Physiology of the renal system Flashcards
1
Q
How is body water balanced?
A
- Urine = greatest independent control in water body balance maintenance
- Plasma = fluid compartments of blood (55% of blood volume)
- Haematocrit = proportion of blood occupied by cells
- Measure body fluid: inject known substance into given compartment, calculate volume distribution (volume required to contain total amount of drug in body at same concentration of that in plasma)
* Vd = Q/Cp - Osmotic pressure: force (per unit area) required to oppose net movement of molecules from side to the other (semi-permeable plasma membrane = interface between 2 solutions)
- Osmotic pressure = inverse of water potential
- Role of kidney: elimination of endogenous/exogenous compounds, maintenance of chemical homeostasis (pH), maintenance of volume status, and endocrine signalling
- Role of lower urinary tract: storage of urine, urination at appropriate time/place, and maintenance of continence
2
Q
How does the renal system interact with other systems?
A
- GI system: gut regulates input, kidney regulates output where gut provides K+/H+/HCO3- and kidney returns equilibrium
- Cardiovascular: maintenance of blood pressure by volume regulation → filling pressure and regulates ionic composition for cardiac muscle function
- Respiratory: pH regulation in metabolic/respiratory acidosis/alkalosis, joint metabolic pathway of renin/angiotensin system regulation
- Endocrine: renin-angiotensin system regulates aldosterone secretion and renal Na+/K+/H2O regulation, vitamin D regulation → Ca2+ regulation and target of central hormone by vasopressin
- Autonomic NS: afferent innervation and efferent nerves control blood flow in kidneys, ANS innervation of bladder and urethra controls storage of urine and micturition
- Haematology: erythrocyte production regulation through erythropoietin, haematological malignancies lead to renal failure through deposition of antibodies
- Musculoskeletal: response to crush injury, pelvic floor important in maintenance of continence, and skeletal muscle controls external urethral sphincter
3
Q
Explain filtration in the kidneys
A
- Occurs in the glomerulus, semi-permeable membrane separates cells/plasma in capillaries from filtrate (forms Bowmann’s space)
- Forces that drive flow are same as those determining movement in capillary beds:
1. Hydrostatic = ↑ pressure drives fluid out
2. Osmotic/oncotic = ↑ pressure in capillaries (due to plasma proteins) impedes flow, ↑ osmotic force along length of capillaries, but not equilibrium - Total osmotic pressure of plasma is high due to low protein level, most of constituents of plasma have low molecular size + mass → equal distribution across glomerular capillary so osmotic pressure affects driving force
- High osmotic pressure = difficult preventing flow using hydrostatic pressure
* Osmotic pressure = nCRT - estimation (nC = 0.28osm.kg-1) - Over short capillaries, hydrostatic pressure remains constant, oncotic pressure is initially equal to plasma, but increases due to loss of water (never exceeds hydrostatic)
- Net perfusion = Capillary hydrostatic pressure - (oncotic pressure + Bowmann’s space hydrostatic pressure)
- Efferent capillary leaves glomerulus, enters portal vein, travels to second capillary bed surrounding loop of Henle (hydrostatic pressure here is similar to systemic capillary but osmotic is higher)
4
Q
Difference between diffusion and bulk flow
A
- Diffusion = movement from high to low concentration (insufficient for glomerular filtration)
- 3 layer separating blood from lumen of Bowman’s capsule: endothelial cells of glomerular capillaries, glomerular basement membrane, and epithelial cells of Bowman’s capsule
- Endothelial cells have small holes and negatively charged glycocalyx (creates charge barrier)
- Basement membrane has fixed -ve charged proteins as a barrier to diffusion
- Podocytes (epithelial cells) have small processes projecting to neighbours, forming barrier to movement of fluid to allow filtrate to pass
- Bulk flow = movement of solution of high pressure to area of low pressure, moving solvent carries dissolved solutes (solvent drag)
- Molecules filtered mostly less than 10kDa in size (Na+/K+/Cl-/glucose/urine), larger molecules filter in damaged glomeruli
- Glomerular filtration rate (GFR) = 120ml.min-1/108L.day-1
- Rest of nephron reabsorbs most of flow, Bowman’s space hydrostatic pressure = driving force of filtrate
- Filtration factor = glomerular flow rate/ renal plasma flow (about 0.2)
- 2 ways to locally increase glomerular capillary pressure: dilate afferent arterioles and contract efferent arterioles
- Distal efferent vasodilation = fall in GFR, changes in diameter of afferent or efferent arteriole in direction of kidney and body can regulate GFR
5
Q
Transport in proximal convoluted tubule
A
- Selective distribution of ion channels, exchangers, and cotransporters (secondary active transport) and pumps (primary active transport) on apical and basolateral membrane is key for directional movement
- Movement of ions through cells (transcellular) and between cells (paracellular)
- Na+ movement creates osmotic gradient for transcellular water movement (electrochemical gradient of Na allows secondary active transport of other substances)
- Proximal convoluted tubule is quite water permeable so filtrate is isotonic with interstitial space, in cortex is isotonic with plasma, so by end of tubule 70% of water is reabsorbed
- H2O movement occurs by both trans and paracellular routes
- Through paracellular route due to net hydrostatic and osmotic forces where water moves between cells and tight junctions that link epithelial cells and through transcellular due to AQP1 molecules
- 90% of glucose transported on apical by low affinity/high capacity sodium glucose transporters (SGLT2), rest is carried by SGLT1 (high affinity/low capacity)
- Basolateral transport of glucose is through GLUT2 (or GLUT1) transporters but both apical and basolateral transporters use secondary active transport mechanisms
- SGLT2 inhibitors used in diabetes treatment where inhibiting glucose transport causes glucosuria so ↓ glucose levels
- Difference transporters contribute to amino acid transport, second reactive transporters that use electrochemical gradient of Na to be reabsorbed
- Cl- has both passive and active movement, main active movement is through antiporter of another anion (HCO3-/HCOO-)
- Cl- concentration increases along length of proximal tubule and as it increases it drives passive paracellular CL- movement down its concentration gradient
- At basolateral membrane there is the organic anion transporter for anion excretion but luminal membrane has multiple resistance associated protein for excretion
6
Q
Transport in the loop of Henle
A
- Aids in reabsorption of water and salts, also establishes a high osmolarity in medulla of kidney (important for producing concentrated urine)
- Thick ascending limb: create hyperosmolar interstitial space in medulla to drive water loss from descending limb and cortical duct, can sustain osmotic pressure gradient of 200mOsm.kg-1 and uses Na+-2Cl- cotransporter to move ions and this is a member of the cation couple chloride transporters where K+ recycling through apical is important to ensure transporter is able to transport large quantities of Na+ and Cl-
- Descending limb: majority of water movement is paracellular and driven primarily by osmotic gradient
- Furosemide: inhibitor of cotransporter, act in ascending limb and blocks Na+-2Cl- cotransporter, causes natriuresis and diuresis, used in cardiac and renal failure, but causes K+ loss leading to cardiac dysrhythmias, hypovolaemia, mild metabolic alkalosis, and loss of Mg2+ + Ca2+
7
Q
Transport in the distal tubule
A
- Includes transport of NaCl through cotransporter on apical where Na-K-ATPase is driving Na reabsorption on basolateral membrane and CL leaving cells is cotransported along with K
- Thiazides/thiazide-like drugs act in the distal to block the Na+-Cl- cotransporter, and is a moderately effective diuretic that has uses in antihypertension
- Collection ducts: reabsorption of Na is important so Na is vital for maintaining volume status, K secretion here is also important as build up becomes toxic
- Expression of AQP2 allow for regulation of water reabsorption in cortical ducts
- Expression of Na channel and basolateral Na-K-ATPase is regulated by aldosterone which stimulates synthesis
- Spironolactone = inhibitor of aldosterone (used in heart failure) actins in collecting duct and tubules, blocks effect o aldosterone, moderately effective diuretic
- Urea countercurrent multiplication: in late distal tubule and cortical ducts, as water is removed, urea concentration rises, in medullary collecting duct urea diffuses out of urea-permeable tubule
- Urea permeability is increased by ADH by increasing expression of UT-A1, urea in medullary interstitial space contributes to high osmotic pressure in medulla, causing urea countercurrent out of collecting duct, into loop of Henle, further aiding water reabsorption in medulla
8
Q
Osmoregulation
A
- Primary hormone is ADH (known as vasopressin) produced by hypothalamus and released from pituitary gland
- ADH acts in distal tubules and collecting duct to increase water permeability by increasing AQP2 in apical of collecting duct
- Receptors for ADH are found on basolateral surface, V2 receptors are coupled by Gs which activates adenyl cyclase
- Activation of cAMP → activation of PKA causing insertion of vesicles (contain pre-formed AQP2) allowing body to respond quickly to changes in osmolarity
- cAMP also triggers cascade of transcription/translation → production of new AQP2 vesicles
- Along length of proximal tubule, osmolality stays at 285mOsm.kg-1 as Na : H2O reabsorption is in proportion
- Descending tubule: H2O reabsorbed = ↑ osmolality to 600mOsm.kg-1
- Ascending limb: Na is reabsorbed so osmolality decreased to 90mOsm.kg-1
- In absence of ADH, post ascending limb, osmolality stays low due to little water reabsorption along tubule system
- Flow rate enters system at 125ml.min-1 (GFR), absorption long length of tubule but little reabsorption in absence of ADH = large urine produced
- Maximum ADH production = more water absorption in collecting ducts → osmolality increases past ascending limb
- Flow rate start the same, but decrease in distal tubule to 45ml.min-1 where more water is reabsorbed so volume leaving nephron is low → low urine output in presence of max ADH
- Urea: maintains osmolality in renal medulla, in presence of selective protein starvation, urea production is low, UT-A1 is regulated by ADH similar to AQP2
- Medullary interstitial space is high, cells survive surround environment by adaption of accumulation of range of organic osmolytes: sorbitol, inositol, glycerophosphorylcholine, and betaine
9
Q
What is the effect of osmolality on circulating ADH concentration?
A
- Concentration of ADH ∝ rate of secretion at equilibrium with first order clearance
- Rate created varies quickly as small osmolality changes causes profound changes in ADH concentration
- Dominant osmolytes in circulation are Na+ and Cl-, but these are not the dominant osmolytes ingested, all intakes (except fat) reach circulation from gut in a water-soluble form and so contributes osmolytes that can affect osmolality
- Post absorption: carbs are converted into simple sugars, transported into cells so do no contribute significantly to osmolality (expect in diabetes mellitus), C6H12O6 is oxidised to CO2 (rapidly excreted), and water, so only transiently increases osmolality
- Proteins are broken down into amino acids, rapidly taken up by cells, plasma change in osmolality is small, nitrogen removed has high renal clearance causing high flux but still osmolality is low
- Hyperosmolar hyperglycaemic state: glucose concentration gets high that it become a large contributor to osmolality leads to dehydration and if sufficient, can lower glucose that lead to hyponatraemia, causing altered mental status, seizures, and other neurological signal, also increase blood viscosity and clotting risk
10
Q
Mechanism of the renin-angiotensin system
A
- Juxtaglomerular apparatus (JGA) = complex of late distal tubule in association with renal afferent arteriole (both of same nephron), they granular cells in afferent arteriole
- Of JGA, macular densa causes thickening of wall of early distal tubule
- Aim of renin-angiotensin-aldosterone system = increase effective circulating volume
- Renin release decrease in Bp in afferent arteriole, decrease in Na+ conc in distal collecting tube, increase in sympathetic NS innervation
- Aldosterone: triggers for aldosterone release are ATII and hyperkalaemia, convergence of these signalling pathways means where aldosterone alone only regulates ATII action of the kidney, K+ and volume regulation could not be independently regulated
- Renin-angiotensin system can be inhibited in 4 different locations to control blood pressure: ACE inhibitors, AT1 receptor agonists, aldosterone receptor antagonists, and renin inhibitor
- Angiotensin II receptors: main receptors in periphery, for effect of ATII then AT1 is the receptor and is mainly coupled through Gq which is linked to an increase in IP3/DAG signalling and increased Ca2+ release from intracellular stores cause contraction
- Actions to increase circulating volume of angiotensin II:
1. Increase Na+/H+ exchanger in proximal tubule, increases Na+ and water reabsorption
2. Increase in aldosterone release from adrenal cortex increases distal Na+ absorption
3. Cause ADH release
4. Cause thirst - helps to replenish volume by changing water input - Efferent and afferent vasoconstriction helps to maintain GFR
11
Q
How is sympathetic innervation of afferent arteriole activated?
A
- 3 action of sympathetic activation to afferent arteriole include:
1. Vasoconstriction upstream of granule cells causes a further fall in pressure sensed by these cells, and amplifies fall in wall pressure generated by a fall in blood pressure
2. Direct stimulation of renin release from the granule cells
3. Afferent arteriole vasoconstriction drops glomerular hydrostatic pressure to glomerulus so lowers GFR - Noradrenaline = key recognised sympathetic effector transmitter in afferent arteriole
- On vascular smooth muscle cells, vasoconstriction is caused by an action of alpha1-adrenpceptors and these are Gq coupled
- On granule cells (for the regulation of renin release), main receptors are beta1- adrenoceptors and these are GS coupled
- Third stimulus to renin release: fall in blood volume → venous pressure falls as venous system = main source of capacitance in circulation
- Fall in venous pressure causes a fall in pressure in vasa recta, and an increase in uptake of fluid from renal interstitial space = greater loss of fluid from filtrate, particularly in descending limb of the loop of Henle
- This decreases Na+ delivery to distal tubule (acts as a further stimulus to renin release)
- ADH release following haemorrhage decreases cardiac filling, causes activation of baroreceptor reflex, and central actions of ATII all cause an increase in release of ADH following haemorrhage
- Release → increase in water reabsorption and maintenance of circulating volume
- This lowers osmolality as mechanism does not retain Na+, so acute response to haemorrhage will involve hyponatraemia
12
Q
Interaction between osmoregulation and volume regulation
A
- Volume regulation disturbs osmoregulation, body accepts decreased osmolality in order to maintain a low volume
- Increased osmolality, stress, decreased volume, and nicotine → increase ADH release, whereas decreased osmolality, ↑ volume, and alcohol → decrease ADH release
- Atrial natriuretic peptide (ANP): 28-amino acid peptide with a 17-amino acid ring, increases venous return and → increased atrial filing that increases ANP release
- ANP travels to kidney, acts on ANPA,B receptors (NPR1-2) activating intrinsic guanylyl cyclase activity (increased cGMP)
- Similar peptide produced in the kidney called urodilatin
- Action of ANP downstream of cGMP include:
1. Causes a receptor-mediated increase in cGMP, which dilates afferent glomerular arteriole, ↑ GFR which ↑ Na+ delivery to kidney
2. Decreases Na+/Cl- cotransport activity in distal tubule
3. Decreases ENaC and Na+/K+ ATPase activity in cortical collecting duct - Net efferent = ↑ in renal Na+ excretion in urine and is natriuretic
prostaglandins - Both PGE2 and PGI2 are produced tonically and both increase Na+ excretion
- Tonic system inhibition → fall in prostaglandins, and Na+ retention
- People with normal renal function, effect of NSAIDs may be insignificant, but it becomes more important in renal failure
- Dopamine: synthesised in kidneys, mainly by epithelial cells on proximal tubule in part from sympathetic nerve terminals
- Dopamine tonically acts via both D1 receptors to increase cAMP, and decrease activity of Na+/H+ exchanger in proximal tubule → increased Na+ excretion (natriuretic)
