LECTURE 12 (Urine concentration + dilution)

Question 1

Describe how Antidiuretic hormone/Vasopressin controls urine concentration

Answer 1

1) When osmolarity of body fluid increases above normal (body fluid is too concentrated), posterior pituitary gland secretes more ADH
2) ADH increases permeability of DISTAL TUBULES and COLLECTING DUCTS to water
3) Allows large amounts of water to be reabsorbed and decreases urine volume, but not rate of renal excretion of solutes

OPPOSITE happens when osmolarity is reduced (too much water)

Question 2

How do you dilute the filtrate as it passes along the tubule?

Answer 2

By reabsorbing solutes to a greater extent than water

Question 3

Describe the Tubular fluid flowing through the Proximal tubule

Answer 3

• Solutes + water are reabsorbed in equal proportions -> little chance in osmolarity occurs -> proximal tubule fluid is isosmotic to plasma
• Tubular fluid reaches equilibrium with interstitial fluid of RENAL MEDULLA, which is HYPERTONIC -> becomes more concentrated as it flows into the inner medulla

Question 4

Describe the Tubular fluid flowing through the Ascending loop of Henle

Answer 4

• Sodium, potassium and chloride are reabsorbed
• Impermeable to water in presence of large amounts of ADH -> tubular fluid becomes more dilute

Question 5

Describe the Tubular fluid flowing through the Distal and Collecting tubules

Answer 5

• Sodium chloride is reabsorbed
• In absence of ADH, this portion of tubule is impermeable to water
  [reabsorption of solutes + failure to reabsorb water -> dilute urine]

Question 6

What does the kidney do when there is a water deficit?

Answer 6

Forms concentrated urine by
- continuing to excrete solutes while increasing water reabsorption
- decreasing volume of urine formed

EXPLANATION: ability of kidney to form a small volume of concentrated urine minimises the intake of fluid required to maintain homeostasis

Question 7

What is the “Obligatory urine volume”?

Answer 7

The minimal volume of urine that must be excreted

Excretion of solute per day / maximal urine concentrating ability

Question 8

What is Urine specific gravity?

Answer 8

A measure of the weight of solutes in a given volume of urine + is determined by the number and size of solute molecules

The more concentrated the urine -> the higher the urine specific gravity

ADDITIONAL INFO: Relationship between specific gravity and osmolality is altered when there are significant amounts of large molecules (e.g glucose) which are heavy and give a false concentration

Question 9

What are the requirements for forming a concentrated urine?

Answer 9

• A high level of ADH = increases permeability of distal tubules and collecting ducts to water -> allow tubular segments to reabsorb water
• A high osmolarity of the renal medullary interstitial fluid = provides osmotic gradient necessary for water reabsorption to occur in presence of high levels of ADH

Question 10

What is the Countercurrent mechanism?

Answer 10

The mechanism by which the renal medullary interstitial fluid becomes hyperosmotic

It depends on:
- special anatomical arrangement of the loops of Henle
- vasa recta

Question 11

What factors contribute to the buildup of solute concentration into the renal medulla?

Answer 11

• Active transport of Na2+ and co-transport of K+, Cl- and other ions out of thick portion of ascending limb of loop of Henle into the MEDULLARY INTERSTITIUM
• Active transport of ions from collecting ducts into the MEDULLARY INTERSTITIUM
• Facilitated diffusion of urea from INNER MEDULLARY COLLECTING DUCTS into the MEDULLARY INTERSTITIUM
• Diffusion of small amounts of water from MEDULLARY TUBULES into MEDULLARY INTERSTITIUM

Question 12

What are the steps involved in causing Hyperosmotic renal medullary interstitium?

Answer 12

1) Loop of Henle is filled with a concentration of 300 mOsm/L, the same as that leaving the PROXIMAL TUBULE
2) Active ion pump in THICK ASCENDING LIMB on loop of Henle reduces concentration inside tubule (200) + raises interstitial concentration (400)
3) Tubular fluid in the DESCENDING LIMB OF THE LOOP OF HENLE + interstitial fluid reach osmotic equilibrium due to osmosis of water out of DESCENDING LIMB
4) Hyperosmotic fluid formed in DESCENDING LIMB flows into ASCENDING LIMB
5) Once fluid is in ASCENDING LIMB, additional ions are pumped into interstitium with water remaining in tubular fluid (interstitial fluid osmolality is 500)
6) Fluid in DESCENDING LIMB reaches equilibrium with hyperosmotic medullary interstitial fluid (500)
7) As fluid flows from the descending to the ascending limb, more solute is continuously pumped out + deposited into medullary interstitium

Steps repeat over and over again until fluid osmolality reaches around 1200-1400 -> “COUNTERCURRENT MULTIPLIER”

Question 13

What are the roles of the distal tubule and collecting ducts in excreting concentrated urine?

Answer 13

Distal tubule = Dilutes tubular fluid since actively transport NaCl out of tubule but is relatively impermeable to H2O

Collecting ducts = In presence of ADH, collecting ducts become highly permeable to H2O which reabsorbs into cortex interstitium

EXPLANATION:
The fact that the large amounts of water are reabsorbed into the cortex, rather than the renal medulla helps to preserve high medullary interstitial fluid osmolarity

Question 14

What are the steps of Urea reabsorption?

Answer 14

1) As water flows up the ASCENDING LOOP OF HENLE and into the DISTAL and CORTICAL COLLECTING TUBULES, little urea is reabsorbed since segments are impermeable to urea
2) In presence of high ADH, water is reabsorbed rapidly but not urea since CORTICAL COLLECTING TUBULE is not permeable to urea
3) Urea transporters in INNER MEDULLARY COLLECTING DUCT (UT-A1, UT-A2 + UT-A3[activated by ADH]) allow for urea to be reabsorbed, but not as much as water -> High concentration of urea in urine

ADDITIONAL INFO: Urea is transported PASSIVELY by DIFFUSION

Question 15

What happens to Urea in the early nephron?

Answer 15

• In Proximal tubule, 40-50% if filtered urea is reabsorbed
  [concentration in tube still increases since water is more permeable]
• Concentration rises since there is passive secretion of urea into the THIN LOOPS OF HENLE by UT-A2

ADDITIONAL INFO: Urea circulation provides an additional mechanism for forming a hyperosmotic renal medulla

Question 16

What features of renal medullary blood flow contribute to the preservation of the high solute concentration?

Answer 16

• Medullary blood flow is low
  [sufficient to supply metabolic needs of tissues but helps to minimise solute loss from the medullary interstitium]
• Vasa recta serve as countercurrent exchangers
  [minimise washout of solutes from the medullary interstitium]

Question 17

How does the countercurrent exchange mechanism work?

Answer 17

1) Blood enters and leaves the medulla by the VASA RECTA at the boundary of the cortex and renal medulla
2) As blood descends into medulla, it becomes more concentrated (due to solute entry from interstitium + loss of H2O)
3) As blood descends back towards cortex, it becomes less concentrated as solutes diffuse back into medullary interstitium + water moves into VASA RECTA

EXPLANATION: Vasa recta do not create the medullary hyperosmolarity but do prevent it from being dissipated

Question 18

What reduces urine concentrating ability?

Answer 18

• Vasodilators
• Large increases in arterial pressure

EXPLANATION: Both increase renal medullary blood flow with “wash out” solutes from the renal medulla which decreases the ability of H2O to flow out into the intersitium -> decreases urine concentrating ability

Question 19

Where does the urea absorbed into the medullary interstitium from the collecting ducts diffuse into?

Answer 19

The ascending loop of Henle

EXPLANATION: returns the urea to the tubular system + prevents its washout from renal medulla

Question 20

What is the equation to calculate Osmolar clearance?

Answer 20

C = U X V / P

C - osmolar clearance
U - urine osmolarity
V - urine flow rate
P - plasma osmolarity

Question 21

What is Free water clearance?

Answer 21

The rate at which solute-free water is excreted by the kidneys. When +ve, excess water is being excreted by the kidneys. When -ve, excess solutes are being removed from blood by the kidneys and water is being conserved.
[difference between water excretion (urine flow rate) and osmolar clearance]

C = V - (U X V / P)

V - urine flow rate
U - urine osmolarity
P - plasma osmolarity

Question 22

Which abnormalities can lead to the impairment of urine concentrating ability?

Answer 22

• Inappropriate secretion of ADH
  [either too much or too little]
• Impairment of the countercurrent mechanism
  [a hyperosmotic medullary interstitium is required for maximum urine concentrating ability]
• Inability of the distal tubule, collecting tubule and collecting ducts to respond to ADH

Question 23

What is “Central” diabetes insipidus?

Answer 23

An inability to produce or release ADH from the posterior pituitary which can be caused by head injuries, infections or can be congenital

CONSEQUENCES:
- distal tubular segments cannot absorb H2O in absence of ADH -> large amounts of dilute urine + thirst mechanism
- Severe dehydration can rapidly occur if not enough fluid intake

TREATMENT:
administration of ADH analog “DESMOPRESSIN” which acts on V2 receptors to increase water permeability in distal and collecting tubules

Question 24

What is “Nephrogenic” diabetes insipidus?

Answer 24

When there are normal/elevated levels of ADH but the renal tubular segments do not respond accordingly

CAUSES:
- failure of countercurrent system to form a hyperosmotic renal medullary interstitium
- failure of the distal and collecting tubules and collecting ducts to respond to ADH

CONSEQUENCES:
- large amounts of dilute urine + thirst mechanism
- severe dehydration if not enough fluid intake

TREATMENT:
- nephrogenic diabetes insipidus can be distinguished from central diabetes insipidus by administration of DESMOPRESSIN -> lack of prompt decrease of urine output within 2 hours -> diagnosis
- correct underlying renal disorder for treatment

Question 25

How can Plasma osmolarity be roughly approximated?

Answer 25

P = 2.1 X Plasma sodium concentration

P - plasma osmolarity

Question 26

What happens in the Osmoreceptor-ADH feedback system?

Answer 26

1) An increase in ECF osmolarity causes OSMORECEPTOR CELLS (located in the ANTERIOR HYPOTHALAMUS near the SUPRAOPTIC NUCLEI) to shrink -> Shrinkage causes them to send nerve signals to additional nerve cells in supraoptic nuclei which relay signals to the POSTERIOR PITUITARY
2) Action potentials stimulate release of ADH from the POSTERIOR PITUITARY which is stored in secretory granules/vesicles in nerve endings
3) ADH enters the blood stream + is transported to kidneys where it increases water permeability of late distal tubules, cortical collecting tubules and medullary collecting tubules
4) Increased water permeability in distal nephron segments increases water reabsorption + excretion of a small volume of concentrated urine

Question 27

What are the two neuronal regions that control ADH secretion?

Answer 27

• Hypothalamus contains two large neurons that synthesise ADH in the SUPRAOPTIC and PARAVENTRICULAR NUCLEI of the hypothalamus
  [when supraoptic and paraventricular nuclei are stimulated by increased osmolarity, nerve impulses increase permeability to Ca2+ ions -> ADH stored in secretory granules in released]
• Anteroventral region of the third ventricle called the “AV3V region” -> upper part is called “subfornical region” and lower part “organum vasculosum of lamina terminalis”, middle part is “median preoptic nucleus”
  [electrical stimulation of this region/stimulation by angiotensin II increases ADH secretion, thirst and sodium appetite]

Question 28

What are the stimuli for ADH secretion?

Answer 28

• Increased osmolarity
• Decreased arterial pressure
• Decreased blood volume
• Nausea
• Nicotine and morphine

Question 29

Describe how decreased arterial pressure and/or decreased blood volume cause stimulation of ADH release

Answer 29

TWO TYPES OF REFLEXES:
- Arterial baroreceptor reflexes
- Cardiopulmonary reflexes

1) Reflex pathways originate in high-pressure regions of the circulation (Aortic arch + Carotid sinus) and in low-pressure regions (Cardiac atria)
2) Afferent stimuli are carried by the VAGUS and GLOSSOPHARYNGEAL NERVE with synapses in NUCLEI OF TRACTUS SOLITARIUM -> projections relay signals to HYPOTHALMIC NUCLEI that control ADH synthesis and secretion

EXPLANATION: When blood volume and pressure are reduced (e.g in haemorrhage), increased ADH secretion causes increased fluid reabsorption by the kidneys -> helps restore blood pressure and volume towards normal

Question 30

Which areas make up the “Thirst centre”?

Answer 30

• Area along the anteroventral wall of third ventricle
• Area anterolaterally to preoptic nucleus

EXPLANATION: Neurons of the thirst centre respond to injections of hypertonic salt solutions by stimulating drinking behaviour

Question 31

What are the different stimuli for thirst?

Answer 31

• Increased extracellular fluid osmolality
• Decreased blood volume and arterial pressure
• Angiotensin II
  [associated with hypovalemia and low blood pressure -> helps restore blood volume + pressure towards normal and decreases fluid excretion]
• Dryness of mouth and mucous membranes of oesophagus

Question 32

Does Gastric distention increase or decrease Thirst?

Answer 32

Decrease thirst

Question 33

What is the “Threshold for drinking”?

Answer 33

When the thirst mechanism is activated due to increase in Sodium concentration -> restores extracellular fluid osmolarity and volume towards normal

Question 34

What is the function of Angiotensin II and Aldosterone in sodium concentration?

Answer 34

When sodium intake is low, increased levels of hormones stimulate stimulate sodium reabsorption by kidneys -> prevent large sodium losses

Question 35

How does angiotensin II and aldosterone have little effect on sodium concentration even during reabsorption?

Answer 35

• Both increase both sodium and water reabsorption by renal tubules -> increase in ECF volume and sodium quantity but little change in sodium concentration
• ADH-thirst mechanism makes sure that increase in plasma concentration is compensated by increase water intake/increased plasma ADH secretion

Question 36

What are the primary stimuli that increase salt appetite?

Answer 36

• Sodium deficits
• Decreased blood volume/pressure
  (associated with circulatory deficiency)

ADDITIONAL INFO: neuronal centres in AV3V region of brain are involved