Renal Flashcards
Which hormone does the kidney use to control RBC production?
Erythropoietin
Why is plasma only 91% water?
Because proteins eg) albumin are very large
What is Van’t Hoff’s equation?
Osmotic pressure = osmolarity x gas constant x absolute temp
What is osmolality?
Osmoles per kg water (not osmoles per litres because 1 litre plasma isn’t 1 litre water)
What does it mean that osmolality is “colligative”?
Proportional to number not type of particle
Why do cells not contribute to colloid osmotic pressure?
They’re not dissolved
What provides ECF osmolality?
NaCl
What provides ICF osmolality?
K+, Cl- and impermeable ions
What is crenation?
Shrinking around cytoskeleton
How does cerebral swelling kill?
Compresses medulla so stops breathing, or compresses veins causing even more swelling
How do you measure intracellular volume?
Total water - ECF volume
Does cortex or medulla have rich blood supply and lots of mitochondria?
Cortex
Does the afferent or efferent arteriole have baroreceptors?
Afferent
What do the podocytes provide?
Fenestrated capillary, basement membrane, diaphragm between foot processes
Why are podocytes negatively charged?
To repeal albumin
Why do some cations remain in the plasma?
Becayse there are -ve proteins there so cations remain due to charge
Filtration fraction = ?
glomerular filtration rate / renal plasma flow
Why does the remaining plasma cause decreased net filtration pressure?
High proteins and % haematocrit
Kidney flow = ?
Change in pressure / Ra + Re
What does dilating afferent or constricting efferent cause?
Increased pressure but decreased flow
Glomerular capillary pressure = ?
Venous pressure + AV pressure gradient x efferent resistance/total resistance
What is the autoregulatory range?
Large blood pressure range across which the glomerular filtration rate doesn’t change
What are the two ways to reduce flow?
Myogenic or tubulo-glomerular
What is the myogenic mechanism to reduce flow?
High blood pressure stretches afferent so it constricts
What is the tubulo-glomerular feedback mechanism to reduce flow?
Macula densa senses NaCl uptake, releases ATP, stimulates afferent arteriole constriction
What do mesangial cells do?
Contract to reduce capillary membrane area
Why can severe muscle damage cause renal failure?
Myoglobin can block filtration pores
What is “clearance”?
Expresses rate of excretion as a function of plasma concentration
Clearance = ?
Rate of excretion / plasma concentration
What is excretion measured in?
moles/min
What is clearance measured in?
ml/min
Why do positive molecules have highest filterability?
Attracted to and pulled through membrane
Why do -ve molecules have higher filterability if they are very small?
Can slip through when small
What happens to clearance if renal handling is constant?
Stays the same because if plasma concentration is doubled then excretion rate is doubled
What does it mean if clearance is less than or greater than GFR?
If less then not freely filtered, if greater then must also be secreted
Rate of excretion = ?
GFR x plasma conc
Clearance = ?
GFR
Excretion = ?
urine production x urine concentration
Clearance = ?
urine production x urine concentration / plasma concentration
What is the filtration coefficient?
Product of surface area and hydraulic conductivity
What is the protein reflection coefficient?
Goes 0 (permeable) to 1 (impermeable)
What may reduce the filtration coefficient?
Filtration pores becoming blocked or mesangial cells contracting to reduce capillary membrane area
What may increase Pc - Pb?
Increased in UTI obstruction
How do you measure clearance?
Find something produced at a constant rate and freely excreted then use clearance = rate of excretion / plasma conc eg) creatinine
What does the clearance ratio compare?
The clearance of something to the clearance of inulin
What is the clearance ratio of PAH like? Why is this useful?
Greater than 1 because it’s very efficiently secreted, so clearance of PAH is effective renal plasma flow (use Fick principle for this but need arterial and venous concentrations)
For protein channels, what is flux proportional to?
Electrochemical gradient ( x permeability)
What is the maximum rate of transport for carrier proteins called?
Transport maxima
Why doesn’t NaCl concentration in tubule not change?
Water follows it
What are some possible anions in the Cl- anion exchanger?
OH-, HCO2-, HCO3-, oxalate or sulphate
Where is Cl- reabsorption greatest?
Late PCT
Which anions are secreted in the PCT?
Prostaglandins, cAMP, bile salts, drugs eg penicillin
Which cations are secreted in the PCT?
Creatinine, adrenaline, noradrenaline, dopamine and drugs eg morphine
How are -ve ions transported into a -ve cell?
Enters in exchange for an anion, anions are recycled because there’s more Cl- to reabsorb than anions to secrete
What is the evidence for isotonic reabsorption?
Either inject inulin and use micropuncture to compare early and late PCT (PCT has higher conc) or use split oil drop to test how things are absorbed
What happens to anions in the tubule?
Protonated and are then uncharged so can diffuse back
Why is the tubule acidic?
Because of Na+/H+ exchanger
When is K+ released?
Exercise, acidosis (displaced by H+), dehydration (cellular shrinkage) and cell lysis
When is K+ taken in/ when does K+ conc decrease?
Hyperhydration, insulin, adrenaline
What happens to the ECG during hyperkalaemia?
QRS gets smaller because cardiac muscle gets inexcitable and T wave gets faster because of inwardly rectifying K+ channels
What happens to K+ during hypokalaemia?
T wave gets smaller and you get a U wave
Why do you get arrhythmias outside normal K+ range?
More excitable atria and slower repolarisations because of changes in channel conductance and inwardly rectifying channels
Which is the main regulatory hormone of K+?
Aldosterone
In what area is aldosterone important for Na+ reabsorption?
DCT
What stimulates aldosterone?
Angiotensin II
How does ADH affect K+ control?
Keeps excretion constant but alters concs, increases SK activity and reduces tubular flow rate
Why is renal K+ control slow?
Only 2% of body K+ is in the ECF
What detects high extracellular K+? WHat does it release?
Zona glomerulosa - aldosterone
Which pump does aldosterone stimulate
Na+/K+
Which hormones stimulate Na+/K+ pump?
Aldosterone, adrenaline, insulin
How does insulin stimulate Na+/K+ pump?
Stimulates Na+/glucose which stimulates Na+/K+
What causes hypokalaemia?
Diuretics, diarrhoea, vomiting, reduced food intake
What causes hyperkalaemia?
Renal failure, doctor error, cell lysis, acidosis
How do you treat hyperkalaemia?
Ca2+ will stabilise membrane potentials and adding glucose and insulin makes Na+/K+ pump work faster
How does plasma pH affect plasma conc Ca2+?
Influences charge on albumin - albumin binds to Ca2+ so if H+ changes then plasma conc of Ca2+ will change
What happens to bone during chronic acidosis?
It buffers H+ so get demineralisation
What are the symptoms of acidosis?
Central sympotoms - nausea, fatigue, confusion, coma, death
What are the symptoms of alkalosis?
Muscle symptoms - hypokalaemia, hypocalcaemia because more -ve plasma buffers, hyperexcitability, cramps, tetany
Metabolism of which amino acids produces H2SO4?
Cysteine and methionine
Metabolism of which amino acids produces HCO3-?
Aspartate and glutamate
Why is it more common to be pushed toward acid production?
Can’t be breathed out like CO2 can?
What are some fast extracellular buffers?
HCO3-, HPO42-, bone and plasma proteins
What are some slow intracellular buffers?
HCO3-, HPO42-, proteins esp. histidine
Why must kidney produce new HCO3-?
Needs to be added to reduce losses to metabloic acids but there isn’t enough so kidney has to produce it
What is a problem with HCO3- production?
Would produce H+ so must be secreted and buffered
What is the main filtrate buffer?
HPO42-
How is the kidney a net bicarb producer but almost none is excreted?
H+ secreted, HCO3- reabsorbed as CO2, so more bicarb produced because if CO2 is increasing then too much bicarb is being used to buffer H+
Which cells secrete bicarb?
Type B intercalated in the collecting duct
Which amino acid is bicarb produced from?
Glutamine
What is ammoniagenesis?
Making ammonia from glutamine in PCT
What happens to the glutamine in ammonia genesis?
Glutamine > glutamic acid > alphaKG > Krebs cycle > glucose. SO get 2HCO3-, excrete 2NH4+ and make half a glucose
What happens to the ammonium produced from glutamine?
Splits to ammonia in cell and recombined in tubule - now trapped so excreted
Where is NH4+ reabsorbed?
Ascending limb
What does NH4+ substitute for on which transporter?
K+ on the Na+-K+-2Cl- co-transporter
What do osmoreceptors in the hypothalamus detect?
Osmotic pressure, not [Na+]
What is AVP?
Arginine vasopressin (ADH)
Where is ADH broken down?
PCT
What are the two ADH receptors?
V1 = vascular smooth muscle, low affinity V2 = collecting duct, high affinity
Which circulatory factors affect ADH production?
Arterial baroreceptors can stimulate or inhibit release, so can cardiopulmonary receptors via vagus and glossopharyngeal
Which osmoregulatory factors affect ADH release?
Nervous inputs from GI tract via vagus, liver osmoreceptors detecting water absorption from food
What kind of neurone terminals do act pots from osmoreceptors arrive at?
Magnocellular
What kind of neurones does ADH travel down?
Magnocellular
WHich organ contains the osmoreceptors?
OVLT (organum vasculosum laminae terminalis)
How does osmodetection link cell size to ion channel activity?
When cells shrink they depolarise to increase action potential frequency because stretch-inactivated non-selective cation channels show increased activity
How do you show osmotic pressure regulated ADH release?
Make diuresis easy to detect by stomach-tubing water. Exteriorise carotid arteries to form carotid loops so solutions can be introduced here not into veins. Hypertonic NaCl caused reduction in urine flow rate in carotid artery but not vein. Urea had no effect.
What is the integrated response of osmoreceptors and circulatory stretch receptors?
Largest changes in plasma ADH if osmotic pressure and blood pressure are reduced
Which aquaporins does the adluminal membrane always have?
AQP3 and AQP4
If ADH decreases, which aquaporins is removed by endocytosis?
AQP2
What’s the maximum urine osmotic pressure?
1200mosm
What are the main waste solutes?
SO4 2- and HPO4 2-
What is the mechanism of activation of AQP2?
ADH > V2 receptor (GPCR) > adenyl cyclase > cAMP > PKA > vesicles phosphorylated using serine 256 > fuse with collecting duct luminal membrane
How does ADH increase urea permeability of medullary collecting duct and thin ascending limb?
Stimulating phosphorylation and activation of urea transporters in luminal membrane
What is the main urea transporter?
UT-A1
What is the luminal/adluminal membrane urea transporter?
UT-A3
What is the urea transporter in the thin descending limb?
UT-A2
What does angiotensin stimulate?
Na+/H+ exchange
What does aldosterone stimulate
K+/H+-ATPase
What pH is cortisol released in response to?
Low
What does PTH cause in prolonged acidosis?
Acid secretion
What decreases and increases metabolic acid?
Vomiting decreases, HCO3- loss increases
If pH is normal what is causing the PCO2 change?
Non-respiratory causes
What is the ideal glomerular filtration rate?
125ml/min
What is normal tissue fluid osmolarity? Why is it the same in tubular fluid?
280 mosm - isotonic reabsorption
If low Na+ conc, what happens to the fluid at the top of the loop of Henle? What if high Na+ conc?
Just excrete the hyposmotic solution. If high, add aquaporins
Osmolality control is at the expense of what?
Volume control
What does hyponatraemia cause?
Nausea
Why is 200mosm the maximum gradient? What is used instead?
Fixed stoichiometry of pumps, back-leakage, instead use countercurrent multiplication
Is fluid from the DCT hyposmotic or hyperosmotic?
Hyposmotic
If conc triples, how much water is reabsorbed?
2/3
Where does most H2O reabsorption occur?
Cortex
What does heart failure cause?
Lower effective circulating volume, causing response in kidney like hypovolaemia so blood volume expands causing oedema
What can be used to treat heart failure?
HKCC2 or KCC blocker
Where does urea diffuse from and to?
Collecting duct > thin ascending limb
What does high medullary urea allow?
Water reabsorption from descending limb so NaCl because concentrated and can be passively absorbed
What does countercurrent exchange avoid?
Filling medulla with water, balanced by vasa recta
What are the three stimuli to thirst?
High plasma osmotic pressure, reduced extracellular fluid volume, dry throat
What is osmotic thirst due to?
High osmotic pressure detected by less sensitive hypothalamic osmoreceptors in the OVLT
What is hypovolaemic thirst due to?
Reduced extracellular volume detected by arterial and cardiopulmonary stretch receptors - inputs inhibit thirst centres and angiotensin stimulates thirst in hypovolaemia
What are the two types of diabetes insipidus?
Nephrogenic (failure to respond to ADH) or neurogenic (failure to produce ADH)
How do you treat neurogenic diabetes insipidus?
Fake ADH called desmopressin acetate
What determines the volume of the ECF? Why?
[Na+] because volume = amount/conc
Why does increase filtration fraction mean more is reabsorbed?
Peritubular capillary collid osmotic pressure raised and hydrostatic pressure lowered, Na+/fluid reabsorbed because renal interstitial hydrostatic pressure falls
How does extracellular fluid expansion increase ABP which increases Na+ excretion?
Higher ABP means higher net filtration rate and GFR, more filtered and less reabsorbed so more lost in urine, pressure natriuresis because water follows so decreased extracellular fluid volume, increased colloid osmotic pressure increases Na+ excretion
What modulates activity of renal sympathetic nerves?
Inputs from cardiopulmonary receptors and arterial baroreceptors (reduced volume/ABP inhibits sympathetic outflow less)
What does NA to alpha1 receptors on PCT do?
Increase NHE3 activity so more Na+ reabsorbed
Which hormones affect Na+ excretion?
Angiotensin II, aldosterone, ANP
Where is angiotensinogen always present?
Blood
Where is renin released from?
Juxtaglomerular cells
When is renin relased?
If ABP decreases - either detected by afferent arteriole or decreases cardiopulmonary and arterial stretch > sympathetic nerves > NA > beta1 > renin release
What does macula densa sense and what does it do about it?
Detects low NaCl, increases renin release using prostaglandin
What does angiotensin promote secretion of?
Renin as more NaCl reabsorbed (+ve feedback)
What does selective efferent constriction ensure?
Some filtration remains to remove waste products
Which exchanger does angiotensin stimulate and what does this cause?
Na+/H+ exchanger, increases Na+ reabsorption
What 4 things does angiotensin II do?
Increases Na+ reabsorption, constricts efferent arteriole, stimulates Na+ appetite, stimulates aldosterone release
What does aldosterone act on?
Cortical collecting duct
What does aldosterone promote?
Na+ reabsorption, K+ secretion and excretion and H+ excretion
What does aldosterone act as a transcription factor for?
Three genes (aldosterone induced proteins)
What does aldosterone do in principal cells?
Increased Na+ channel to stimulate Na+/K+ channel and increased Ca2+-activated K+ channel by DNA. Upregulates SK and ENaC
What does aldosterone do in type A intercalated cell?
Increases K+/H+ exchanger (non-genomic effect)
What are the stimuli to release aldosterone?
AII, increased plasma [K+], decreased plasma [Na+]
What is aldosterone deficiency?
Addison’s disease
What symptoms does aldosterone deficiency cause?
Reduced plasma volume, circulatory collapse, deregulation of extracellular K+
What does aldosterone excess cause?
Conn’s disease?
What are symptoms of excess aldosterone?
High ABP, high ECF, K+ depletion, alkalosis because exchanged with H+
How does MSP drop cause renin release?
Detected by low-pressure baroreceptors > brain stem > renal sympathetic nerve > granule cells > NA > renin release
ECF expansion has opposite effect to haemorrhage EXCEPT WHAT?
ANP secretion increased
What happens during low volume?
Lower MSP > decreased renal blood pressure > GFR > less NaCl in filtrate
What are the seven role of angiotensin?
Peripheral vasoconstrictor, dipsogen, simulates Na+ hunger, increase NHE in PC, constrict efferent, causes aldosterone release
What secretes ANP?
Atrial myocytes during increased atrial stretch
What does ANP cause?
Opposite to aldosterone and AII. Has natriuretic effect so it increases Na+ loss and decreases ECF volume
How does ANP work?
Increases cGMP > PKG > decreased ENaC and Na+/K+ATPase
What does ANP inhibit secretion of?
Renin, aldosterone, ADH
Why does ANP cause dopamine release?
Slows Na+/K+ATPase so less solutes reabsorbed and isotonic fluid excreted
What does ADH do to the afferent arteriole? WHY?
Dilates it for pressure natriuresis
Why does ANP dilate mesangial cells?
Increases filtration surface area so increases GFR
What can hypocalaemia cause?
Spontaneous action potentials because threshold is decreased and -ve charge on glycoproteins isn’t bound which mimics depolarisation, motor nerves susceptible so can cause contraction of larynx muscles, prolonged QT interval, tetany of respiratory muscles
What can hypercalaemia cause?
Increased threshold for action potentials, phosphates may precipitate causing kidney stones, muscle weakness
WHich two hormones are hypercalcaemic?
PTH and 1,25-DHCC
Which hormone is hypocalcaemic?
Calcitonin
Where is the non-free calcium in the blood found?
Bound to proteins or complexed with anions
What secretes PTH?
Chief cells of the four parathyroid glands
What does PTH do?
Raises Ca2+, lowers PO4 2-
What does PTH act on?
Bone and kidney directly,, via 1,25-DHCC in gut
What’s the process of PTH inhibition following calcium detection?
Low-affinity GPCR receptor > PLC > DAG and IP3 > IP3 binds to EP so calcium released > PKC activated > PTH synthesis and secretion inhibited
What do osteoprogenitor cells differentiate into?
Osteoclasts and osteoblasts
Where do osteoprogenitor cells come from?
Haematopoietic stem cells
What do osteoblasts do?
Lay down bone, secrete collagen, secrete Ca2+ and phosphate to form matrix
What do osteoclasts do?
Break down bone using acid and enzymes
What is an osteocyte?
Mature bone cell surrounded by calcified matrix connected by cytoplasmic extensions
How does PTH cause rapid output of Ca2+ from bone fluid and slower mineralisation of bone?
Reduces laying down of bone by osteoblasts (stimulates them to secrete RANK-L and IL-6 which are cytokines which stimulate osteoclasts), stimulates Ca2+ uptake in osteocytes where it travels down cytoplasmic extensions and is released into ECF and interstitial fluid
Where is most filtered Pi reabsorbed?
PCT
What are the three types of Na+/Pi transporter?
IIa = 3:1, IIb = 3:1, IIc = 2:1
How does PTH affect phospahte reabsorption transport?
Decreases Tmax
How does decreasing plasma Pi cause rise in free Ca2+?
Favours calcium phosphate dissolution
Which kind of plasma Ca2+ is filtered?
Free
Where is most Ca2+ reabsorbed?
PCT
How is Ca2+ transported out of tubule?
NCX
How does most Ca2+ enter the tubule?
TRPV5/6 (channels)
What allows calcium shuttling from luminal to adluminal membrane?
Calbindin-D
Why can Ca2+ movement be regulated in the DCT and CD?
Movement here is transcellular not paracellular
How does PTH affect calcium reabsorption in the PCT?
Decreases it
What does PTH phosphorylate to increased calcium reabsorption?
NCX
How is the type IIa transporter controlled?
PTH produces PKA and PKC which phosphorylate NHERF-1 so it dissociates from the transporter which is then available for endocytosis
What does a thyroparathyroidectomy cause?
Lowered ability to recover from hypo/hypercalcaemia
What is the pathway of 1,25-DHCC production from cholesterol?
Cholesterol > vitamin D3 > 25-HCC > 1,25-DHCC or 24,25-DHCC
Where does vitamin D3 > 25-HCC?
Liver
Where does 25-HCC > 1,25-DHCC or 24,25-DHCC?
Kidney
What stimulates and inhibits 25-HCC > 1,25-DHCC?
Ca2+ inhibits, PTH, growth hormone and prolactin stimulate
What stimulates and inhibits 25-HCC > 24,25-DHCC?
Ca2+ stimulates, PTH, growth hormone and prolactin inhibits
What does 1,25-DHCC do?
Increases calcium and phosphorus reabsorption in kidney and increases absorption in the small intestine enabling bone mineralisation
What is a synergist of 1,25-DHCC?
PTH
What happens if there’s inadequate 1,25-DHCC?
Abnormal bone mineralisation
How does 1,25-DHCC work?
Increases TRPV5/6 and calbindin-D in DCT, CD and small intestine, increases type II Na+/Pi absorbers and type III in the small intestine
What secretes calcitonin?
C cells of the thyroid gland
What does calcitonin do?
Inhibits absorption of bone by osteoclasts so bone deposition favoured
How does calcitonin work?
Ca2+ acts on receptor, forms IP3, Ca2+ increases stimulating calcitonin (feed-forward)
What GI hormone stimulates calcium release?
Gastrin
What are the renal effects of calcitonin?
None
How does calcitonin protect maternal bone against excessive demineralisation?
Ensures demand met by gut absorption, sex steroids stimulate production so after menopause there’s increased osteoclast activity so bone demineralisation
What problem with the thyroid causes hypercalcaemia? Hypocalcaemia?
Hyperparathyroidism, hypoparathyroidism
What causes milk fever?
Insensitivity to PTH
What happens in PTH excess?
Ca2+ excretion increases due to increased filtered load
What is the reversal potential?
Eqm potential
What is nAChR permeable to?
Sodium in and potassium out
Where are positive charges on channel which cause rotation and opening?
S4 section
What is K channel blocker?
Tetraethylammonium
What is Na channel blocker?
TTX
What is NaKATPase blocker?
Digitalis and ouabain
What is the descending limb permeable to?
Water
What is the thin ascending limb permeable to?
Solute passively
What is the thick ascending limb permeable to?
Solute actively
What do osmorecetors detect is isotonic fluid or haemorrhage?
No change
What does the pneumotaxic centre do?
Inspiratory cutoff
What does the apneustic centre do?
Drive inspiration, phrenic nerve
Another name for the CPG?
Pre-Botzinger complex
Where is NHE found and what does it do?
Proximal tubule, for ion and water reabsorption (makes tubule acidic and cell alkaline)
Where is bicarb transporter found and what does it do?
Early proximal tubule for ion and water reabsorption
What is the difference between SGLT-1 and SGLT-2?
SGLT-1 is for late proximal tubule and and is for 2Na+, SGLT-2 is for early proximal tubule and is for one Na
Where is the anion-Cl- transporter and what is it for?
Late proximal tubule for ion reabsorption
Where is KCC transporter and what is it for?
Late proximal tubule, for ion reabsorption, unregulated K+ absorption, active NaCl transport, water reabsorption
Where is the NKCC2 transporter and what does it do?
Think ascending limb, for unregulated K+ reabsorption, active NaCl transport, water reabsorption
Why is NKCC2 energetically favourable?
Low intracellular NaCl conc
Where is SK found and what is it for?
Distal tubule and collecting duct, regulating K+ secretion
Where is NHE3 found and what does it do?
Proximal tubule and ascending limb, for bicarb reabsorption and ammoniagenesis
What stimulates NHE3?
Sympathetic nerves and angiotensin
Where is NBC1 and what does it do?
Proximal tubule and ascending limb, for bicarb reabsorption and ammoniagenesis
Where is Cl-/bicarb exchanger and what is it for?
Type A intercalated cell of collecting duct for bicarb reabsorption, ammonia trapping and ammoniagenesis
Where is K+-H+ATPase found and what is it for?
Collecting duct for ammonia trapping
Where is H+-ATPase and what is it for?
Collecting duct, for ammonia trapping (makes lumen acidic)
