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Physiology > Renal Physiology and pH > Flashcards

Renal Physiology and pH Flashcards

1
Q

Give the equation for filtration rate:

A

Filtration rate = filtration pressure x SA x hydraulic permeability

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2
Q

How would you measure GFR? Why use inulin?

A
  • Infuse inulin at a steady rate until [arterial] is constant
  • GFR = rate of infusion/plasma concentration (effectively measures efficiency of filtration)
  • Use inulin as: freely filtered, not synthesised or metabolised, non-toxic, does not alter renal function.
  • Can also use creatine (released from muscles) using difference between blood and urine concentration.
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3
Q

What is clearance? How would you calculate it?

A

The volume of plasma that would have to be fully cleared of substance to give the excretory rate
- I.e. high clearance means removed quickly by kidneys

Equation: Clearance of X = ѵ (urine flow rate) x [X]u/[X]a in ml/min

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4
Q

How could you measure total bodily fluid volume?

A

Single Injection method:
- Injection into compartment and concentration measured at intervals
- Liner decay (on log graph) means concentration can be extrapolated back
- Using Evan’s blue dye

Constant perfusion method:
- Priming injection given then infused at a constant rate
- Concentration of marker = concentration in ECF when perfusion rate = excretion rate

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5
Q

Suggest markers used to measure bodily fluid volumes and why:

A

Requirements:
- Non-toxic
- Not metabolised or produced by body
- Doesn’t cross into other areas
- Easily measurable
- Distribute evenly
- Volume should be fixed

Examples: inulin, mannitol, thiosulphate, Na+ radioisotopes.

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6
Q

How can renal plasma flow rate be measured?

A

Using clearance: if completely cleared then clearance = renal flow rate
- Measure para-amino Hippurate (PAH) levels, since filtered and actively secreted

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7
Q

What is effective renal plasma flow?

A

Takes into account that PAH is filters in peritubular capillaries which get 90% of blood flow so RPF≈ERPF/0.9

Blood flow worked out using Fick’s principle (blood flow worked out using concentration in blood and urine of known marker concentration)

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8
Q

What evidence is there for isosmotic fluid reabsorption?

A

Simple micropuncture:
- Sampling early and late PCT fluid shows no osmotic change
- Measured using inulin since freely filtered so change to [inulin] proportional to change in volume of fluid
- [Inulin] decreases so volume decreases

Split oil drop experiments:
- Mineral oil injected into Bowman’s capsule to stop PCT flow
- Second injection of test fluid (e.g. isotonic NaCl) splitting oil drop
- With time, drops move closer together = shows decrease
- Test fluid resampled and still isotonic with plasma

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9
Q

What evidence is there for the medullary osmotic gradient?

A
  • A kidney from a dehydrated (urine concentrating) animal is frozen and sectioned
  • Solute concentrations estimated from melting points of different regions
  • Suggests osmotic pressure constant in the cortex and rises from medullary boundary to inner medulla.
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10
Q

What evidence is there that cell volume changes allow ECF osmolality detection?

A

Experiments on magnocellular cells in hypothalamus:
- Cell can be placed in hypotonic solution but suction applied intracellularly to decrease pressure and cause cell shrinkage
- Stretch-inactivation of Na+ channels reduced so depolarisation stimulated.

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11
Q

What evidence is there for aldosterone being the major [K+] controller?

A
  • Adrenalectomized dogs are infused with aldosterone at a constant rate
  • Can regulate their Na+ concentration when [Na+] in food differed
  • Cannot regulate [K+] when altered in food
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12
Q

What are the 4 general functions of the kidneys? (Broad catagories)

A
  • Extracellular fluid regulation (pH, electrolyte balance and osmotic pressure)
  • Long-term blood pressure regulation
  • Excretion of metabolic waste
  • Regulation of erythropoiesis
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13
Q

Describe how ultrafiltration occurs (including anatomy):

A
  • Fluid under pressure is pushed through fenestrations in the capillary, basement membrane and then podocyte foot processes
  • Filters sizes between 7,000-70,0000Da
  • Filters charge: filters have -ve charge which repels protein (anionic at physiological pH) which retains cations in plasma.
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14
Q

What is a Donnan equilibrium?

A
  • During ultrafiltration, cations are retained since proteins are repelled by -ve filtration barrier
  • Retains cations at physiological pH
  • Anions are too small to be directly affected by -ve filtration barrier
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15
Q

What is the Van’t Hoff law?

A

Colloid osmotic pressure is proportional to the concentration of particles.

  • Proteins do not obey this law (particularly albumin)
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16
Q

What factors increase GFR? (Think Starling’s equation).

A
  • Kf : increased SA for filtration due to relaxation of mesangial cells
  • Pc : increased renal arteriole pressure and decreased afferent arteriole resistance (both increase flow rate)
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17
Q

What factors decrease GFR?

A
  • πc : Increase in colloid osmotic pressure (e.g. starvation) or decreased renal plasma flow
  • Pb : increased intratubular pressure (obstruction by kidney stone)
  • Pc : increased efferent arteriole resistance (decreased renal blood flow outweighs increased pressure for filtration)
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18
Q

What autoregulation mechanisms does the kidney have to minimise the effect of blood pressure changes on GFR?

A

Myogenic mechanisms:
- Smooth muscle in arteriole contracts when stretched using non selective cation channels (Na+/Ca2+) causing contraction

Tubuloglomerular feedback:
- Increased GFR increases rate of Na+ and Cl- to macula densa
- Causes ATP release which constricts efferent arteriole
- Adenosine may also result in afferent and mesangial cell control

Renin-angiotensin system: controls ratio of afferent/efferent arteriole constriction.

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19
Q

Why is [Cl-] the controlling variable for GFR feedback to the macula densa?

A
  • Though increased GFR will lead to more Na+ and Cl-, [Cl-] is controlling factor
  • Since NKCC2 pumps always saturated with Na+ as high affinity but Cl- transporters not (lower affinity)
  • Hence small changes in [Cl-] are more significant.
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20
Q

Which molecules are reabsorbed in the PCT?

A

PCT for CONSERVATION (reabsorption)

  • Glucose
  • Amino acids
  • Protein
  • Hydrogen carbonate
  • Secretion of anions using low-specificity pumps (e.g. bile salts, oxalate, aspirin, PAH)
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21
Q

How is glucose reabsorbed in the PCT?

A

Na+ coupled secondary active transport (all filtered out unless hyperglycaemia occurs leading to glucosuria (=glucose in urine)):
- SGLT-2 transporters (1Na+/1 glucose)
- SGLT-1 transporters (1Na+/2 glucose)
- SGLT-2 density higher at start of PCT; SGLT-1 higher at end
- Na+/K+ pump created Na+ gradient; glucose moves down by facilitated diffusion

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22
Q

How are proteins (and amino acids) reabsorbed in the PCT?

A

Amino acid reabsorption:
- 5 different non-selective transporters depending on properties (acidic; basic; neutral; Imino acids; glycine)
- Creates competition for certain transporter types

Protein reabsorption:
- Partially degraded by peptidases on brush border then taken up by endocytosis
- Vesicles fuse with lysosomes then hydrolysed and ααs moved by f.diffusion
- Smaller peptides (e.g. ADH, angiotensin II) completely hydrolysed in tubule

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23
Q

How is HCO3- reabsorbed in the PCT?

A
  • NHE3 transporters lower cell pH and allow carbonic acid formation in lumen
  • Carbonic anhydrase aids CO2 and H2O formation
  • CO2 absorbed and remade into HCO3-
  • Secondary active transport out of cell (NBC1 (uses Na+ to symport which is rare) and HCO3-/Cl- antiport pump AE1)
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24
Q

What evidence is there for isosmotic fluid reabsorption in PCT being driven by Na+/K+ pump?

A

Treatment with 2,4-DNP:
- Leads to very reduced water reabsorption
- Since 2,4-DNP uncouples oxidation from ATP synthase so no active transport occurs.

Treatment with ouabain:
- Shows Na+ drives it since blocks Na+ transporter specifically.

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25
Q

How does the LoH uncouple water and NaCl reabsorption? Describe transport in each section of LoH:

A

Using counter current multiplier effect:
- Modest transverse gradient (set by transporter maxima) to be multiplied into steep longitudinal gradient.
- Thin ascending limb = passive NaCl reabsorption into interstitium
- Thick ascending limb = NaCl actively transported out and water follows via leaky tight gap junctions in descending limb
-

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26
Q

Describe movement of substances in the collecting duct:

A

Cortical CD:
- Fluid entering is hypoosmotic to plasma so water moves out
- Extra NaCl absorbed driving more water out
- Extent of NaCl absorption changed by ADH.

Medullary CD:
- When ADH is high and CD water permeable, water drawn out causing concentrated urine

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27
Q

What are vasa recta and what is their function?

A

Long capillary tubes allowing solute and water diffusion without destroying medullary gradient.
- Counter current exchange diffusion with blood
- higher colloid osmotic pressure of blood and incomplete equilibration allows blood to carry away reabsorbed solute.

28
Q

What is the effect of urea in the kidney?

A
  • Nephron mostly poorly permeable to urea (concentration in tubular fluid rises)
  • ADH increases urea permeability of inner medullary collecting duct (IMCD) allowing passive diffusion into interstitial fluid.
  • Urea recycling between LoH and IMCD allows high [urea] to build up, increasing osmotic pressure
  • Can contribute 50% of osmotic pressure in concentrating kidney
29
Q

How does a change in blood pressure result in renin release?

A

Afferent arteriole acts as internal baroreceptor:
- Fall in pressure leads to renin release

Macula densa senses change in flow rate:
- Decrease in flow rate stimulates renin release (as suggests upstream constriction to maintain filtration pressure given reduced volume)

30
Q

Why is constriction of the afferent arteriole not sufficient to increase filtration rate?

A
  • Increases filtration fraction
  • However, also increases pressure in peritubular capillaries which reduces reabsorption
  • Also increases back leakage at Bowman’s capsule due to raised interstitial pressure
31
Q

How can sympathetic nerves increase water retention?

A

Release of hormones:
- Renin (and then angiotensin II and aldosterone)

Constriction of renal arteries:
- makes efferent resistance > afferent resistance
- Increases filtration fraction
- Increased reabsorption back into blood in peritubular capillaries (increased COP)

Directly stimulates Na+ reabsorption in PCT by adding NHE3 transporters.

32
Q

How is renin release stimulated?

A

When BP is low (retention mode)
- Stimulation by sympathetic nerves through NA secretion
- On β1 adrenoreceptors (Gs) on specialised smooth muscle cells

[Often in conjunction with direct stimulation of PCT for Na+ reabsorption via α1-adrenoreceptors (Gq)
to add NHE3 transporters]

33
Q

How does renin result in angiotensin II formation?

A
  • Renin secreted by smooth muscle cells in afferent arteriole
  • Renin catalyses the production of angiotensin I from angiotensinogen
  • Angiotensin I to II catalysed by ACE in lungs
34
Q

Detail the effects of angiotensin II:

A
  • Na+ absorption in PCT (binds AT1 receptor to increase NHE transporter density)
  • Stimulates aldosterone synthesis and secretion
  • Stimulates hypovolaemic thirst
  • Stimulates sodium appetite
  • Vasoconstriction of efferent arteriole
35
Q

What are the effects of vasoconstricting the efferent renal arteriole?

A
  • Reduced RBF since resistance increased overall
  • Therefore a fall in pressure in peritubular capillaries and vasa recta (promotes Na+ reabsorption)
  • Slight increase in filtration fraction but GFR reduced due to lower blood flow
  • Stabilisation of GFR (important in severe hypovolaemia)
36
Q

Detail the effects of aldosterone:

A

Acts on CD by stimulating new protein synthesis in principle cells:
- Increased transepithelial potential
- Promote Na+ reabsorption through ENaC channels and in long term Na+/K+ATPase
- Promote H+ and K+ secretion (through small conductance SK channels

37
Q

How is aldosterone secretion stimulated?

A

Angiotensin II:
- Binds to AT2 receptors in distal nephron stimulating aldosterone synthesis

Increased [K+]:
- Secreted by zona glomerulosa of adrenal gland

38
Q

What is ANP? Where is it produced?

A

Atrial natriuretic peptide:
- Produced by atrial myocytes when stretch increases
- Suggests high BP

39
Q

Detail the effects of ANP:

A

Acts to reduce BP by reducing ECFV:

  • Inhibition of Na+ reabsorption in collecting duct (increases cGMP which phosphorylates ENaC channels reducing their activity)
  • Inhibition of Na+ reabsorption in PCT: cells locally secrete dopamine which inhibits reabsorption
    Inhibition of renin
  • Dilation of glomerular mesangial cells: increased SA for filtration
  • Vasodilation of afferent and efferent arterioles (efferent more) raising relative glomerular hydrostatic pressure
  • Inhibition of ADH secretion in supra optic nucleus (SON)
40
Q

What is Addison’s disease?

A

Adrenal insufficiency:
- Aldosterone deficiency causing reduced ECF volume and low BP
- Can be improved by intaking large amount fo salt.

41
Q

How is Ca2+ reabsorbed in the PCT and LoH?

A

Fixed reabsorption in PCT

  • Paracellularly due to +ve transepithelial potential; increases solvent drag

Transcellular absorption:
- Entry into cells through TRPV5/6 and moved through by calbindin-D
- Exits through Ca2+/ATpase and NCX (Na+/Ca2+) transporter.

Fixed reabsorption in LoH: paracellular (in ascending limb) and transcellular

42
Q

Describe the different properties of NCX and Ca2+/ATPase:

A

NCX is low affinity, high transport capacity

Ca2+/ATPase is high affinity, low capacity

43
Q

How can PTH increase Ca2+ in the DCT and CD?

A
  • Variable reabsorption in CD and DCT: increases Ca2+ reabsorption by phosphorylation of NCX transporters
  • Increases 1,25-Dihydroxycholecalciferol (1,25-DHCC) which increases:
  • TRPV5 and 6 expression
  • Calbindin-D
  • NCX and type II Na+/Pi channel densities.
  • No paracellular transport as potential is wrong direction
44
Q

How is phosphate reabsorbed in the PCT?

A

Taken into cells by:
- Type IIa (3Na+/HPO42- transporter)
- Type IIc (2Na+/HPO42- transporter)
- Type III 2Na+/H2PO4- transporter.
(Na+ gained from Na+/K+ transporter)

Exits cells through:
- Anion/HPO42-
- Anion/H2PO4- transporters (A- commonly oxalate)

45
Q

How does PTH decrease phosphate reabsorption?

A

PTH can bind on both cell surfaces (luminal = Gq receptor and interstitial = Gs receptor) causing decreased type IIa and c receptor density:
- Phosphorylation of scaffold protein NHERF-1 causes its dissociation from channel
- Allows channel to be endocytosed
- Effect on type IIa is faster than for type IIc

46
Q

Name some factors which can affect the ECF [K+]:

A
  • Hormones (insulin, aldosterone, adrenaline)
  • Acid-base balance (acidosis increases [K+] as H+ brought into cells and K+ pushed out)
  • Plasma osmolality (cell shrinkage causes K+ excretion)
  • Cell lysis (due to damage)
  • Exercise (K+ leaves muscles during contraction - effect opposed by adrenaline)
47
Q

How is K+ reabsorbed in the PCT and LoH?

A

PCT:
- Paracellular diffusion through leaky tight gap junctions

LoH thick ascending limb:
- Transcellular by secondary active transport
- Entry through NKCC2; exit via Cl- symporters
- Paracellular diffusion ascending limb due to transepithelial potential

48
Q

How can the DCT/CD show such a wide range of K+ transport?

A

Can show either secretion or reabsorption! Depends on:

  • Na+/K+ ATPase density and activity
  • The electrochemical gradient for K+ loss
  • Permeability for Na+ and K+ of the luminal membrane (SK channels; Na+/K+ pump)
  • Reabsorption of K+ by type A intercalated cells (to maintain H+ homeostasis)
49
Q

What hormonal and physical controls affect K+ homeostasis?

A
  • High [K+] causes aldosterone synthesis and release
  • Changes flow rate: increased flow rate increases secretion of K+
  • ADH stimulates K+ secretion (though slows flow rate; increases luminal K+ permeability)
50
Q

What is the Henderson-Hasselbalch equation? What is normal physiological pH?

A

Normal physiological pH: blood = 7.4; CSF = 7.3 within very small range.

Henderson-Hasselbalch: relates concentrations of conjugate pairs and pH:
pH = pKa + log10([base]/[acid])

51
Q

How can ingestion affect pH?

A

Excess non-volatile fatty acids:
- Sulphuric acid from methionine and cysteine
- H2PO4- from phospholipids and phosphorylated proteins

52
Q

What is the isohydric principle and how can it be applied to the HCO3-/H2CO3/CO2 system?

How is pH calculated from this buffer system?

A

Isohydric principle: if multiple buffers interacting; control of one component allows control of the whole system:

pH = composite pKa + log10([HCO3-]/[H2CO3]) = 6.1 + log10([HCO3-]/0.03 x pCO2)

Effectively: 6.1 + log10(kidneys/lungs)

53
Q

Describe how [pCO2] is measured and resulting physiological buffering:

A

Measured by central chemoreceptors in IVth ventricle
- CO2 diffuses across BBB
- Lower pH increases AP frequency
- Stimulates increased breathing rate

Physiological buffering;
- CO2 formed is excreted from lungs
- HCO3- regulated by liver and kidneys
- Tissue buffering: hydroxyapatite in bone accepts protons in acute acidosis

54
Q

How is [HCO3-] regulated by kidneys and liver?

A

Kidneys:
- New HCO3- produced from glutamine (produces 2 moles of HCO3- and NH4+)
- Excess is eliminated and excreted in urine through urea formation

Liver:
- Forms glutamine for breakdown in kidneys by combining NH4+ with α-ketoglutarate
- Low pH promotes more glutamine conversion

55
Q

What is the urea cycle in the liver?

A
  1. Catabolism of primary carboxyl and amino acid groups produces NH4+ and HCO3-.
  2. NH4+ is toxic and is turned into glutamine by combination with α-ketoglutarate
  3. Glutamine converted to urea in kidneys:

2(HCO3- + NH4+) = CO2 + H2O + urea

  1. CO2 produced con be blown off by lungs, shifting equilibrium away from HCO3-.
56
Q

How do plasma proteins and the phosphate system help to regulate pH?

A

Plasma proteins:
- Can reversibly bind CO2 to amine groups
- E.g. in Hb CO2 binds to imidazole groups on histidine amino residues of α/β chains

Phosphate system:
- Shifts equilibrium between H2PO4-/HPO42-

Together contribute approx. half of buffering capability

57
Q

How are the products of glutamine degradation transported in the PCT?

A

NH4+ transport: Into lumen
- Closely resembles K+ in size and charge hence uses same transporters
- Replaces H+ in NHE3 transporter into lumen
- Diffusion through leaky gap junctions

HCO3- transport: into interstitium:
- Reabsorbed through conversion to CO2 and H2O

58
Q

Why is the pH of tubular fluid limited?

A

Transepithelial potential:
- Acidity of PCT fluid limited as NH4+ (alkaline) can diffuse through gap junctions

59
Q

How are the products of glutamine degradation transported in the LoH?

A
  • HCO3- reabsorbed slowly (no CA) in thick ascending limb
  • NH4+ reabsorbed by replacing K+ in NKCC2 and K+/Cl- transporters
  • Transepithelial potential pushes out NH4+
  • NH3 diffuses across cells (extra proton excreted
60
Q

How are the products of glutamine degradation transported in the DCT/CD?

A
  • Remaining HCO3- is reabsorbed by type A intercalated cells (see above sections)
  • Ammonium trapping: NH4+ converted to NH3 then trapped as NH4+ once in lumen
  • NH3 diffuses into lumen passively and is transported out by rhesus glycoprotein transporters (Rhbg and Rhcg from interstitium then only Rhcg to lumen)
  • Conversion provides H+ ions for HCO3- cycle
  • Leads to low pH of urine
61
Q

How is H+ secretion stimulated? (During acidosis)

A

Increased HCO3- filtered load in PCT by increased H+ secretion from type A cells

Decreased plasma pH (and decreased HCO3-):
- Increases gradient for HCO3- efflux via NBC1 and Cl-/HCO3- exchanger
- Lowers pH inside cells which increases secretion

Increased pCO2
- Enters cells and lowers pH – causes H+ removal via NHE3
- K+/H+ ATPase insertion in type A cells.

Increased K+ reabsorption [DCT/CD]:
- K+/H+ ATPase insertion [CD] in type A cells.

Hypovolaemia
- Angiotensin II (Na+/H+ transporter stimulated)

62
Q

How does HCO3- secretion occur during alkalosis?

A
  • Type B intercalated cells (opposite to type A) secrete HCO3-
63
Q

How might chronic respiratory alkalosis occur?

A
  • High altitude results in decreased pO2
  • Compensated for by hyperventilation
  • Decreases pCO2
  • Kidneys/liver compensate by increasing HCO3- secretion
  • Not enough HCO3- left in blood to push equilibrium towards CO2 production
  • Therefore pH of blood still high.
64
Q

How does diabetic ketoacidosis occur?

A
  1. H+ released from prolonged incomplete oxidation of fatty acids
  2. Buffered by HCO3-
  3. More glutamine broken down into NH4+ and HCO3- to compensate
  4. More ammonium produced and therefore must be excreted
  5. If excess NH4+ cannot be excreted (limit) then acidosis results
65
Q

What effect does vomiting have on plasma pH?

A
  • Excreted gastric acid not united with HCO3- in duodenum
  • Causes metabolic alkalosis
  • Ventilation rate slowed (compensated metabolic alkalosis)
66
Q

How might failure of K+ homeostasis cause alkalosis?

A

Hypokalaemia results in alkalosis

  • K+/H+ are exchanged to maintain electrical neutrality in cells
  • Less K+ induces more H+ in cells which reduces pH
  • Increases H+ secretion and HCO3- reabsorption
67
Q

What does a nomogram show?

A

Shows arterial blood pH against blood plasma pCO2 (or [HCO3-]).

Visualises where areas of alkalosis/acidosis are and whether they are primary pulmonary or metabolic.

Physiology (8 decks)

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