Renal physiology

Question 1

What are the main functions of the kidney?

Answer 1

• regulation of ionic composition of blood (very important - excess sodium + chloride are excreted)
• regulation of blood pH (when pH changes = alkylosis or acidosis) -> works in conjunction with the lungs
• regulation of blood volume -> affects blood pressure (if blood volume high -> excrete more, low blood volume -> get thirsty, and hold onto more water)
• regulation of blood pressure (baroreceptors)
• maintenance of blood osmolarity (normal = 300 mOsmol)
• production of hormones -> erythropoietin, activated vitamin D (calcitrol) - also function as endocrine organ, production of red blood cells, ingest vitamin D and is activated in the kidneys
• regulation of blood glucose levels (filters glucose or reabsorbs glucose, kidneys can also create glucose from other things)
• excretion of wastes and foreign substances (not most essential function - surprisingly)

Question 2

What is the nephron?

Answer 2

Functional unit of the kidney
- have many in the kidney

Question 3

What is the renal corpuscle?

Answer 3

• ## first part of the nephron

Question 4

What are the barriers to filtration? What is filtered?

Answer 4

1. size of the molecule (pores restrict + basal lamina) - most proteins are too large, red + white blood cells too large
2. charge (repels negative charges) - except small negative charge molecules
3. volume of filtration restricted by podocytes
   * Ions, glucose, bicarbonate and amino acids are filtered - glucose should be 100% reabsorbed

Question 5

Should the following be in the urine? Yes or no? Why?
1. Leukocytes
2. Nitrite
3. Urobilinogen
4. Protein
5. pH
6. Blood
7. Specific Gravity
8. Ketone
9. Bilirubin
10. Glucose

Answer 5

1. No -> white blood cells should not be in the urine only in blood, probably an infection if yes
2. No -> supposed to have nitrate, converted to nitrite by bacteria - have a tract infection
3. Yes -> too much = bad (lots of red blood cell destruction/ death), too little = bad (hepatocytes - less enzyme function, damaged/ dead hepatocytes -> liver dysfunction
4. No, amino acids yes -> too big of a molecule + small proteins are repelled, if there is, means damage to corpuscle

Question 6

Should the following be in the urine? Yes or no? Why?
5. pH
6. Blood
7. Specific Gravity

Answer 6

5. 4.6-8.0 = normal, ~6 usually -> too acidic = bad (in state of acidosis), too basic = bad (in state of alkylosis)
6. No -> urinary tract infection, or damage to kidney
7. 1.001 (50 mOsM) - 1.06 (1400 mOsM)

Question 7

Should the following be in the urine? Yes or no? Why?
8. Ketone
9. Bilirubin
10. Glucose

Answer 7

8. some is ok -> too many ketones = making too many, ketoacidosis (related to diabetes)
9. No -> should be excreted in intestines + conjugated by liver -> may be caused by blockage - liver obstruction, too much bilirubin = jaundice
10. No -> kidney should reabsorb all of it

Question 8

Describe bilirubin metabolism

Answer 8

• red blood cell popped/ died, normal
  -> give up hemoglobin to recycle (goes to spleen)
  -> Haem (toxic, contains ion) from hemoglobin is turned into biliverdin then bilirubin in the spleen
  -> bilirubin goes to the liver, side group is added here to produced conjugated bilirubin, which makes it excretable in bile through the bile duct of the liver
  -> travels through duodenum (small intestine) to the large intestine
  -> in the large intestine some of the conjugated bilirubin is metabolized (by bacteria which have enzymes) into urobilinogen which enters the blood, the rest is excreted as bilirubin through the intestines
  -> urobilinogen from the blood enters the kidneys and both urobilinogen and urobilin can be excreted in the urine

Question 9

What are the nephron categories?

Answer 9

Labelled of of appearance + have slightly diff function
1. Cortical nephrons -> corpuscle sits much higher in the cortex -> loop of Henle enters only slightly into the medulla *80%
2. Juxtamedullary nephrons -> corpuscle sit lower in cortex -> right next to medulla -> loop of Henle extends deep into the medulla, almost to bottom *20% (if higher, more concentrated urine can be)

Question 10

What are the functional segments of the nephron in order of travel?

Answer 10

• Renal corpuscle
• Proximal tubule
• Descending limb of the loop of Henle
• Ascending limb of the loop of Henle
• Distal convoluted tubule
• Collecting duct

Question 11

How do cell types change throughout the nephron?

Answer 11

• epithelial cells are diff structurally throughout the nephron - signalling molecules also change
• cuboidal (tall), polarized, fringe faces lumen of tubule, microvili (increase surface area) -> proximal tubule cells = lots of mitochondria, produce lots of ATP
• simple squamous: thin limb segments of the loop of Henle -> not lots of mitochondria, doesn’t have to move much, mostly water
• cuboidal (heterogenous): collecting duct -> responsible for water + solute reabsorption, principle cells, inter-collated, have microvilli (mixture of cells)

Question 12

What is the glomerular filtration rate (GFR)? What is it affected by?

Answer 12

• the amount of fluid filtered in a day by the kidneys
• normal value of 180 L/day (125 mL/min)
• affected by
  -> net filtration pressure - like starling forces (mostly affected by the renal blood flow and blood pressure Pgc)
  -> filtration coefficient (mostly affected by the spaces in between podocytes and integrity (permeability) of the basal lamina
• kidneys have slow decline as you age - cannot regenerate, max capacity peak at 18

Question 13

What are the forces that go into net filtration pressure?

Answer 13

1. Hydrostatic pressure of glomerular capillaries (PGC), pressure due to presence of fluid (blood) in the glomerulus -> pressure out towards bowman’s capsule (+filtration)
2. Colloid osmotic pressure of the glomerular capillaries (πGC), pressure due to the presence of proteins in glomerulus (+reabsorption)
3. Hydrostatic pressure of Bowman’s capsule (PBC), pressure due to presence of fluid (filtrate) in the bowman’s capsule (+ reabsorption)
4. Colloid osmotic pressure of Bowman’s capsule (πBC), pressure if there is presence of proteins in Bowman’s capsule -> should not be there, should be 0 (+filtration)

Question 14

What is the equation for net filtration?

Answer 14

Net filtration = (PGC + πBC) - (PBC +πGC)
= filtration - reabsorption
*normal is 10, if pressure is too great = damage to corpuscle from high pressure - can get nephron apoptosis

Question 15

1. How can GFR be regulated by blood flow?
2. What would happen if both the afferent and efferent arteriole were restricted?

Answer 15

1. GFR can be increased or decreased quickly by constricting or dilating the arterioles surrounding the corpuscle
   - Afferent arteriole constricts -> pressure goes down, (PGC), restricts blood in corpuscle -> GFR goes down, net filtration goes down
   - efferent arteriole constricts -> pressure goes up (PGC), GFR increases, net filtration increases
2. Happens regularly due to angiotensin -> decreases pressure, restricts afferent, so less blood, easier to move out

Question 16

What is the filtration coefficient?

Answer 16

• the net filtration pressure mostly contributes to the GFR
• but surface area available for filtration and permeability of barriers can contribute to the GFR

Question 17

What would be the consequence of the following?
1. Increasing space between podocytes
2. Increasing the permeability of the basal lamina
3. Increasing the size of the glomerular pores

Answer 17

1. physiologically normal adaptation = more filtration (greater volume)
2. increases filtering of proteins -> condition called alport syndrome may cause this, start filtering proteins, increases pressure, can cause kidney damage (should not happen)
3. damage to basal laminae

Question 18

Describe the auto-regulation of the GFR

Answer 18

• blood pressure fluctuates throughout the day
• need protection of glomerulus from damage if GFR gets too high
• need to ensure constant filtering of blood
  Two auto-regulatory mechanisms that function to keep GFR mostly constant throughout the day:
  1. Myogenic response
  2. Tubuloglomerular feedback

Question 19

What is the myogenic response?

Answer 19

blood pressure increases
-> afferent arteriole stretches
-> stretch sensitive ion channels open (mechanically gated)
-> smooth muscle cells depolarize
-> voltage-gated calcium channels in the smooth muscle open
-> smooth muscle of the afferent arteriole contracts (constricts afferent arteriole)
-> diameter decreases - reduce GFR
*in order so that GFR doesn’t spike when bp increases

Question 20

What is the tubuloglomerular feedback?

Answer 20

When GFR increases due to higher blood pressure:
-> increased filtered load of ions (NaCl) into capsular space
-> macula densa cells detect rise in NaCl (signalling cascade)
-> macula densa cells release a chemical messenger (ATP which is cleaved extracellularly to adenosine)
-> adenosine causes vasoconstriction of the afferent arteriole
-> GFR is therefore reduced
* in other tissue adenosine causes vasodilation, in kidney cause vasoconstriction (diff reception)
If the GFR decreases due to lower blood pressure:
-> macula densa cells release nitric oxide instead, causing vasodilation of the afferent arteriole
-> tubule fluid flows slower, increases GFR
* macula densa cells have cilia (non motile) which detect the fluid as it moves by

Question 21

How do you measure GFR?

Answer 21

• difficult to physically measure the fluid moving into Bowman’s capsule without being invasive
• but can measure urine easily
  Excretion = filtration - reabsorption + secretion
• measuring total urine production is insufficient to determine how much fluid was filtered in a day (need to look at what is in there)
  Excretion (substance X) = filtration (substance X) - reabsorption (substance X) + secretion (substance X)
• if susbtances X isn’t reabsorbed and isn’t secreted, then the rate that substance X is excreted is equal to the rate it was filtered

Question 22

What are the values of normal, insufficient, moderate failure, and failure of GFR measurements?

Answer 22

Normal value = 100-150 mL/min
Renal insufficiency = 50-99 mL/min
Moderate renal failure = 10-49 mL/min
Renal failure = less than 10 mL/min

Question 23

What is eGFR?

Answer 23

• estimated GFR is a simpler measurement, but has many issues with estimations
• age is taken into account, due to natural kidney decline that occurs with aging and muscle mass
• however, handling and production of creatinine isn’t the same in all people
  -> variables: creatinine, age, sex, race (very inaccurate - caused problems for people who needed to be put on dialysis earlier)
  -> standardized eGFR calculations have “coefficient” estimations for race, but these are not accurate and has resulting in harm -> not properly estimating GFR and therefore missing diagnoses of chronic kidney disease

Question 24

Why is it important to calculate GFR?

Answer 24

Once know someones GFR can see how much substance someone can handle (e.g. administering something)
-> Filtered Load (amount filtered/ day) = (substance)plasma * GFR

Question 25

How do you estimate GFR?

Answer 25

• plasma creatine measured and/or alternate measurement of cystatin C
• if measured value is higher than expected, then used to indicate a decline in kidneys ability to filter total fluid -> the calculated eGFR results in medical interventions (treatment)
• for creatinine: higher muscle mass should equal more creatinine production -> attempts to accurately predict normal ranges of plasma creatinine levels -> previous inaccuracies for estimations are being corrected
• continued research to find better metabolite to measure GFR

Question 26

What is the filtered load?

Answer 26

• how much of a substance found in the blood that can be filtered can be calculated using the measured/ estimated GFR
  Filtered load = (substance)plasma * GFR

Question 27

What is reabsorbed in the following segments of the tubule? (overview)
Proximal tubule
Descending limb
Ascending limb
Distal convoluted tubule
Collecting duct

Answer 27

Proximal tubule = glucose, amino acids, H2O, Na+, K+, Cl-
Descending limb = H20 and minimal Na+
Ascending limb = only ions, Na+, K+, Cl-, Mg2+, Ca2+
Distal convoluted tubule = Na+, K+, Cl-, Ca2+
Collecting duct = Na+, H2O

Question 28

What are the different types of tubule transport?

Answer 28

1. Secretion: from the interstitium into the lumen
2. Transcellular: Goes through both cell membranes (apical and basal lateral)
3. Paracellular: can pass in between the cells (tight junctions)

Question 29

Describe sodium reabsorption + examples

Answer 29

• ion that drives reabsorption throughout the tubule
• 30x concentration gradient from filtrate to tubule cells
• Na+ would like to move into tubule cells but requires transporters
  Examples:
  1. Sodium channel -> ENaC
  2. Sodium symporters -> Na+/ glucose symporters (SGLT1 & SGLT2)
  3. Sodium exchangers -> Na+/ H+ exchanger (NHE3) - antiporter
  4. Sodium/ potassium ATPase

Question 30

Describe the anion transport of chloride + examples

Answer 30

• ion reabsorption should remain electroneutral
• chloride is the major anion reabsorbed
• chloride challenges -> transport is against an electrical gradient into tubule cells (negative) -> transport out of tubule cells must have a chemical gradient
  Examples:
  1. Chloride channels
  2. Chloride symporters (i.e. NCC) - only one has to have favourable movement to function
  3. Chloride multiporters (i.e. NKCC2) - move 4 things

Question 31

Describe water reabsorption + examples

Answer 31

• as ions like sodium and chloride are being reabsorbed in tubule epithelial cells, water would like to follow via osmosis
• can do so only if there are transporters in the membranes for water
  Examples:
  1. Water channels - osmosis, human genome encodes many different channels, including aquaporins (AQ) I, II, III & IV
  2. Paracellular water reabsorption - occurs in the proximal portion of the tubule and nowhere else

Question 32

Describe the transport mechanisms in the proximal tubule

Answer 32

Overall theme - reabsorbs almost everything
1. Na+/ H+ antiporter on apical membrane(acid/ base balance) -> angiotensin 2 regulated
- Sodium/ potassium ATPase (on every cell basolateral membrane) - keeps Na+ concentration low in the cells to allow the other symporter to keep working -> also angiotensin 2 regulated
2. Na+/ Amino acid symporter, secondary active transport (Na+ moves w/ gradient), amino acids against gradient
- amino acid uniporter at basolateral membrane
3. Na+/ Glucose symporter, secondary active transport (Na+ moves w/ gradient) -> SGLT2 moves 1 Na+, 1 glucose -> SGLT1 moves 2 Na+, 2 glucose
- glucose uniporter on basolateral membrane
4. Aquaporins -> aquaporin 1, moves by osmosis
5. Paracellular transport, slightly leaky -> H2O, K+, and Cl- (maintain electroneutrality)

Question 33

Describe the transport mechanisms in the loop of Henle: descending limb tubule

Answer 33

Overall theme - reabsorbs water
1. Aquaporin 1 -> reabsorbing water (same channel on both membranes, apical and basolateral) -> concentration of the medulla is very high, why water can move out of these cells
2. Few sodium channels (very minimal) + Na+/K+ ATPase still on basolateral membrane, not very metabolically active though
* no hormones act on the descending limb

Question 34

Describe the transport mechanisms in the loop of Henle: ascending limb

Answer 34

Overall theme - reabsorbs ions
1. Na+ channels
2. NKCC2 -> ion multiplier, symporter, brings 4 ions across w/ one conformation change (Na+ w/ gradient - drives transport, 2 Cl- w/ concentration gradient, against charge, and K+ against gradient) -> exist Cl- channels (not used frequently, only if there is build up of Cl-) and K+/Cl- symporters (K+ drives transport) on basolateral membrane
3. K+ channel, potassium ions move back into the lumen across the apical membrane, recycling itself for symporter (limited potassium)
4. Paracellular transport of ions (Na+, Ca2+, and Mg2+) leak out between the cells
* impermeable to water, incapable of moving

Question 35

Describe the transport mechanisms in the distal convoluted tubule

Answer 35

Overall theme - reabsorbs ions
1. NCC -> Na+, Cl- symporter -> K+/Cl- symporter on basolateral membrane
2. Ca2+ channels -> has Ca2+ and Na+ antiporter on basolateral membrane (3 Na+ into cell, Ca2+ out of cell) - parathyroid hormone acts on this exchange (makes work more efficiently), similar exchange as in the cardiac system
3. Na+ channels along with the Na+/K+ ATPase (3 Na+ out, 2 K+ in)on the basolateral membrane again

Question 36

Describe the transport mechanisms in the collecting duct: principal cells

Answer 36

Overall theme - reabsorbs ions and water if necessary
1. Na+ channels - regulated by aldosterone hormone (makes more channels, moves more channels to membrane) -> still Na+/K+ ATPase on basolateral membrane (also responsive to aldosterone
2. Potassium leak channels (allows to be secreted and excreted, responds to aldosterone) - apical membrane
3. K+ gated channel - closed “big capacitance” -> allows secretion only when gate is opened (regulated by aldosterone)
4. Aquaporin 2 -> responds to anti-diuretic hormone, causes to be more permeable to water

Question 37

Describe uric acid handling

Answer 37

• from nucleotides -> purines breakdown
• increased levels or uric acid (urate) in blood is called hyperuricemia (animal meat will increase these levels + beer)
• both gout and kidney stones can be caused by hyperuricemia (gout = crystals form in the join, pain - like arthritis)
• most of the filtered uric acid is reabsorbed in the proximal tubule (body likes some uric acid, helpful metabolite)
• if in excess in the blood, uric acid is then secreted back into the tubule
• increased uric acid can result in either gout or uric based on kidney stones (some people are predisposed to gout + kidney stones)

Question 38

Describe the hormonal regulation of sodium balance

Answer 38

• when sodium levels are high, the ECF volume increases as does blood pressure
• have receptors to detect changes in blood pressure and filtrate composition to activate these pathways
• two hormone systems regulate body levels of sodium:
  1. Renin-Angiotensin-Aldosterone system (RAAS) -> sodium levels are low
  2. Atrial Natriuretic peptide (ANP) -> sodium levels are high

Question 39

Describe the Renin-Angiotensin-Aldosterone system (RAAS)

Answer 39

• Renin is the rate limiting enzyme secreted by juxtaglomerular cells
  -> the liver secretes angiotensinogen (protein which doesn’t have a function)
  -> renin secreted by juxtaglomerular cells (in corpuscle region) converts angiotensinogen to angiotensin I (peptide - no hormonal function)
  -> ACE (angiotensin converting enzyme) in endothelial cells cut parts off of angiotensin I to convert to angiotensin II (small peptide hormone)
  -> angiotensin II travels in the circulation, and stimulates the release of aldosterone from the adrenal glands (a steroid hormone)
  -> both can function to conserve Na+ in the blood

Question 40

What is angiotensin II?

Answer 40

• peptide hormone
• stimulates renal and cardiovascular effects
• increased reabsorption of Na+ (sodium is already low - want in the proximal tubule vasoconstriction of the afferent and efferent arteriole, decreasing GFR

Question 41

Describe the activation of AT1 by angiotensin II

Answer 41

• AT1 receptor allows the exchange of Na+ and H+ -> more sodium reabsorption
• angiotensin II binds to this receptor and causes increased sodium reabsorption both at the apical membrane (Na+/ H+ antiporter) and at the basolateral membrane (Na+/K+ ATPase)

Question 42

What is aldosterone?

Answer 42

• aldosterone increases reabsorption of Na+ in principal cells
• released due to angiotensin II, or high levels of plasma K+
  -from adrenal gland, adrenal cortex layer specifically

Question 43

What is the mineralocorticoid receptor activation by aldosterone?

Answer 43

• can insert more Na+ channels to apical membrane (increases Na+ reabsorption)
• moves to nucleus, increases mRNA transcription (genomic effects), increasing proteins + Na+ channels (Na+/K+ ATPase)
• movement of K+ channels to apical membrane

Question 44

Describe the regulation of renin release

Answer 44

Detection of low sodium by:
1. Baroreceptors
-> carotid sinus baroreceptors that reflex to juxtaglomerular (JG) cells (sympathetic innervation)
-> JG cells are also intrarenal baroreceptors
(from low blood pressure)
2. Chemoreceptors
-> macula densa cells release a paracrine factor (when Na+ levels are low)

Question 45

What is the function of macula dense cells?

Answer 45

• macula densa cells can detect NaCl content in the filtrate due to the activity of the ion multiplier (NKCC2)
• when NaCl levels are low, prostaglandins are released -> prostaglandins cause a signalling cascade which activates receptors on JG cells to promote renin release
• when NaCl levels are higher, macula densa cells release ATP (& adenosine), this inhibits JG cells = no secretion

Question 46

What is tubuloglomerular feedback?

Answer 46

Macula densa cells also have cilia which bend in response to filtrate flow rate
- if filtrate flow rate is low then (also low Na+):
-> NO (nitric oxide) and prostaglandins released, so GFR increases (b/c of NO- acts on afferent arteriole) and more renin is released (b/c of prostaglandins), respectively
- if filtrate flow rate is high then (also high Na+):
-> ATP (& adenosine) released and GFR decreases and renin is inhibited

Question 47

What is atrial natriuretic peptide (ANP)?

Answer 47

• produced by atrial cells of heart
• peptide hormone
• stimulus of high blood pressure
• stretch receptors in the atria detect increase in blood in the atria
• actions to reduce sodium reabsorption by: -> inhibits aldosterone release from the adrenal cortex -> increases GFR (ANP is a vasodilator of the afferent arteriole)
• released when Na+ is higher -> vasodilator, released when blood pressure is high

Question 48

What causes the release of the anti-diuretic hormone?

Answer 48

• high plasma osmolarity
• low blood pressure
• low blood volume
• when all working together, result in maximal ADH release
  -> ADH activation of V2 receptors on principal cells - increasing water reabsorption in the collecting duct (permeability of collecting duct to water can vary a lot) -> increased movement of aquaporin channels to the apical membrane
  -> if want to decrease absorption, can keep channels in vesicles, cause collecting duct to be completely impermeable to water

Question 49

What changes when there is no anti-diuretic hormone present vs when it is present in the nephron?

Answer 49

1. No ADH -> aquaporin 2 channels are all endocytosed in the collecting duct (impermeable to water) - osmolarity doesn’t change compared to the distal convuluted tubule (large volume, dilute urine)
2. ADH present -> aquaporin 2 channels present, permeable to water, the osmolarity increases through the collecting duct (low volume, concentrated urine)