %) of water is reabsorbed at the early DCT.

B. Facultative Reabsorption: 13%

• Occurs at late DCT and collecting ducts through AQP2 under effect of anti-diuretic hormone (ADH).

Urine Concentration and Dilution Requirements

Requirements for excreting concentrated urine:

1. Hyperosmotic renal medulla (from 300 to 1200 mosm/L).

   • A- Countercurrent multiplier system of loop of Henle

   • B- Countercurrent Exchange system of vasa recta

   • C- Osmotic Equilibrating system of DCT and collecting duct

   • D- Role of Urea

2. High levels of ADH: Facultative water reabsorption.

Production of Concentrated Urine

Urine becomes hypertonic in the collecting ducts because:

1. Renal medullary interstitial fluid is hypertonic.

   • Responsible Mechanisms:

     • Countercurrent multiplier

     • Countercurrent exchanger

     • Osmotic equilibrating device

     • Role of urea

Countercurrent Multiplier System of Loop of Henle

1. In the thick ascending limb of the loop of Henle (TALH): $NaCl$ moves from the tubule to the interstitium. This creates a high solute concentration in the medulla.

2. The descending limb of the loop of Henle:

   • Permeable to water, but much less to NaCl and urea.

   • As the descending limb penetrates deeper into the medulla, water diffuses by osmosis to hypertonic interstitium.

   • Result: Fluid passing down the descending limb becomes progressively hypertonic→1200 mOsm/L

3. The thin ascending limb is impermeable to water but permeable to $NaCl$. $NaCl$ diffuses passively to interstitium.

   • Result: Increased osmolarity in kidney interstitium while tubular fluid becomes progressively hypoosmotic→ 100 mOsm/L (The thin ascending limb is the Diluting segment).

Fundamental feature of loop of Henle

• Proportionally more solute is reabsorbed in ascending limb than water is reabsorbed in descending limb. Therefore:

  • Interstitium becomes hypertonic

  • Tubular fluid delivered to distal tubule is hypotonic

Countercurrent multiplication – loop of Henle

• The fluid in the descending limb and the ascending limbs circulate in opposite direction and the reabsorption of $NaCl$ in the ascending limb multiplies the passive water reabsorption from the descending limb

Countercurrent Exchange System of Vasa Recta

• The medullary capillaries (vasa recta) have a similar countercurrent arrangement to that of the loop of Henle.

• Countercurrent exchange of solutes and water ensures that the osmolarity of vasa recta plasma is always similar to that of the surrounding interstitium. This minimizes solute washout and maintains the medullary gradient.

• Limited perfusion (sluggish blood flow) of the renal medulla helps to maintain this gradient.

Countercurrent Exchange System of Vasa Recta (cont-)

1. Descending Limb: Blood enters 300 mosm/L

   • $Na^+,Cl^-, urea$ diffuse from interstitium to blood along conc. gradient

   • H20 from blood to hyperosmotic interstitium

   • Result: Blood becomes hyperosmotic at tip of medulla (1200 mOsm/L)

2. Ascending Limb: Blood enters 1200mosm

   • $Na^+,Cl^-,urea$ diffuse from blood to interstitium along conc. gradient

   • Water diffuses from interstitium to hyperosmotic blood

   • Result: Solutes($Na^+,Cl^-,urea$) recirculate in medullary interstitium (trapped) WHILE water leaves interstitium to the general circulation

Countercurrent exchange:

• Completely passive.

Osmotic Equilibrating Device: Distal Convoluted Tubules & Collecting Ducts

1. Hypotonic fluid (100 mOsmol/L) enters the distal tubule.

2. In the presence of circulating ADH, water is reabsorbed by osmosis from the late distal tubule and collecting duct. ADH increases the permeability of these segments to water.

3. In the cortical collecting duct, tubular osmolarity will approach 290 mOsm/L.

4. H2O diffuses from the lumen to the interstitium which become progressively hyperosmotic as it enters the medulla (from 300 mOsm/L→ 1200 mOsm/L).

5. H2O diffuses until osmotic equilibrium is reached.

Role of Urea (Urea Cycle)

• At the PCT: 40% of filtered urea is reabsorbed passively.

• All the rest of the nephron is relatively impermeable to urea.

• Urea becomes concentrated and trapped in the tubular fluid as other solutes and water are reabsorbed.

• At the inner medullary collecting ducts (permeable to urea), urea moves to the interstitium according to concentration gradient → medullary hyperosmolarity.

• This occurs under the effect of ADH by activation of urea transporters. ADH enhances urea recycling within the medulla.

• Some of the urea recirculates in ascending loop of Henle, DCT and back to medullary collecting duct.

• Result: maintainance of high urea conc in inner medullary interstitium→ contributes to 40% of medullary interstitium hyperosmolarity.

• 40% - 60% of urea is excreted in urine.

• That’s why high protein diet increase the ability of the kidneys to concentrate urine (while ↓protein ↓urea ↓conc of urine). Dietary protein intake influences urea production and its contribution to medullary osmolarity.

Diuretics

Diuretics act on different parts of the nephron to inhibit reabsorption of sodium and water, leading to increased urine output. Different classes of diuretics target specific transporters and segments of the nephron.

Role of ADH

What happens next (to H2O) ? Answer: depends on plasma concentration of antidiuretic hormone (ADH) (vasopressin)

• Detected by Hypothalamus: Very sensitive.

  • Anterior pituitary

  • Posterior pituitary

  • osmoreceptors

  • Supraoptic nucleus

  • Paraventricular nucleus

• Plasma osmolarity

• Plasma volume: Less sensitive Detected by blood pressure receptors: ADH ↑

Antidiuretic Hormone (ADH)

• ADH (also known as vasopressin) is a peptide hormone produced in cells in the supraoptic and paraventricular nuclei of the hypothalamus; it is transported to, and released from, the posterior pituitary. ADH release is carefully regulated to maintain fluid balance.

• ADH is released in response to a rise in plasma osmolarity as small as 1%. This sensitivity ensures rapid correction of osmolarity imbalances.

• Release of ADH is inhibited when plasma osmolarity falls.

• Changes in plasma ADH concentration account for the range of urine osmolarities (50-1200 mosm/litre).

• Its half-life is 10-15 min.

• The set point for the ADH response is shifted in syndrome of inappropriate anti-diuretic hormone secretion (SIADH)

• ADH secretion is directly related to plasma osmolarity

Actions of ADH

1. water permeability of collecting duct ↑AQP2. ADH increases the number of AQP2 channels in the apical membrane, enhancing water reabsorption.

2. $Na^+$ reabsorption in Thick ascending limb of Loop of Henle (probably not in humans)

3. urea reabsorption in inner medullary collecting duct ↑urea transporters UTA1

Action of ADH in Collecting Ducts

• In the collecting duct, aquaporin (AQP)-3 and AQP-4 water channels are present at the basolateral membrane.

• Blood-borne ADH binds to its V2 receptor on the basolateral membrane, which stimulates adenylyl cyclase to generate cAMP and thereby activate protein kinases.

• This increases the insertion of AQP-2 water channels into the apical membrane and so increases water permeability across the collecting duct

Diabetes Insipidus

• Very little water reabsorption from the collecting duct

• Production of large volumes of dilute urine at all times→ polyuria

• The patient will need to imbibe very large amounts of water to maintain water balance due to associated polydipsia

1. Central diabetes insipidus

   • congenital absence of ADH

   • acquired – head trauma/surgery

2. Nephrogenic diabetes insipidus

   • V2 receptor mutations and ADH level in the blood can be high

   • AQP-2 mutations

   • acquired; e.g., lithium therapy

Treatments

• Central DI: Treat with ADH analogue, Possibly carbamazepine

• Nephrogenic DI: Resistant to ADH, Treat with pharmacochaperones

SIADH and NSIAD

Too much water reabsorption in the collecting duct: low urine output despite marked plasma hyponatremia and hypoosmolarity

• acquired – severe disease, drugs

1. Syndrome of inappropriate ADH secretion: SIADH

   • Elderly

   • Water restriction rapid correction of hyponatremia ➣ (central pontine myelinolysis)

2. Nephrogenic syndrome of inappropriate antidiuresis: NSIAD

   • caused by V2 receptor gain of function mutations leading to V2 constant activation

   • Treated by restricting water intake

Comparison between central diabetes insipidus and SIADH

(Check external source for comparison table)

Water Diuresis

• Increased urine flow rate (No change in urine excretion of solutes)

• Causes:

  • Excess ingestion of water

  • Lack of ADH

  • Defect in ADH receptors in Distal segment of nephron (nephrogenic Diabetes Insipidus)

• Diuresis is mainly due to decrease in water reabsorption in distal segment of nephron. No change to the water reabsorbed proximally

Osmotic Diuresis

• Increase urine flow rate as well as the excretion of solutes

• Causes:

  • Increase plasma glucose level (DM)

  • Increase level of poorly reabsorbed solutes/ anions

  • Diuretic drugs (Lasix)

• Diuresis is mainly due to decrease reabsorption of solute in PCT or LOH. Decrease solute reabsorption results in decrease in water reabsorption proximally as well as distally

A Genetically Engineered Cabbie: Case Study

• Maternal uncle, 43-y old, normal development, London Cabbie

• “I can hold my pints (half a liter drink), but don’t need to go to the toilet”

Biochemistries

• DIAGNOSIS: NSIAD

Control of Extracellular Volume

• Vital role of sodium in controlling extracellular volume

• Concept of effective circulating volume

• Monitoring effective circulating volume

• Responses to changes in effective circulating volume

  • Renal sympathetic nerves

  • Renin-angiotensin system

  • Aldosterone

  • Atrial natriuretic peptide

Control of Extracellular Volume

• Conclusion: the volume of extracellular fluid is determined by its $Na^+$ content

  $P<em>{osm}$ is normally kept fairly constant. Therefore, the water content (i.e. volume) of extracellular fluid is determined by its content of osmotically active solute. The major solute in extracellular fluid is sodium. (Na+ and its associated anions account for>95% of plasma) osmolarity). $P</em>{Na}$ is normally kept fairly constant

Sodium Balance

The osmolality (and sodium concentration) of extracellular fluid is normally kept constant by rapidly acting negative feedback systems: ADH and thirst

Effective Circulating Volume

• Hypothetical volume which is regulated by the kidneys

• Refers to portion of ECF in arterial system that is perfusing the tissues

• Unmeasurable by current methods

• Host response to "ineffective arterial perfusion" is the same as the response to volume depletion

Monitoring Effective Circulating Volume

• arterial pressure (baroreceptors)

• venous pressure (atrial receptors)

• juxtaglomerular apparatus

• Physiologically, the ECV is the pressure perfusing the arterial baroreceptors in the carotid sinus and glomerular afferent arterioles

Responding to Changes in Effective Circulating Volume

Effective circulating volume” is an index of the “fullness” of the Effective circulating volume

• Normally, “effective circulating volume” α extracellular volume, however in disease states they become uncoupled

Effective Circulating Volume Depletion

• Low blood volume and pressure

• Reduce Baroreceptors discharge from the carotid sinuses leading to sympathetic system activation

• decrease perfusion of the glomerular afferent arterioles which upregulates RAAS- (↑Renin, ↑ angiotensin II & ↑Aldosterone) and sympathetic activity, resulting in systemic vasoconstriction and renal sodium (and volume) retention

• Thus, sodium and water retention leading to oedema represents an appropriate compensatory response to ECV depletion

Extracellular volume depletion

• arterial and/or venous pressure

• renal sympathetic nervous activity

  • constricts afferent arterioles

  • renal blood flow

  • GFR

  • stimulates reabsorption in proximal tubule and loop of Henle

  • stimulates renin release from juxtaglomerular apparatus (JGA)

Renin-Angiotensin-Aldosterone System

• Angiotensinogen --(Renin (enzyme))--> Angiotensin I --(Angiotensin converting enzyme (ACE))--> Angiotensin II

• Angiotensin II leads to:

  • Vasoconstriction

  • Thirst

  • Aldosterone

  • Sodium and water retention in proximal tubule and collecting duct

  • blood volume and blood pressure

Action of aldosterone in collecting duct

• Increased Transcription

Extracellular volume expansion

• ANP renin secretion

• renal sympathetic nervous activity

• GFR etc. angiotensin II aldosterone

• atrial natriuretic peptide (ANP) leading to↑ $Na^+$ excretion as a compensatory mechanism

Blood Volume & Pressure Controls Renal Salt Excretion

• Complex system for sodium regulation

Summary

• Countercurrent mechanism – loop of Henle

• Countercurrent exchange – vasa recta

• Antidiuretic hormone (vasopressin) secretion, syndrome of inappropriate ADH secretion, NSIAD

• Actions of antidiuretic hormone

• Diabetes insipidus

• Role of urea

• Effective circulating volume monitoring

• Renin-Angiotensin-Aldosterone system

References

An understanding of the information covered in this lecture is relevant to the following core conditions: hypertension, SIADH and diabetes insipidus, heart failure.

Further reading

• W. Boron & E. Boulpaep, Medical Physiology, second edition, Chapter 38, 40.

• Pocock & Richards. Human Physiology, 3rd edition, OUP, p363-371, 550-553

• Ganong F. Review of Medical Physiology. 23rd Ed, sec VIII

• Guyton AC and Hall JE. Textbook of Medical Physiology,, 12th Ed ,unit V