renal physiology Flashcards
renal blood supply
- 20-25% of cardiac output
- 1-1.2L/min
- high flow for filtration rather than metabolism
- glomerulus has afferent and efferent arterioles
what makes up filtration barrier
- capillary endothelium (fenestrated, charged)
- basement membrane (3 layers, size, charge)
- epithelial podocyte (slit diaphragm, size, charge)
what determines glomerular filtration
- pressure gradient between glomerular capillary and Bowman’s capsule
- permeability of glomerular capillary
- SA of glomerular capillary
effective filtration pressure
= (glomerular hydrostatic pressure + capsular osmotic pressure) - (glomerular osmotic pressure + capsular hydrostatic pressure)
main driving force for filtration
blood pressure in glomerular capillaries
forces opposing filtration
osmotic pressure in glomerular capillary and fluid pressure in Bowman’s capsule
what is renal clearance (not formula)
the rate at which substance S is cleared by the kidneys per unit time
formula for renal clearance
Clearance (Cs) = Us x V / Ps (in mL/min)
- Us = concentration of S in urine (mg/L or mol/L)
- V = volume of urine produced per unit time (mL/min or L/hour)
- Ps = concentration of S in plasma (mg/L or mol/L)
what is glomerular filtration rate
- GFR - amount of fluid filtered per unit time
- Usually around 180L/day
- tightly regulated
- varies from person to person, declines from age 30
conditions for a substance to be used as a measure of GFR
substance must:
- not be reabsorbed from the tubule
- not be secreted into the tubule
- not be metabolised
substances used to measure GFR
- inulin - polysaccharide not metabolised by body. Not found in body, must be injected (exogenous)
- creatinine - waste product produced by muscles. Already in body so most commonly used
filtered load
amount of a particular substance (solute) filtered per minute
filtered load = GFR x solute plasma conc
units are g/min or mol/min
reabsorption
movement of substance from renal tubule back into capillaries
some solutes such as glucose, Na+, Cl-, water are only reabsorbed (not secreted)
secretion
movement of substance from capillarie into renal tubule (not Bowman’s capsule)
some solutes are only secreted (not reabsorbed) e.g. drugs, organic cations, organic anions
secretion of p-aminohippurate
- organic anion
- represents secretion of all drugs
- actively secreted by cascade of basolateral apical transporter
why are some solutes secreted and reabsorbed by renal tubule
some solutes e.g. K+, ammonia, H+, urea are regulated according to homeostatic requirements
how is reabsorption across tubular epithelium improved
variety of epithelial types
cells held together by TIGHT junctions
microvilli increase surface area!
paracellular pathway
- water and solutes can move between cells without entering
- leaky - used for bulk reabsorption
- single barrier
- connects tubular lumen and lateral interstitial space
- no requirement for transport proteins, limited selectivity
- permeability depends on ‘tightness’ of tight junction
transcellular pathway
- water and solutes can move through cells
- two barriers: apical (mucosal) and basolateral (serosal) membrane
- connects tubular lumen and LIS or peritubular space
- tighter control through membrane transport proteins, so selective and energy dependent
- e.g. hormonal control
what is reabsorbed in proximal tubule
most reabsorption occurs here:
- 66% sodium, water, chloride
- all of the filtered glucose
- all of the filtered amino acids
- most of K+ (90%) , PO43-, Ca2+
- 80% of the filtered HCO3-
- half of urea
sodium reabsorption in kidney
66% in PCT
25% in TAL
5% in DCT
3% in CCT
reabsorption of solutes in PCT
driven by Na+ reabsorption:
- Na+ moves down its concentration gradient
- Na+/K+ ATP pump keeps conc. Na+ inside the cell low, so Na+ can move into cell
- this creates sodium gradient on luminal side compared to inside cell
- transport of many solutes is coupled to Na+ reabsorption via a transporter protein e.g. glucose (through SGLT1 or 2), amino acids
- once glucose is inside cell, it can move into interstitium via facilitated diffusion through sodium independent GLUT2
- secondary active transport
how much glucose is reabsorbed
- at normal filtered loads all glucose reabsorbed - none in urine
- high plasma glucose (e.g. diabetes mellitus) - filtered load exceeds re-absorptive capacity of transporters as they become saturated - glucose in urine (glucosuria)
movement of water
sodium absorption in leaky epithelium results in a huge water gradient over the epithelium, which drives trans and paracellular reabsorption of water
water absorption in PCT
has leaky epithelium so high water permeability, so paracellular and transcellular (via aquaporin 1) can take place
water absorption in CCT
has tight epithelium so has low water permeability so only transcellular absorption can take place through aquaporin 2
role of loop of Henle in reabsorption
- descending limb (tDLH) removes water from filtrate
- ascending limb (TAL) removes NaCl from filtrate
- makes interstitium around tubule in medulla hyperosmotic (forms Hyperosmotic medullary gradient HOMG)
- leaves filtrate inside tubules very dilute
- more water needs to be reabsorbed in CD (dependent on hydration)
role of DCT and collecting duct
fine tune electrolytes, pH and water
- reabsorb the remaining NaCl (8%) and water (up to 7%)
- secrete K+ and H+
hormonal control
- Na+ reabsorption/ K+ secretion by aldosterone
- water reabsorption by ADH (anti-diuretic hormone)
counter-current multiplier system in loop of Henle
tDLH is leaky epithelium, reabsorption of 25% water, which makes urine concentrated
TAL is more tight epithelium so impermeable to water, reabsorption of 25% NaCl. This makes medulla hyperosmotic (very salty) so more water is drawn out of tDLH which makes urine more complicated
distribution of water in body
2/3 in ICF and 1/3 in ECF
how much of our body weight is water
55-60%
distribution of water in ECF
1/5 in plasma
4/5 in interstitial fluid
osmolarity
based on number of osmotically active ions (can bind water) or solutes
can be estimated by density of solutions (gravity)
145 mM of NaCl = 290 mosmol/L
osmolarity and tonicity prefixes
iso = same
hypo = lower
hyper = higher
tonicity
based on effect of a solution on cells
osmolarity of ECF/ICF
275-295 mosmol/L
where is most water lost in body
kidneys via urine (urine output is adjusted to maintain balance)
water reabsorption in nephron
66% in PCT
25% in tDLH (leaky epithelium)
2-8% in CCT (varies based on your hydration)
0.5-7% excreted in urine
water reabsorption in PCT
driven by Na+ reabsorption
facilitated by aquaporins (transcellular) and via leaky tight junctions (paracellular)
what does changing body osmolarity cause
fluid shifts between ECF and ICF to equalise osmolarity
what effect does changing water content of cells have
changes size
changes structure
function = impaired
why must be regulate water
in order to regulate osmolarity to regulate cell size
what effect does no drinking (dehydration) have
water lost from ECF
ECF osmolarity increases (more conc than ICF)
water moves from ICF (lower osmolarity) to ECF (higher osmolarity) until osmolarity balances
cells become smaller
how is body osmolarity regulated
- TBW changes alter plasma (ECF) osmolarity
- this is detected by osmoreceptors in hypothalamus
- this stimulates pituitary gland to secrete more/less ADH
- ADH alters permeability of renal collecting duct so water retained/excreted to balance initial change in TBW
ADH synthesis
- in cell body of central neurons (hypothalamus)
- axonal transport to posterior pituitary
2 major stimuli for ADH release
- increased ECF osmolarity
- decreased blood volume
effects of ADH in nephron
- inserts water channels (aquaporins) in luminal membrane of CD
- increases H2O reabsorption in the collecting duct
method of action of ADH
- ADH (vasopressin) binds to the receptor on the basolateral side of the principal cell in the collecting duct
- this via a cascade of events increases the insertion of vesicles containing AQP2 into the apical membrane
- this increases water permeability of the apical membrane
without ADH:
collecting duct is relatively impermeable to water
majority of water remains in CD and is not reabsorbed
increased water loss in urine
large volume of dilute (low osmolarity) urine
with ADH:
collecting duct more permeable to water
water reabsorbed from CD (“down” HOMG)
decreased water loss in urine
small volume of concentrated (high osmolarity) urine!
osmotic regulation of ECF
fast, controlled by ADH
regulation of ECF by volume
slow, when you drink isotonic liquid, corrected by sodium excretion/retention
iso-osmotic water and salt losses due to diarrhoea, vomiting etc
ECF volume decreases
no change in osmolarity since both water and salt is lost so no difference in osmolarity between ECF and ICF so no gradient for water to move out of cells
so cells are ok but circulating volume decreases
corrected via sodium excretion/retention (slow)
iso-osmotic water and salt gains due to renal failure, excess IV fluids
ECF volume increases
no change in osmolarity
cells are ok but circulating volume increases
corrected via sodium excretion/retention (slow)
gains/losses of just water
excess intake/not drinking
spread over both compartments (ECF and ICF)
problems with cell size and function
corrected via ADH mechanism (fast)
hypo-volaemia
decreased blood volume
increased pulse
decreased blood pressure
increased urine concentration
hyper-volaemia
increased blood volume
shortness of breath
hypertension
3 detectors of changes in ECF
high pressure baroreceptors (aorta, carotid)
low pressure baroreceptors (vena cava, right atrium)
intra-renal baroreceptors and macula densa (juxtaglomerular apparatus)
high pressure baroreceptors
(pressure sensors)
in carotid sinus and aortic arch
signals to brainstem CVS centres
inputs to brainstem –> renal nerve activity (sympathetic)
low pressure baroreceptors
(volume sensors)
in atria, vena cava, pulmonary blood vessels
signals to brainstem cardiovascular centres
response to high blood volume
atria release atrial natriuretic peptide (ANP) in response to signal from low pressure receptors. This increases filtered load of Na+, decreases Na+ reabsorption, and decreases renin secretion. This causes less water to be reabsorbed, so more is excreted
afferent arteriole intra-renal sensor
- juxtaglomerular cells
- mechanoreceptors
- sense BP
- fall BP falls, renin is released which stimulates angiotenin II formation
macula densa intra-renal sensor
chemoreceptors
sense NaCl concentrations
can stimulate afferent arteriole to alter glomerular filtration and renin release
renin-angiotensin-aldosterone system
renin enzyme secreted by juxtaglomerular apparatus (JGA) when BP is low
renin cleaves angiotensinogen into angiotensin I
angiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE)
angiotensin II is the active form, a potent vasoconstrictor, stimulated tubular Na+ reabsorption and stimulates aldosterone release, which causes BP to increase
how is renal blood supply regulated so that filtration is relatively constant despite variations in blood pressure
- intrinsic (autoregulation) by myogenic vascular smooth muscle in afferent arteriole and tubuloglomerular feedback via JGA
- extrinsic by sympathetic vasoconstrictor nerves and angiotensin II
content of normal urine
95-98% water
Creatinine
Urea, uric acid
H+, NH3
Na+, K+
Drugs (anti-viral, diuretics)
Toxins
pH 4.8-7.2
content of pathological urine
Glucose (glucosuria, diabetes)
Protein (proteinurea)
Blood (erythrocytes, haematuria)
Haemoglobin (haemoglobinurea)
Leukocytes
Bacteria (infection)
functions of kidneys
Filters blood
Water homeostasis (hydration, BP)
Salt / ion homeostasis (Na+, K+, Ca2+, BP)
Hormone production (EPO - RBC production)
Excretion of drugs, endogenous metabolites, toxins etc.
Re-absorption of nutrients (amino acids, glucose etc.)
pH regulation
Metabolism
Gluconeogenesis
importance of salt/ion homeostasis
K+ is vital for resting membrane potential in all cells, action potentials and signalling in neurons, rhythm generation in pacemaker cardiomyocytes
Kidney failure can result in hyperkalaemia which is too much potassium
what is filtration
process by which certain substances and fluid is filtered from the blood (in glomerular capillaries), through the filtration barrier, to the Bowman’s space, and into the tubular system
produces a ‘plasma-like’ filtrate of the blood
rate of 125mL/min or 180L/day
secretion
adds additional wastes from the blood, to the filtrate
some substances such as drugs need to be completely secreted (are not filtered)
reabsorption
removes useful solutes from the filtrate and returns them to the blood
some substances need to be partly (Na+, K+)/entirely (glucose) re-absorbed
factors affecting renal filtration
renal blood flow
filtration barrier
driving forces/gradient between glomerular capillary and bowman’s space
permeability of glomerular capillary
surface area of glomerular capillary
what makes up filtration barrier
Fenestrated capillary endothelium, shared basement membrane, epithelial podocyte (pedicels and filtration slits)
what is filtered and not filtered through filtration barrier
Small substances (low molecular mass) are freely filtered - e.g. Na+, K+, Cl-, water, urea and glucose
Large substances (high molecular mass) are not filtered - e.g. Hb, Serum albumin
how much urine is produced per day
1.5L
renal blood supply
20-25% of cardiac output
1-1.2L/min
high flow for filtration rather than metabolism
mostly goes to glomerular capillaries
forces for filtration
Glomerular hydrostatic pressure (60mmHg)
- BP in glomerulus
- Pressure exerted by fluid in glomerulus
- Main driving force for filtration
Capsular osmotic pressure
- Negligible bc its nearly isosmotic
forces against filtration (into glomerulus)
Glomerular osmotic pressure
- Largely determined by albumin and other larger plasma proteins - high osmotic drive
Capsular hydrostatic pressure
- Pressure exerted by filtrate (fluid in Bowman’s space)
glomerular filtration rate
Amount of fluid filtered by the kidneys per unit time
Normally around 180L/ day (125mL/ minute)
cannot be readily measured - must estimate using substances that are only filtered e.g. inulin or creatinine
filtration fraction
how much of the blood reaching kidney is being filtered
FF = GFR/RPF
RPF - renal plasma flow (1/2 of renal blood flow)
solutes that are only reabsorbed
Glucose
Water
Na+
Cl-, PO4- and Ca2+
solutes that are only secreted
Organic cations such as histamine or morphine
Organic ions such as bile salts, penicillin or PAH
solutes that are both reabsorbed and secreted
K+
NH3
H+
HCO3-
Urea
stimuli for RAAS system
Reduce renal perfusion pressure (BP) in afferent arteriole
Decreased delivery of NaCl to macula densa
Renal sympathetic nerves (activated by baroreceptors)
Low plasma volume → increases renin production
