SEM 2 SBA Flashcards
RAAS
-low ECF volume so slow flow through tubule –> more time for reabsorption or decrease in renal perfusion (BP)
-decrease in GFR
-low [Na+] at macula densa
-sympathetic stimulation
-renin released from juxtaglomerular cells
-renin converts angiotensinogen (produced by liver) to
Ang I
-Ang I -> Ang II by ACE (on endothelium of lung vessels)
-Ang II binds to (AT1 receptor - Gq) :
On vascular SM :
-vasoconstriction
-increasing TPR + BP
On adrenal glands :
-stimulates aldosterone release from zona glomerulosa
-aldosterone increases Na+ reabsorption
-water follows with it by osmosis
-increases blood volume –> decreases Na+ in urine
Macula densa
Region of contact between afferent arteriole + distal tubule of same nephron
Juxtaglomerular (granular) cells
Modified SM cells along afferent arteriole
Renin secreting
Mechano-sensors - detect BP + blood volume
Effect of ANP on renal?
- causes natriuresis (increased Na+ excretion)
- water follows –> diuresis (increased water excretion)
Effect of ANP on vasculature
- causes vasodilatation of vessels
- stimulates G pathway
- stimulates Guanulate Cyclase (GC)
- produces cGMP from GMP
- cGMP activates PKG
- PKG causes vasodilation
- decrease TPR + BP
Effect of ANP on horomes
- acts on kidney to decrease renin release
- reduces Ang II
- reduces vascular tone
- ANP reduces aldosterone release
- ANP inhibits renin release
- reducing Ang II + aldosterone
- it inhibits aldosterone directly
- reduces ADH release
- to decrease Na + reabsorption
- to decrease water uptake
- decreases collecting duct permeability
- excrete more Na+, decrease blood volume + BP
- opposes RAAS
Pressure natriuresis
- increase renal arterial pressure
- forcing more Na+ excretion
- vasoconstriction
- decreases flow
- increases pressure drop so Pc constant
- renal arterial auto-regulation
- increase in medullary capillary pressure
- afferent arteriole, glomerulus, efferent arteriole leads to peritubular capillaries
- higher pressure in peritubular capillaries
- plasma moves into interstitial space
- rise in pressure in interstitial area
- reduces reabsorption of Na+ from tubule
How to excrete Na+?
Cardiac natriuretic peptides (ANP)
Pressure natriuresis
PCT
- Active re-absorption of NaCl (65%), AA, glucose
- Passive re-absorption of K+, HCO3-
- Secretion of NH3, drugs
LOH
- Asecending is H2O impermeable but active re-absorption via Na+/ K+/ 2Cl-
- Descending is H2O permeable –> salty medulla but low permeability to ions
DCT
- Regulates pH by absorbing HCO3- + secreting H+ into filtrate
- Aldosterone increases absorption of Na+ and Cl-
Collecting ducts
- Absorption of Na+ and urea from filtrate
- ADH increases absorption of H2O by inserting aquaporins2
ADH
-binds to V2 receptor on basolateral membrane
-Gs activates AC intracellular pathway
-increase cAMP
-increase PKA
-ADH causes translocation of vesicles to luminal membrane where aquaporins are inserted
-water flow down osmotic gradient into conc interstitial
tissue (thus blood)
Countercurrent flow
=tubular fluid moves down in descending limb + moving up in other
-on thick ascending limb pumping NaCl out of tubular fluid into interstitial fluid between 2 limbs
-impermeable to water so no water out ascending
-solutes build up in interstitium as you move down
-at bottom intersitium very hyperosmotic
-hyperosmotic gradient
-fluid enters into descending
-fluid osmolality same as plasma (300)
-as it moves down, water leave due to hyperosmotic interstitium pulling water out
-water moves out
-tubular fluid becomes hyperosmotic
-fluid moves down descending becoming more
hyperosmotic.
-fluid moves up
-water trapped as impermeable to water
-osmolality of tubular fluid –> hypoosmotic
-when tubular fluid leaves LoH it’s hypoosmotic (diluter
than plasma)
Effect of Na+ not being removed?
Wherever Na+ goes water will follow so
- decreased Na+ removal
- reduces ECF volume
- decreases blood volume
- decreased CO
- decreased BP + oedema
Uses of loop diuretics eg Frusemide?
Chronic heart failure - low ECF volume, CVP, CO
Acute pulmonary oedema - venodilatation
Acute renal failure - increased renal blood flow
Thiazide drugs eg Bendrofluazide + Chlorothiazide
- blocks Na+/ Cl- at DCT
- preventing reabsorption of Na+ and Cl- .
- more Na+ in DCT
- more water move into tubule
- some Na+ move into blood again via other transporters
- transporters working harder
- ↑K+/H+ excretion at DCT
- hypokalemia + metabolic alkalosis
- removing excess Na+ stimulate macula densa
- increased RAAS
- more aldosterone
- Na+ reabsorption
- ↑K+/H+ excretion
- -hypokalemia + metabolic alkalosis
Thiazide drugs eg Bendrofluazide + Chlorothiazide
4*
- blocks Na+/ Cl- at DCT
- preventing reabsorption of Na+ and Cl- .
- more Na+ in DCT
- more water move into tubule
- some Na+ move into blood again via other transporters
- transporters working harder
- ↑K+/H+ excretion at DCT
- hypokalemia + metabolic alkalosis
- removing excess Na+ stimulate macula densa
- increased RAAS
- more aldosterone
- Na+ reabsorption
- ↑K+/H+ excretion
- risk of hypokalemia + metabolic alkalosis
Uses of thiazide drugs eg Bendrofluazide + Chlorothiazide?
- Hypertension - diuresis causes decreased BV + CO so causing vasodilatation to decrease TPR
- Heart failure - low ECF volume, CVP, CO
- Oedema
Osmotic agents eg Mannitol
- filtered but not reabsorbed
- high conc increases tubule osmolarity
- decrease reabsorption of H2O
- acts at PCT, DCT, collecting duct
- no effect on electrolyte excretion
Uses of osmotic agents eg Mannitol?
- Reduce intracranial + intraocular pressure : mannitol doesn’t enter CNS -> creates osmotic gradient –>H2O leaves CNS into plasma
- Prevent acute renal failure
- Prevent ANURIA - distal nephron can dry up when filtration is low
- Excretion of poisoning
Site 1, 2 of PCT
- 1
- reabsorption of Na+ with passive movement of Cl- + H2O
- net reabsorption of NaCl + H2O
- 2
- exchanging of Na+ and H+
- carbonic anhydrase makes H+ inside cell by making carbonic acid
- breaks into H+ and HCO3-
- H+ out of cell in exchange for Na+
- HCO3- reabsorbed with Na+
- H+ + HCO3- in lumen –> carbonic acid
- dissociate into H2O + CO2
- CO2 diffuses into cell so HCO3- reabsorbed
Site 3 of LoH
- transport of NaCl by Na+/K+/2Cl-
- thick ascending limb impermeable to H2O
- so interstitial region here (in medulla) is hypertonic
- reabsorption of H2O from collecting duct as it passes via medulla
Site 4,5,6 of DCT
- 4
- reabsorption of Na+ and Cl- followed by H2O
- 5
- aldosterone increases ENaC channels on luminal membrane and Na+/K+ on basolateral membrane
- Na+ reabsorbed via ENaC
- in exchange for K+ efflux into luminal membrane
- 6
- Na/H exchanger stimulated by aldosterone
5 + 6 can produce K+ loss (in response to Na
reabsorption) + alkalosis (due to increased proton
excretion) –> hypokalaemia + alkalosis
Carbonic anhydrase inhibitors eg Acetazolamide
2*
- mild diuretics
- inhibit carbonic anhydrase
- decrease formation of H+ in luminal cells of PCT
- loss of NaHCO3 into lumen
- loss of H2O
- Used in non-renal effects eg glaucoma as aqueous humor formation dependent on CA activity
K + sparing diuretics eg Spironolactone
- 5 + 6
- competitive antagonist of aldosterone
- inhibit ENaC channels
- less Na+ entering cells, reabsorption, inhibit Na+/K+ATPase
- less Na+ in, less K+ out, losing water
- Useful in CVS diseases linked to overproduction of aldosterone so volume overload
Aldosterone
-Steroid hormone synthesised by zona glomerulosa of
adrenal gland
-Released by Ang II on AT1 receptors
-Goes to DCT + collecting ducts
-diffuses via membrane + acts on nuclear receptors
(ligand-activated transcription factors)
-binds to mineralocorticoid receptor
-changes in transcription
-increase in luminal ENaC channel (sodium
channel) + Na+/K+ pump on basolateral membrane
-more Na+ into tubular cells
-increase [Na+] in cell so we increase Na+/K +pumps
-3Na+ out and 2K+ in
-Na+ from tubule lumen into plasma
-water follows
-conserving Na+, water –> increases blood volume + BP
-increased activity of Na+/K+ pump means more K+ taken from blood put into cell and passively secreted into lumen down conc gradient
-K+ excretion
-hyperaldosteronism –> hypokalemia
What does adrenal gland produce?
- Ouside adrenal gland is capsule
- Zona glomerulosa producing mineralocorticoid aldosterone
- Zona fasiculata producing glucocorticoids (primary
cortisol) - Zona reticularis producing sex steroids (weak androgens)
- Medulla producing catecholamines : A + NA
Liddle’s syndrome
- Rare genetic form of high BP associated with epithelial ENaC
- changes AA seq of ENaC
- open more often so increased renal Na+ reabsorption
- greater Na+ into cell –> blood
- greater movement of water into plasma
- increased blood volume + pressure sensed by RAAS system
- turn off renin release, Ang II, aldosterone release
- low renin + aldosterone
- continued increase in blood volume + pressure
- hypertension
Conn’s syndrome
Hypernatremia, hypokalaemia, alkalosis
-Primary hyperaldosteronism by overproduction of
aldosterone from adenoma of zona glomerulosa of adrenal cortex
-unregulated by renin so aldosterone releasing consistently
-increased ENaC so Na+ reabsorption
-increased Na+/K+ATPase driving Na+ into plasma
-water follows
-increase in ECF volume + BP
-JGCs detect BP so decrease renin secretion
-but irrelevant as tumour releasing aldosterone regardless of renin/Ang II
-K+ excretion by Na+/K+ pump due to aldosterone:
*ENaC driving Na+ into cell changes electrical gradient across cell, so K+ move into lumen
*increased permeability of apical membrane to K+
-aldosterone stimulates H+/K+antiport in intercalated cells
-removes H+ into lumen + brings K+ into cell
-however K+ reabsorption less than
-alkalosis + hypokalaemia
Renal artery stenosis
- narrowing of renal artery
- increased pressure drop across narrowing
- BP decreased in kidney
- decreased flow
- sensed by kidney
- secretes renin
- produces Ang II.
- vasoconstriction of vessels + increase aldosterone
- increased Na+ retention + water retention
- high BP
Factors that stimulate renin release?
- ↓ BP + BV –> ↓ renal blood flow via afferent arteriole mechanoreceptors
- ↓ Na at macula densa
- Symp nerve activation of β1 adrenoreceptors
Due to changes in baroreceptors activity + cardiac volume receptors
Atrial natriuretic peptide (ANP) + brain natriuretic peptide (BNP)
found in specialised cardiac myocytes
released by ↑ cardiac filling pressures (↑ECFV)
vasa recta
- Delivers O2 + nutrients to cells of LoH
- Permeable to both H2O + salts
- Could disrupt salt gradient established by LoH so acts as counter-current multiplier system as well
- vasa recta descends into renal medulla
- water diffuses out into surrounding fluids
- salts diffuse in
- vasa recta ascends - reverse occurs
- conc of salts in vasa recta same
- salt gradient at LoH constant
- water removed to not dilute longitudinal osmotic gradient
- medullary blood flow in vasa recta is slow
- sufficient to supply metabolic needs of tissue, but minimize solute loss from medullary interstitium
*Low BF in VR ~5% of renal BF to minimise solute loss from interstitium + maintains medullary interstitial gradient
-reabsorbed Na+ in descending carried to inner medulla equilibrating with interstitial fluid - ↑osmolarity
-Na+ in ascending returns to systemic circulation
-solute in ascending is product of flow rate + conc
If blood flow in VR increases then solutes washed out of medulla+ its interstitial osmolality decreased
If BF decreased - opposite
Amiloride
Blocks ENaC at *5
Reduces Na+ reabsorption and K+ loss
Captopril
- ACE inhibitor
- inhibits production of Ang II
- decrease aldosterone levels
Sources of acid?
-Metabolism of carbs + fats produces volatile CO2
CO2 + H2O ⇌ H2CO3 ⇌H+ + HCO3-
-Metabolism of proteins produces non-volatile acids
H2SO4 (from S-containing AA) + HCl
pH control
-ICF + ECF buffering systems
-Respiratory system - controls pCO2
-Kidneys - bicarbonate retention or secretion
via
Bicarbonate system
H+ + HCO3- ⇌ H2CO3 ⇌ CO2 + H2O
Phosphate system
H+ + HPO42- ⇌ H2PO4-
Protein system
H+ + Pr- ⇌ HPr
eg H+ + Hb- ⇌ HHb
Resp mechanisms of pH control
-chemosensitive area in medulla monitors [H+] based on CO2 that can cross BBB (CSF only buffered by HCO3-)
-plasma pH detected by peripheral chemoreceptors in aortic arch + carotid bodies
-signal to increase/decrease respiratory ventilation
-↓/↑ pCO2
-adjusted pH
H+ + HCO3- ⇌ H2CO3 ⇌ CO2 + H2O
Renal mechanisms of pH control
- formation + “reabsorption” of HCO3-
- secretion of H+
- bicarbonate, phosphate, ammonium buffer systems
- in all systems HCO3- being reabsorbed into blood
PCT controls pH
85% HCO3- reabsorbed + secrete H +
(no ATPase)
-HCO3- filtered by glomerulus
-[HCO3-]tubular fluid = plasma
-HCO3- + secreted H+ –> carbonic acid in tubular lumen
-carbonic acid dissociates -> CO2 + H2O
-catalysed by carbonic anhydrase on luminal brush border
-CO2 crosses tubular cell down conc grad
-CO2 recombines + H2O -> carbonic acid via carbonic anhydrase
-carbonic acid dissociates -> H+ and HCO3-
-HCO3- back into blood with Na+ via basolateral Na/HCO3 symporter
-H+ back into tubular fluid in exchange for Na+
-H+ appear in urine as water so urine pH unchanged
-net result = reabsorption of HCO3-, slight fall in tubular pH, no change in PCO2 of tubular fluid
Late DCT + collecting duct control pH
- in intercalated cells of late DCT + collecting duct
- H+ATPase pump vital
- H+ pumped in
- pH drops by end of collecting duct
- low [HCO3-] as most reabsorbed
- so H+ react with other buffers
Phosphate buffer
- phosphate ions poor buffers in ECF due to low conc but when filtered at glomerulus, phosphate exceeds Tm
- excess phosphate gets conc
- further secretion of H+ into lumen buffered by HPO42-
- effective buffer due to pK = 6.8 (close to pH of filtrate) + lipid-insoluble from –ve charge even after accepting H+ so can’t carry it back into blood
- H+ATPase pumps H+
- binds to mono-hydrogen phosphate + accepts it readily
- phosphate retains a –ve charge so traps H+ in urine
- HCO3- enters back into blood via antiporter with Cl-
Ammonium buffer
- tubular epithelium produces NH3 from glutamine with glutaminase
- glutamine broken down -> 2NH3 + α-ketogluterate
- α-ketogluterate broken down in TCA cycle -> 2 carbonic acid molecules
- dissociate -> 2H + and 2HCO3-
- H+ and NH3 -> NH4+
- sent into urine via antiport with Na+
- HCO3- back into blood with Na+
- NH4+ excreted into lumen acts as buffer for excess H+
- replenish ECF + ICF pools
- NH4+ secreted as ammonium salts
Role of phosphate + ammonium buffer?
prevent acidic urine
ammonia produces new bicarb to replenish
Respiratory acidosis
Alveolar hypoventilation
- eg obstructed airways
- CO2 accumulates
- ↑pCO2
- ↓pH
Respiratory alkalosis
Hyperventilation
- (eg anxiety)
- fall in CO2
- ↓pCO2
- ↑pH
Metabolic acidosis
Excessive production of acid by organs or exogenous acids
- (eg diabetic ketoacidosis)
- erxcessive loss of HCO3- from GIT from diarrhoea
- failure of acid excretion by kidneys
Metabolic alkalosis
Excessive ingestion of alkaline antacids
Excessive loss of H+ from GIT from vomiting
Excessive diuretic (thiazide) use
Chronic loss of Na+, K+, Cl- –> H+ secretion
Diabetic ketoacidosis
- Type I (enough insulin production in type 2 to avoid DKA)
- Excessive ketone production.
- Osmotic diuresis; glucose in urine –> water following by osmosis so dehydration + loss of electrolytes –> renal failure
- Form of metabolic acidosis
- body can’t glucose due to lack of insulin
- starvation state
- fat breakdown for energy
- producing ketones
- fruity breath
- ‘Breathing deeply’= Kussmaul breathing (deep freq breaths)
- reflex to stimulate CO2 loss from lungs to balance metabolic disturbance
- initial breathing response to metabolic acidosis is fast + shallow
- overtime deep, laboured, gasping = kussmaul breathing
Potassium balance
- Determines ICF osmolality, cell volume, ECF volume
- Affects vascular resistance by affecting polarisation of vascular SM cell)
- For heart + skeletal muscle cells
- Affects vascular resistance
Hyperkalaemia
- more K+ outside cell
- diff between K+ in cell vs outside cell
- RMP less negative
- more depolarised
Hypokalaemia
- less K+ outside
- huge diff
- outside less positive
- RMP more negative
- hyperpolarised
Factors that move K+ in/out cell
IN:insulin, aldosterone, β-adrengic stimulation, alkalosis
OUT:DM, Addison’s (aldosterone def), β-adrengic blockade, acidosis, cell lysis, exercise, increased ECF osmolarity
Causes of hyperkalaemia
- Acute (after prolonged exercise)
- Long term use of K+ sparing diuretics
- Addison’s disease
- Increased release from damaged body cells during chemo
Effect of hyperkalaemia
Plasma [K+]>7mM –> asystolic cardiac arrest
Treatment of hyperkalaemia
Insulin/Glucose infusion to drive K+ back into cells
Causes of hypokalaemia
-Long-standing use of K-wasting diuretics
(thiazide + loop diuretics)
-Hyperaldosteronism / Conn’s Syndrome
-Prolonged vomiting (indirectly via Na+ loss)
-Profuse Diarrhoea
Effect of hypokalaemia
↓ release of A, insulin, aldosterone
Treatment of hypokalaemia
Oral/IV K+
PCT ion reabsorption
- 60-70% of Na+ and K+ reabsorbed
- Constant fraction, amount reabsorbed changes with GFR
- Passive + paracellular transport via tight junctions
- K+ channels
LoH ion reabsorption
- 90% of filtered K+ reabsorbed in PCT + LoH
- Ascending impermeable to water
- Thick ascending limb contains Na/K/2Cl cotransporter that works by secondary active transport
- Water leaves in descending limb + ions leave in ascending limb
DCT + collecting duct ion excretion
- Excretion of K+ via principal cells of late DCT + CD
- Na+/K+ ATPase on basolateral membrane
- K+ high in cell so diffuses into blood
- K+ channel at luminal membrane
- ENac - aldosterone sensistive
- increased Enac
- Na+ flows in so K+ out into lumen
- more Na+ reabsorbed by principle cell
- more K+ secreted
- also K/Cl symporter on luminal membrane moving K+ out
3 determinants of K secretion control:
1) activity of Na-K-ATPase pump
2) electrochemical gradient
3) permeability of luminal membrane channel
What determines K+ secretion?
K+ intake
Blood pH
Tubular flow rate
How does aldosterone affect K+ secretion?
- Increased synthesis + activity of Na/K-ATPase at basolateral membrane = 3Na out, 2K+ in, build up inside then move out
- Upregulates epithelial ENaC at luminal membrane = Na+ in, K+ out
- Increased permeability of luminal membrane to K+
How alkalosis affects K+ secretion
- increase pH
- increase in Na+/K+ ATPase activity
- ↓plasma [K+]
- hypokalaemia
How acidosis affects K+ secretion
- low pH
- increased plasma [H+] inhibits Na+/K+ ATPase at basolateral membrane
- less K+ secreted
- hyperkalaemia
How tubular flow rate affects K+ secretion
- higher rates of distal tubular flow
- increases K+ secretion
- rapidly washed away
- low [K+] tubular fluid
- increases [K+] gradient :)
- ADH stimulates K+ conductance of luminal membrane
Addison’s disease
Hyponatremia, hyperkalaemia, acidosis, low cortisol + aldoesterone =Primary adrenal insufficiency -adrenal glands produce insufficient cortisol + aldosterone -body secreting more Na+ -low serum Na+ -body retaining K+ -hyperkalemia CAUSES : autoimmune, TB, CAH EFFECTS : Anorexia/weight loss, hyperpigmentation due to excess ACTH TREATMENT : Hydrocortisone - (replaces Cortisol) Fludrocortisone - (replaces Aldosterone)
Secondary adrenal insufficiency
- pit gland produces no adrenocorticotropin (ACTH) -common
- ACTH stimulates adrenal glands to produce cortisol
- Low ACTH output
- low cortisol production
- adrenal glands shrink due to lack of ACTH stimulation
Bladder
Transitional epithelium
Impermeable to salt and water
Permeable to lipophilic molecules
Sphincters
Internal – smooth muscle, involuntary control
External – striated muscle, voluntary control
Sensory innervation of bladder
- Pelvic nerve (S2-4) – para
- small myelinated Aδ Fibres (stretch + volume receptors)
- unmyelinated C fibres (pain from overstretching)
- Hypogastric nerve (T11-L2) – symp
- nociceptive C fibres
- Pudendal nerve (S2-4) – somatic
- nociceptive C fibres
Motor innervation of bladder
- Pelvic nerve (S2-4) – para
- contract detruser via Ach (mus R) + ATP (purigenic R)
- relax internal sphincter via NO (cGMP) + Ach (nicotinic R)
- encourages micturition
- Hypogastric nerve (T11-L2) – symp
- relax detrusor indirectly via NA (α-R) + directly via NA (β-R)
- contract internal sphincter via NA (α-R)
- inhibits micturition
- Pudendal nerve (S2-4) – somatic
- no effect on detrusor
- contract external sphincter via tonic release of Ach (on nicotinic R)
- inhibits micturition
Receptive relaxation
- Bladder empty
- sphincters closed
- tonic activity of symp + somatic nerves
- low bladder pressure
- Arrival of urine
- detrusor relaxes progressively
- symp activity inhibits paras transmission
- little increase in pressure
- sphincters still closed
Micturition reflex
- bladder starts to fill
- Aδ fibres sense stretching
- bladder is full
- internal sphincter relaxes
- urine flows into urethra
- flow of urine into urethra activates pudendal afferents
- tonic contraction of external sphincter removed by inhibition of somatic input
Modified by voluntary control
Incontinence
Stress = pelvic floor injury
Urge = detrusor instability
Neuropathic = head, spinal, peripheral nerve injury
Anatomical = vesicovaginal fistula
Atonic- overflow
Automatic- destruction of spinal cord: unannounced emptying
Neurogenic- freq + uncontrolled (inhibiting signals get interupted)
Treatments of incontinence
- Antimuscurinics to relax detrusor so less spasms of detrusor
- Bladder retaining (Kegel’s exercises ) to strengthen pelvic floor
- Botox toxin for spastic urethra
- Sacral nerve stimulation to re-establish micturition reflex
- Stem cells / 3D printed bladder
Effect of ions on cardiac contractility
Alkalosis: Increases contractility
Acidosis: Decreases since H+ competes with Ca2+ for binding sites on troponin
Effect of ions on calcium binding
H+ competes with Ca2+ ions for protein binding
- Acidosis: hypercalcaemia
- Alkalosis: less H+, more Ca2+ bound to proteins so hypocalcaemia
- muscle contraction dependent on intracellular Ca2+ not extracellular.
- hypocalcaemia refers to decreased extracellular Ca2+
- Ca2+ affects Na+ channel function at neuronal membranes
- plug it during Na+ influx
- modulating its permeability + excitability.
- in hypocalcaemia insufficient Ca+ blocks channel
- more Na+ influx
- destabilise membrane potential
- increased neuronal excitability leading to tingling, tetany
Role of kidney?
Control volume and composition of body fluids
Remove waste material from body (e.g. Urea)
Acid-Base Balance
Act as endocrine organ – EPO (controls RBC content), renin, produce active form of vit D 1α-hydroxylase
Constrictions of ureter
-Junction of ureter and renal pelvis
-Cross ext. iliac/pelvic brim
-Passage via wall of bladder
Retroperitoneal
Anatomy of kidney
- pyramids+medulla = parenchyma - functional portion of kidney
- within parenchyma 1 million microscopic nephrons
- filtered fluid from nephrons drain into papillary ducts
- drain into minor + major calyces
- filtrate becomes urine
- Nephron = functional unit, made up of glomerulus + tubule
- Types of nephrons : cortical + juxtamedullary
- Cortical nephrons lie in cortex (85% of nephrons), have short LoH which work during normal conditions
- Juxtamedullary nephrons have long LoH which work during periods of high activity
Ultrafiltration
- Forms glomerular fluid (passive ultrafiltrate of plasma where proteins + complete cells filtered out)
- Passive process driven by net pressure drop across glomerular membrane
1) Fenestrated capillary endothelium
2) Glomerular basement membrane = basal lamina (thick + fused), has holes with negative charges so anything dissolved in water (Na+) can pass through but RBCs can’t due to negative charges (unless barrier breaks down)
3) Podocytes surround capillaries of glomerulus that have 4nm filtration slits, enclose, strengthen vessels, allows them to withstand large filtration pressures
Filtration slits 4nm allowing small NaCl, glucose, urea not albumin so remain in blood
Nephrotic syndrome has appearance of protein in urine (proteinuria)
Starling’s principle
Fluid movement due to filtration across wall of capillary dependent on balance between hydrostatic + oncotic pressure gradient across capillary
REVISED
Jv = LpA { ( Pc - Pi ) - σ(πp - πg) }
Jᵥ: net filtration
Lₚ: Hydraulic conductance of endothelium, how Leaky endothelium is
σ: reflection coefficient for intercellular gaps
A: wall area
Hydrostatic pressures :
Pc : capillary BP
Pi : interstitial fluid pressure
Osmotic pressures :
πp = plasma proteins
πi = Interstitial proteins
πg = Glycocalyx proteins
(P꜀ - Pᵢ): hydraulic pressure diff
(πₚ - πᵢ): osmotic pressure diffHydrostatic pressure
pushing force by capillary pushing fluid into bowmann’s capsule
Oncotic pressure
pulling force by capsule also exerting pressure onto capillary
Starling force balance reversed
in peritubular capillaries BP falls below colloid pressure (due to protein being more conc in plasma) so greater force driving fluid back from tubule into capillary
- small amount of urine remaining in tubules
- along tubule, BP in afferent arteriole higher than colloid pressure when enter glomerulus
- net filtration pressure out of capillaries into tubule
- in efferent arteriole, pressure drops
- colloid pressure rises as fluid lost from capillaries
- so protein more conc –> exerting greater force driving fluid back from tubule into capillary
- so fluid being reabsorbed back into surrounding tissue + peritubular capillary where it comes into contact with tubule wall/nephron
- most reabsorbed otherwise volume depleted
- remaining in end is urine
GFR
=how much filtrate removed from blood each min NOT how much blood passes through glomerulus each min
Glomerular filtrate = same composition as plasma except protein free + no cellular components eg RBC
GFR ≈120ml/min
GFR ≈180L/day so plasma filtered 60 times daily
-Affected by hydrostatic, oncotic pressure, permeability of capillary filtration barrier, SA
-Indicator of renal function
-Fast filtration rate coupled with many nephrons so functions with only 1 kidney + reduced function in that kidney
GFR intrinsic control - autoregulation
Ensure renal plasma flow (RPF) + GFR constant with acute changes in BP
-Bayliss Myogenic Response: F = ∆P/R
Direct vasoconstriction of afferent arteriole with increase in perfusion pressure
-Tubularglomerular feedback TGF
Flow dependent signal detected in macula densa which alters tone (causes contraction) of afferent arteriole
Bayliss myogenic response
-Prevents BF during changes in BP
-Vital in renal, coronary, cerebral circulation
F = ∆P/R
F : BF, ∆P : change in pressure, R : resistance
When you increase perfusion pressure in kidney, you get short + brief increase in vessel radius so blood flow rises briefly but as smooth muscle stretches in afferent arteriole, it quickly constricts, reducing flow to normal :
- increase in perfusion pressure
- immediate increase in vessel radius (few seconds)
- blood flow rises briefly
- stretch on smooth muscle in afferent arteriole
- results in contraction
- reduction in diameter
- increase in resistance
- flow returns to control value in 30secs
Tubularglomerular feedback
GFR increases, so increased fluid flowing through tubule, fluid flows pass macula densa, change [NaCl] in luminal fluid, change osmolality so sensed by macula densa + juxtaglomerular cells, send signals to constrict afferent arteriole, change resistance of afferent arteriole. Outcome is to constrict afferent arteriole, so with increase flow, change in osmolality + [NaCl], elicits signal of ATP release from macula densa cells to activate JG cells –> increased resistance of afferent arteriole so decreased GFR :
- changes in flow alters luminal [NaCl]+luminal osmolality
- increase flow rate past macula densa
- macula densa detects change luminal osmolality
- renin released from juxtaglomerular cells of macula densa -vasoconstraction of afferent
- increased resistance in afferent
- decrease in hydrostatic pressure in glomerulus
- GFR decreases
GFR: extrinsic control – renal symp nerves
Renal symp nerves reduces GFR by resetting autoregulation to lower level
Occurs in:
Standing upright (orthostasis)
-Heavy exercise
-Haemorrhage and other forms of clinical shock
PURPOSE: Conserve body fluid volume
Symp aided by circulating vasoconstrictor hormones eg A, Ang, ADH
Excretion rate equation
= GFR – reabsorption rate + secretion rate
Measuring GFR
- Select substance that’s only filtered + not absorbed, secreted, metabolised
- Perfect standard is Inulin
- Rate of filtration through glomerular membrane = Rate of entry into bladder
- Inulin: inert polysaccharide freely filtered through glomerular membrane, not reabsorbed, secreted, metabolised but :
- prolonged infusion
- repeated plasma samples
- difficult routine clinical use
- Clinically use creatinine for GFR measurement but varies with muscle mass plus no infusion needed
Measuring eGFR
=estimated Glomerular Filtration Rate
Simple - requires one blood test but :
*sig error possible (especially for extremes)
*invalid for pregnant women (25% lower creatine), children, racial groups
-CKD Stages 1-5
-End stage CKD GFR <15 or on dialysis
Clearance
=plasma volume that’s completely cleared of substance by kidney per unit of time (ml/min)
-Inulin Clearance= 125ml/min = GFR
-Clinically creatinine is used
-Intrinsic inert substance, released at steady level from plasma, no infusion required, not reabsorbed but some secreted into tubule
-Creatinine clearance = 150ml/min
-However use of antibiotic Trimethoprim is competitive inhibitor of creatinine, competes with Crn for same transporters that secrete Crn from tubular blood into urine –> increase in serum levels of Crn
-Cs = (Us x V)/Ps
V: urine flow rate
Because inulin not reabsorbed, secreted, metabolised it varies with muscle mass
Renal plasma flow
= (amount of PAH in urine per unit time) / (diff in PAH conc in renal artery or vein)
Normal value is 660ml/min
Leaky podycyte
- loss of protein from blood
- less capillary oncotic pressure
- less fluid moving form ECF into blood
- nephrotic syndrome
Where does insulin act
Liver: glycogenesis, glycolysis, lipogenesis
Muscle: glucose uptake, AA uptake, glycogenesis
Adipose tissue: glucose uptake, FFA uptake, lipogenesis
Secretions of Islets of Langerhans?
insulin (β cells 65%)
glucagon (α cells 20%)
somatostatin (δ cells 10%)
Insulin precursors
Cleaving of C peptide = insulin from pro-insulin
Cleaving of signal seq = pro-insulin from pre-pro-insulin
- insulin polypeptide is originally pre-pro-insulin
- signal seq cleaved off –> proinsulin
- C peptide cleaved off –> insulin
- insulin receptor is tyrosine kinase
- becomes phosphorylated when activated
- activates further signaling pathways :
- inserting glucose transporters into membrane + glycogenesis
Phosphorylation of tyrosine kinase receptor
type of insulin receptor
ATP after large meal –> insulin
- β cell membrane has GLUT transporters
- glucose diffuses into cell
- glucose enters glycolysis + TCA cycle producing ATP
- ATP closes ATP sensitive K channels
- K+ can’t leave
- cell depolarises
- vgcc open
- Ca2+ enter
- exocytosis of insulin vesicles
Glucagon
Acts on liver to antagonise insulin
Stimulates: gluconeogenesis, glycogenolysis, ketogenesis
Glucagon synthesis
- peptide hormone starts as pro-glucagon
- cleaved to glucagon in α-cells
- pro-glucagon gene processed to give diff products GLP-1
- GLP-1 produced in lower intestine
- GLP-1 increases insulin secretion
- GLP-1 binds to receptors on β-cells
- leads to closure of K channels
- depolarises membrane
- aactivates vgcc
- exocytosis of insulin containing vesicles
- GIP not from proglucagon, but similar effects to GLP-1
- GIP released in upper small intestine
- GIP slows rate of gastric emptying
- potentiates insulin’s response to glucose especially after sugary/fatty meal
- both GLP-1 + GIP are incretins
- rapidly degraded by DPP-4
Prediabetes
Fasting blood glucose limit: 7 mmol/l
Random blood glucose limit: 11.1 mmol/l
Fasting levels high but not high enough for diabetes: impaired fasting glyceamia
Random levels high but not enough for diabetes: impaired glucose tolerance
Oral glucose tolerance test tests fasting levels then gives patients 75g of glucose + tests levels 2 hrs later
