Renal: Physiology - Renal function and micturition Flashcards
What structures make up the nephron?
Renal tubule
Glomerulus
How many nephrons are in the human kidney?
~1 million
What is Bowman’s capsule?
Blind, dilated end of tubule into which tuft of capillaries invaginates to form the glomerulus
What supplies the glomerulus? Which is the larger of the two?
Afferent and efferent arterioles
Afferent is larger in diameter
What are the two layers of the glomerulus?
Capillary endothelium
Specialised epithelium of capsule
Describe the structure of the glomerular endothelium, including the cell types found
Fenestrated endothelium with pores 70-90nm in diameter
Surrounded by glomerular basement membrane (basal lamina) without visible gaps or pores
Also surrounded by podocytes: specialised cells with pseudopodia which interdigitate to forms filtration slits ~25nm wide along capillary wall
Mesangial cells between the endothelium and basal lamina
What is the mesangium?
Mesangial cells and the extracellular matrix they secrete
List 5 properties of mesangial cells
- Contractile
- Role in regulation of filtration
- Secrete ECM
- Take up immune complexes
- Involved in progression of glomerular disease
What is the total area of glomerular capillary endothelium across which filtration occurs in humans?
~0.8m^2
What are the characteristics of substances permitted free passage by the glomerulus?
Neutral charge
Up to 4nm in diameter
What size substances are excluded from glomerular filtration?
> 8nm in diameter
Three distinctive histologic features of the proximal convoluted tubule
- Apical tight junctions
- Lateral intercellular spaces
- Striated brush border
Describe the epithelium of the descending limb and thin portion of ascending limb of loop of Henle
Thin, permeable
What is the difference between cortical and juxtomedullary nephrons?
Cortical: glomeruli in outer cortex, short loops of Henle
Juxtamedullary: glomeruli in juxtamedullary region of cortex, long loops of Henle that extend down into medullary pyramids
What % of nephrons in humans are juxtamedullary?
~15%
What three cell types make up the juxtaglomerular apparatus?
- Macula densa: specialised cells at the end of the thick ascending limb of loop of Henle
- Lacis cells: extraglomerular mesangial cells with contractile properties
- Granular cells: renin-secreting cells in afferent arteriole
Describe the epithelium of the distal convoluted tubule
Lower than the proximal tubule with fewer microvilli
Describe the epithelium of the collecting ducts
Made of two cell types: principal and intercalated
Compare and contrast the structure and function of P and I cells in the collecting ducts
Principal: relatively tall with few organelles, Na+ reabsorption and ADH-stimulated H2O reabsorption
Intercalated: fewer, also present in DCT, more organelles (microvilli, cytoplasmic vesicles and mitochondria) than P cells, responsible for acid secretion and HCO3- transport
What are the RMICs? What are their function?
Renal medullary interstitial cells
Site of COX-2 and PGES expression
Synthesise prostanoids including PGE2 (role in Na+ and H2O homeostasis)
At what two sites in the kidney is PGI2 secreted?
Arterioles
Glomeruli
Describe the renal circulation. What is the difference in circulation between the cortical and jextamedullary nephrons?
- Interlobar arteries divide into arcuate arteries
- Arcuate arteries give off interlobular arteries in the cortex
- Interlobular arteries supply an afferent arteriole to each glomerulus
- Afferent arteriole divides into multiple capillary branches to form the glomerular tuft
- Capillary branches coalesce to form the efferent arteriole
- Efferent arteriole breaks up into peritubular capillaries which supplies multiple nephrons (in juxtamedullary nephrons they also drain into the vasa recta to supply the deeper portion of the loop of Henle)
- Peritubular capillaries drain into interlobular veins
- Interlobular veins drain into arcuate veins
- Arcuate veins drain into interlobar veins
What is unique about the glomerular capillaries?
Only capillaries in the body which drain into arterioles
Arteriole segments between glomeruli and tubules are technically a portal system
Describe the structure of the descending and ascending portions of the vasa recta
Descending: non-fenestrated endothelium with facilitated transporter for urea
Ascending: fenestrated endothelium, role in conservation of solutes
What is the total surface area of the renal tubules? What is this equal to?
~12m^2
Equal to surface area of renal capillaries
What is the volume of blood in the renal capillaries at any given time?
30-40ml
Where do the lymphatics of the kidney drain?
Via the thoracic duct into venous circulation in the thorax
Describe the structure of the renal capsule. What is the significance of this if the kidney becomes oedematous?
Thin but tough
Renal interstitial pressure increases with renal oedema
Causes decreased GFR and may prolong anuria in AKI
Describe the innervation of the renal vessels
Predominantly sympathetic:
- Efferent fibres to afferent and efferent arterioles, PCT and DCT, and juxtaglomerular apparatus
- Also dense NA innervation of TAL of loop of Henle
Both afferent and efferent fibres travel respectively to and from the lower thoracic and upper lumbar segments of the spinal cord
Cholinergic innervation via vagus nerve (function unclear)
Describe the renorenal reflex
Increase in ureteral pressure in one kidney causes decreased efferent nerve activity in contralateral kidney to increase Na+ and H2O excretion
Describe normal resting renal blood flow in L/min and as a % of CO
1.2-1.3L/min
25% of CO
What is renal plasma flow equal to? When makes a particular substance unsuitable for calculation of renal plasma flow?
Amount of a given substance excreted per unit time / renal arteriovenous difference
Can’t be used if concentration of measured substance is metabolised, stored or produced by the kidney, or if the substance affects renal blood flow
What substance is used to calculate RPF? Why?
PAH (p-aminohippuric acid)
It is filtered by glomeruli and secreted by tubular cells, so its extraction ratio is high (~90% is removed in single pass through kidney)
How is RPF calculated? (Three steps)
- First calculate effective renal plasma flow by: ERPF = (Upah x V) / Ppah
Where Upah = urine PAH (mg/ml), V = urine flow (ml/min), Ppah = plasma PAH (0.02mg/ml) - Then actual RPF can be calculated by dividing ERPF by PAH extraction ratio (0.9)
- Finally from actual PRF, renal blood flow is calculated by dividing by 1 minus the haematocrit
Renal blood flow = RPF x (1/[1-Hct])
What is the glomerular capillary pressure when MAP is 100mmHg? What is the pressure drop across the glomerulus? What is the pressure in the peritubular capillaries and the renal vein?
With MAP of 100mmHg:
Glomerular capillary pressure = 45mmHg (~40% of MAP)
Pressure drop across glomerulus = 1-3mmHg
Peritubular capillary pressure = 8mmHg
Renal vein pressure = 4mmHg
Describe the effect of NA on renal blood flow
Vasoconstriction of interlobular arteries and afferent arterioles
Describe the effect of dopamine on renal blood flow
Renal vasodilation
Natriuresis
Describe the effect of angiotensin II on renal blood flow
Causes constriction of afferent and efferent arterioles
Describe the effect of prostaglandins on renal blood flow
Increased renal cortical blood flow
Decreased renal medullary blood flow
Describe the effect of ACh on renal blood flow
Causes renal vasodilation
Describe the effect of high-protein diet on renal blood flow
Raises glomerular capillary pressure
Increases renal blood flow
Where is dopamine produced?
In the kidney and brain from L-dopa
Over what range of perfusion pressures is the renal blood flow kept constant? How is this achieved?
Between 90-220mmHg, renal vascular resistance varies with pressure to maintain constant renal blood flow
What is the role of angiotensin II in maintaining renal blood flow? What is the clinical significance?
Constricts efferent arterioles to maintain GFR at low perfusion pressures
May explain renal failure seen in patients with poor renal perfusion who are treated with ACEIs
Describe the difference in blood flow and O2 extraction between the renal cortex and medulla
Cortical: high blood flow (5ml/g/min), little O2 extraction as main function is filtration (PO2 50mmHg)
Medulla: lower blood flow (2.5ml/g/min in outer medullar and 0.6ml/g/min), higher O2 extraction due to metabolic work being done (PO2 15mmHg)
Which part of the kidney is most sensitive to hypoxia?
Medulla
What four properties are required in a substance used to measure GFR?
- Freely filtered through the glomeruli
- Neither secreted nor absorbed by the tubules
- Nontoxic
- Not metabolised by the body
What substance can be used to measure GFR?
Inulin (polymer of fructose with MW of 5200)
Define renal plasma clearance
Volume of plasma from which a substance is completely removed by the kidney in a given amount of time (usually minutes)
How is renal clearance calculated?
Clearance = (Ux x V) / Px
Why is inulin preferred over creatinine for measuring GFR?
Some creatinine secreted by the tubules
Normal PCr (arterial plasma level of creatinine)
1mg/dL
Normal GFR in ml/min, L/h and L/day
125ml/min
7.5L/hr
180L/day
Normal clearance value of glucose
0ml/min
Normal clearance value of sodium
0.9ml/min
Normal clearance value of chloride
1.3ml/min
Normal clearance value of potassium
12ml/min
Normal clearance value of phosphate
25ml/min
Normal clearance value of urea
75ml/min
Normal clearance value of inulin
125ml/min
Normal clearance value of creatinine
140ml/min
Normal clearance value of PAH
560ml/min
What is the difference between GFR in women and men?
GFR 10% lower in women than men even after correction for surface area
Normal daily urine volume
1L
How much filtrate is normally reabsorbed?
99%
(GFR is 180L/day, urine output is only 1L/day)
How much fluid is filtered by the kidneys, expressed as a proportion of total body water, ECF volume, and plasma volume?
180L/day
4x TBW
15x ECF volume
60x plasma volume
What factors govern GFR? Express these in a formula
As for other forms of filtration, governed by balance of Starling forces
GFR = Kf [(Pgc - Pt) - (πgc - πt)]
Where:
- Kf = glomerular ultrafiltration coefficient (product of glomerular capillary permeability and effective filtration surface area)
- Pgc = mean hydrostatic pressure in glomerular capillaries
- Pt = mean hydrostatic pressure in tubule (Bowman’s space)
- πgc = oncotic pressure of plasma in glomerular capillaries
- πt = oncotic pressure of plasma filtrate in tubule (Bowman’s space)
How does the permeability of glomerular capillaries compare with skeletal muscle capillaries?
Permeability of glomerular capillaries 50x that of skeletal muscle
Filtration of a substance is inversely proportion to what measure?
Its diameter
Which are more easily filtered and why: anionic or cationic substances? Explain the effect of this phenomenon on filtration of albumin
Cationic more freely filtered due to negatively charged sialoproteins in capillary wall repelling negatively charged substances in blood
Albumin has a glomerular concentration only 0.2% of its plasma concentration, which is less than would be expected on the basis of its 7nm diameter alone
How much protein is found in the urine normally? What is the source of this protein?
<100mg/day
Mostly from shed tubular cells
Why does albuminuria occur in nephritis?
Negatively charges in glomerular wall are dissipated in nephritis, so albuminuria occurs without an increase in the size of membrane pores
What is the effect of mesangial cell activity on Kf?
Can be altered by mesangial cells: contraction of mesangial cells reduces filtration surface area to decrease Kf
Ten factors which induce mesangial cell contraction
- Endothelins
- Angiotensin II
- Vasopressin
- NA
- Platelet-activating factor
- Platelet-derived growth factor
- TXA2
- PGF2
- Leukotrienes C4 and D4
- Histamine
Four factors which induce mesangial cell relaxation
- ANP
- Dopamine
- PGE2
- cAMP
Describe the oncotic pressure gradient across the glomerular capillary
πgc - πt
πt is usually negligible, so oncotic pressure gradient is essentially equal to oncotic pressure of plasma proteins
Is exchange across the glomerular capillaries flow-limited or diffusion-limited?
Flow-limited: some portions of glomerular capillaries do not normally contribute to formation of ultrafiltrate
What is Puf at the afferent and efferent end of the glomerular capillaries? How does this occur?
Afferent end: 15mmHg
Efferent end: 0mmHg
Fluid leaves plasma and oncotic pressure rises as blood passes through the capillaries
What is the effect of afferent vs efferent vasoconstriction?
Either type decreases blood flow to tubules
What happens to GFR when MAP drops below the autoregulatory range (<90mmHg)?
GFR drops sharply
What tends to happen when efferent constriction > afferent constriction?
GFR is maintained
Define filtration fraction. What is the normal value?
Ratio of GFR:RPF
Normally 0.16-0.20
What varies more: GFR or RPF?
RPF
Why does GFR fall less than RPF with a fall in systemic BP? What happens to the filtration fraction?
Because of efferent constriction
Filtration fraction rises due to maintained GFR and decreased RPF
What is the effect of exercise and rising from a supine position to stand upright on renal blood flow?
Both decrease renal blood flow (standing up to a lesser extent)
What is the effect of increasing levels of sympathetic stimulation of the kidney and how are these effects mediated?
- Increased renin: via effect of NA on B1-receptors of juxtaglomerular cells
- Increased Na+ reabsorption: via effect of NA directly on renal tubular cells
- With highest levels of stimulation, renal vasoconstriction leading to decreased GFR and renal blood flow: via a1-receptors predominantly (some contribution from a2)
What is the effect of decreased baroreceptor discharge on renal blood flow?
Induces renal vasoconstriction
What is UxV and what is it equal to?
UxV = urinary excretion of substance X per unit of time (urinary concentration of X in mg/ml x urine flow in ml/min)
Equal to GFR x Px +Tx
Where Px = plasma concentration of X in mg/ml, and Tx = net amount transferred by tubules (secretion - reabsorption)
In what circumstances would clearance of a substance be equal to, more than, or less than the GFR?
Equal to GFR if zero net tubular secretion/reabsorption (Tx 0)
More than GFR if net tubular secretion (Tx positive)
Less than GFR if net tubular reabsorption (Tx negative)
How and where are small proteins and peptide hormones reabsorbed?
In proximal tubules by endocytosis
What is the paracellular pathway? Where in the tubule is it most important?
Tubular epithelium is a leaky epithelium: tight junctions between cells permit passage of some water and electrolytes, this passage is referred to as the paracellular pathway
Appears to be significant factor in the proximal tubule
Where is Na+ actively transported out of the renal tubule?
All parts except the thin portions of the loop of Henle
6 apical transporters involved in Na+ and Cl- movement in the proximal tubule
- Na+/glucose co-transporter: Na+ and glucose uptake
- Na+/PO4 co-transporter: Na+ and PO4 uptake
- Na+/AA co-transporter: Na+ and amino acid uptake
- Na+/lactate co-transporter: Na+ and lactate uptake
- Na+/H+ exchanger: Na+ uptake, H+ secretion
- Cl-/base exchanger: Cl- uptake
3 apical transporters involved in Na+ and Cl- movement in thick ascending limb of loop of Henle
- Na+/K+/2Cl- co-transporter: Na+, K+ and Cl- uptake
- Na+/H+ exchanger: Na+ uptake, H+ secretion
- K+ channels: K+ extrusion (recycling)
Apical transporter involved in Na+ and Cl- movement in DCT
NaCl co-transporter: Na+ and Cl- uptake
Apical transporter involved in Na+ and Cl- movement in collecting ducts
Na+ channel (ENaC): Na+ uptake
Describe transport of sodium through the renal tubules, including where and how it occurs
Moves by cotransport or exchange down its concentration and electrical gradients across the apical membrane in the proximal tubule, thick ascending limb of loop of Henle, DCT and collecting ducts
Pumped into interstitium via Na, K ATPase in basolateral membrane
I.e. Na+ actively transported out of all parts of renal tubule except the thin portions of the loop of Henle
What percentage of filtered Na+ is reabsorbed in the proximal tubule? How is this primarily achieved?
60%
Primarily via Na+/H+ exchanger
What percentage of filtered Na+ is reabsorbed in the TAL of loop of Henle? How is this primarily achieved?
30%
Via Na-2Cl-K co-transporter
What other method of Na+ movement contributes to its reabsorption, outside of active transport / cotransport / exchange?
Passive paracellular movement
What percentage of filtered Na+ is reabsorbed in the DCT? How is this primarily achieved?
7%
Via Na-Cl co-transporter
What percentage of filtered Na+ is reabsorbed in the collecting ducts? How is this primarily achieved? What hormone regulates this process to permit homeostatic adjustments in Na+ balance?
3%
Via ENaC channels
Regulated by aldosterone
Where are glucose, amino acids, and bicarbonate reabsorbed?
Early portion of proximal tubule
How is glucose removed from the urine?
Via secondary active transport: glucose and Na+ bind to sodium-dependent glucose transporter (SGLT)-2 in the apical membrane, and glucose is carried into the cell as Na+ moves down its electrochemical gradient
Na+ is pumped out of the cell into the interstitium via Na K ATPase
Glucose exits by facilitated diffusion via glucose transporter (GLUT)-1 into interstitium
What is the TmG in men and women?
Men: 375mg/min
Women: 300mg/min
What is the renal threshold for glucose?
200mg/dL arterial plasma, 180mg/dL venous plasma
Which isomer of glucose is transported at a higher rate and why?
D-glucose has higher rate of transport as SGLT-2 specifically binds D-glucose
What is the effect of plant glucoside phlorhizin on glucose transport?
Competes with D-glucose for SGLT-2 binding to reduce glucose absorption
How do amino acids leave tubular cells to enter the interstitium?
Via passive or facilitated diffusion (not Na+ dependent)
At what point in the tubules are loop and thiazide diuretics secreted into the urine?
Proximal tubule
Describe the process of tubulo-glomerular feedback
- Na+ and Cl- enter macula densa cells via Na-K-2Cl co-transporter
- Increased Na+ causes increased Na K ATPase activity at basolateral membrane and resultant ATRP hydrolysis causes formation of adenosine
- Adenosine acts on A1 receptors on macular densa cells to increase Ca2+ release to vascular smooth muscle of afferent arteriole
- Afferent arteriole vasoconstricts to reduce GFR; similar (but unclear) mechanism decreases renin secretion from juxtaglomerular cells
And vice versa (decreased flow through loop of Henle and first part of DCT results in increased GFR)
Describe the process of glomerulo-tubular balance. What is its function?
Increased GFR leads to increased solute and therefore H2O reabsorption (primarily in proximal tubule)
Percentage of solute reabsorbed is held constant over range of GFR
What % of H2O is reabsorbed?
In normal conditions 99%
At least 87% even with very large volumes of urine (e.g. DI)
How many of the identified aquaporins play a key role in the kidney?
4
Where is aquaporin-1 expressed in the proximal tubule and what is its role?
In proximal tubule, on both apical and basolateral membranes
Allows water to move rapidly out of tubule along osmotic gradients to maintain isotonicity
Is the proximal tubule hypertonic, hypotonic, or isotonic?
Isotonic until end
Where is aquaporin-1 expressed in the descending limb of the loop of Henle and what is its role?
In descending limb of loop of Henle, on both apical and basolateral membranes
Allows water to move out along its gradient into the hypertonic interstitium, leaving hypertonic fluid in the descending limb
Describe the osmolality of the medullary pyramids. What is the osmolality at the tips of the papillae? How does this compare to plasma osmolality?
Graded increase in osmolality of interstitium of pyramids
Osmolality at tips of papillae reaches 1200mOsm/kg of H20, ~4x that of plasma
Why is the ascending limb of the loop of Henle called the diluting segment? What happens to Na+, K+ and Cl- in this segment?
It is impermeable to H2O, but Na+ K+ and Cl- are actively co-transported out leaving behind hypotonic fluid
Na+ is then actively transported into interstitium via Na K ATPase to keep intracellular Na+ low
K+ diffuses back into both the tubular lumen and the interstitium via ROMK channels
Cl- moves into interstitium via ClC-Kb channels
What % of filtered solute is removed by the end of the proximal tubule?
60-70%
What % of filtered water is removed by the end of the proximal tubule? The descending limb of loop of Henle?
Proximal tubule: 60-70%
Descending limb of loop of Henle: 15%
(~20% of filtered water enters the distal tubule)
Describe solute/solvent movement in the distal tubule
Similar to the thick portion of the ascending limb
Relatively impermeable to H2O
Removal of solute from lumen in excess of solvent causes further dilution of tubular fluid
Which aquaporin is involved in H2O reabsorption in the collecting ducts?
Aquaporin-2
Which gland releases vasopressin?
Posterior pituitary
What three mediators are involved in vasopression action on the collecting ducts?
- V2 receptor
- cAMP
- Protein kinase A
What is the H2O permeability of the collecting ducts in the absence of vasopressin? What is the urine osmolality and flow possible in this setting?
Relatively impermeable (~2% reabsorbed, up to 13% of filtered water excreted)
Urine osmolality as low as 30mOsm/kg H2O
Urine flow as much as 15mL/min
Describe the effect of vasopressin on the H2O reabsorption in the collecting ducts
H2O moves out of hypotonic tubular fluid into cortical collecting ducts, and then into the interstitium
Tubular fluid becomes isotonic and enters the medullary collecting ducts: additional H2O is reabsorbed due to the hypertonicity of the medullary interstitium
Which collecting duct cells are capable of inserting aquaporins in response to vasopressin?
Principle cells
What is the maximal urine osmolality that can be achieved in humans? What is this relative to plasma osmolality?
1400mOsm/kg H2O
5x plasma osmolality
What % of filtered water may be excreted in the absence of ADH?
Up to 13%
Describe the two components of the countercurrent mechanism responsible for maintaining increasing osmolality along the medullary pyramids
Countercurrent multiplier: loop of Henle has high permeability to water in thin descending limb and actively transports Na+ and Cl- out of the ascending limb, as Na+ and Cl- are pumped into the interstitium this creates an environment of relative hypertonicity in the interstitium which draws water from the ascending loop, with ongoing flow of tubular fluid this process repeats until there is a gradient of osmolality from top to bottom of the loop
Countercurrent multiplier: vasa recta maintains the gradient established by the loop of Henle, solutes from the ascending limb of loop of Henle are absorbed by the descending limb of the vasa recta, producing relative hypertonicity within the vasa recta which then draws water into the ascending limb of the vasa recta (this is also how 180L of blood can be filtered daily while only producing 1.5L of urine)
What role does urea play in renal physiology?
Urea helps establish the osmotic gradient in the medullary pyramids and aids ability to form concentrated urine in collecting ducts
How many forms of urea transporter are found in the kidney?
4
What hormone regulates urea transport in the collecting ducts? What is its effect?
ADH
When ADH is high, the amount of urea transported into the medullary interstitium increases, thus increasing the concentrating capacity of the collecting ducts
What effect does high-protein diet have on the ability of the kidneys to concentrate urine?
Increases the ability of the kidneys to concentrate urine (more urea filtered -> more deposited in medullary interstitium -> increased concentration gradient)
Describe the process of osmotic diuresis
Presence of large amounts of non-reabsorbed solutes promotes increased urine volume
Via reduction in Na+ (due to decreased concentration gradient in proximal tubule and ascending limb of loop of Henle) and therefore water reabsorption
What kind of substances can produce an osmotic diuresis? Give four examples
Compounds that are filtered by not reabsorbed (e.g. mannitol)
OR substances present in amounts exceeding the capacity of the tubule to reabsorb them i.e. the renal threshold (e.g. glucose in setting of hyperglycaemia, infusion of large amounts of sodium chloride, or excessive urea - note that moderate increase in urea improves concentrating ability)
What is the difference between osmotic diuresis and water diuresis in terms of mechanism and effect on urine flow?
Water diuresis: amount of water reabsorbed in proximal nephron is normal, maximal urine flow is 16ml/min
Osmotic diuresis: decreased water reabsorption in proximal tubules and loops, very large urine flows with concentration approaching plasma (close to unchanged isotonic proximal tubular fluid)
What is the effect of GFR on urine concentration?
Reduced GFR -> reduced flow through tubules -> increased medullary gradient -> increased urine concentration (even in absence of vasopressin)
How and why is free water clearance calculated?
Can be calculated to quantitate free water gain or loss by excretion of concentrated or dilute urine
Calculated as the difference between the urine volume and the clearance of osmoles
CH2O = V - Cosm
CH2O = V - [(Uosm x V) / Posm]
Where CH2O = free water clearance, V = urine flow, Uosm = urine osmolality, Posm = plasma osmolality
What does a negative vs positive CH2O mean?
Negative = hypertonic urine (urine osmolality > plasma osmolality)
Positive = hypotonic urine (urine osmolality < plasma osmolality)
What is CH2O during maximal antidiuresis and in absence of vasopressin?
Maximal antidiuresis: CH2O = -1.2ml/min
Absence of vasopressin: CH2O = 14.5ml/min
In what parts of the tubule is Na+ transported out?
All except the descending limb of the loop of Henle
What % of Na+ is reabsorbed in normal conditions?
99%
Na+ accounts for what % of osmotically active solute in plasma and interstitial fluid? What is the significance of this?
90%
Prime determinant of ECF volume
What is the range of urinary Na+?
From 1mEq/day (low-salt diet) to 400mEQ/day (high salt intake)
What mechanisms control Na+ excretion?
- Factors affecting GFR
- Factors affecting reabsorption:
- Adrenocortical hormones including aldosterone
- Angiotensin II
- ANP and other natriuretic hormones
- PGE2, endothelin and IL-1
- Rate of tubular secretion of H+ and K+
- Dietary Na+ intake
List six factors affecting Na+ reabsorption
- Adrenocortical hormones including aldosterone
- Angiotensin II
- ANP and other natriuretic hormones
- PGE2, endothelin and IL-1
- Rate of tubular secretion of H+ and K+
- Dietary Na+ intake
What is the effect of aldosterone on Na+ reabsorption? How is this achieved?
Increased tubular reabsorption in association with Cl-, and with secretion of K+ and H+
Occurs via increasing ENaC in collecting ducts
What accounts for the latent period between aldosterone release and effect on Na+ reabsorption?
Latent period of 10-30mins because of time required for altered protein synthesis via action on DNA
What mutation is seen in Liddle syndrome and what effect does this have on Na+ reabsorption?
Increases ENaC activity (defective subunit causes constitutive activation)
Leads to Na+ retention and HTN
What is the effect of ANP on Na+ reabsorption and how is this achieved?
Decreases Na+ reabsorption to induce natriuresis
Via increased cGMP to inhibit transport via ENaC
What is the effect of PGE2, endothelin and IL-1 on Na+ reabsorption and how is this achieved?
PGE2 inhibits Na K ATPase, and also increases intracellular Ca2+ to cause inhibition of ENaC
Endothelin and IL-1 work indirectly by increasing PGE2 formation
What is the effect of reduction in dietary salt intake on Na+ reabsorption?
Increases aldosterone secretion to decrease Na+ excretion
What effect does angiotensin II have on Na+ reabsorption and how is this achieved?
Increased Na+ and HCO3- reabsorption via action on proximal tubules
Describe the escape phenomenon. In what conditions is it reduced or absent?
Prolonged exposure to high levels of circulating mineralocorticoids does not cause oedema in otherwise normal individuals (may be due to increased ANP)
Reduced or absent in nephrosis, cirrhosis and HF
Describe the timing of water diuresis
Begins 15mins post ingestion of large water load
Reaches its maximum in 40mins
What controls water diuresis?
Mostly by decrease in plasma osmolality after water is absorbed
Small decrease in ADH secretion before water is absorbed
How does water intoxication occur and what are the symptoms?
Occurs when water ingested exceeds maximal urine flow of water diuresis (16ml/min), or when water intake is not reduced in setting of increased ADH (e.g. due to administration of exogenous ADH or increased secretion in response to stress such as surgical trauma)
ECF becomes hypotonic leading to increased cellular water uptake and swelling
Can lead to seizure and coma due to cerebral oedema
What is a potential side effect of administration of exogenous oxytocin after parturition (to contract the uterus)?
Water intoxication (has ADH-like effect)
Where does K+ absorption and secretion primarily occur?
Active reabsorption in proximal tubules, secretion in distal tubules and collecting ducts
What is rate of K+ secretion proportional to?
Flow through distal tubule (when increased there is less opportunity for tubular K+ concentration to rise to a level that inhibits further secretion)
What is the effect of the tubular concentration of Na+ and H+ on K+ excretion?
When amount of Na+ reaching the distal tubule is small, K+ excretion is decreased
If H secretion is increased, K+ excretion will decrease as K+ is reabsorbed in exchange for H+ via H K ATPase
What is the effect of water on ADH secretion?
Inhibits
What is the effect of alcohol on ADH secretion?
Inhibits
Describe the concept of splay
Deviation from ideal reabsorption curve (all tubules do not reabsorb substances completely and uniformly as expected when below the transport maximum)
The magnitude of the splay is inversely proportionate to the avidity with which the transport mechanism binds the substance it transports
Diuretic effect of V2 receptor antagonists as a diuretic
Inhibits action of ADH on collecting duct
Diuretic effect of large osmolar load (e.g. mannitol, glucose) as a diuretic
Produces osmotic diuresis (reduces Na+ and H2O reabsorption)
Diuretic effect of xanthines (e.g. caffeine, theophylline) as a diuretic
Decrease tubular reabsorption of Na+
Increase GFR
Diuretic effect of acidifying salts (e.g. CaCl2, NH4Cl)
Supply acid load: H+ is buffered but anion is excreted with Na+ when ability of kidneys to replace Na+ with H+ is exceeded
Diuretic effect of CA inhibitors (e.g. acetazolamide)
Decrease H+ secretion, with resultant increase in Na+ and K+ excretion
Diuretic effect of thiazides
Inhibit Na-Cl co-transporter in early distal tubule
Diuretic effects of loop diuretics
Inhibit Na-K-2Cl co-transporter in thick ascending limb of loop of Henle
Diuretic effects of K+-retaining natriuretics (e.g. spironolactone, amiloride)
Spironolactone: inhibits Na+/K+ “exchange” in collecting ducts via inhibition of aldosterone action (aldosterone receptor antagonist)
Amiloride: inhibits ENaC
What are urinary casts?
Proteinaceous material precipitated in tubules and washed into bladder
List 7 physiological effects of disordered kidney function and briefly explain the mechanism and clinical presentation of each
- HTN: increased renin secretion
- Loss of concentrating and diluting ability: polyuria and nocturia initially, in advanced kidney disease progressive damage cause oliguria and anuria
- Uraemia: reduced filtration and excretion, causes uraemic symptoms (lethargy, anorexia, N+V, seizure, coma)
- Anaemia: failure to produce EPO
- Secondary hypoparathyroidism: due to vitamin D deficiency
- Acidosis: due to failure to excrete acid (because of maximal acidification of urine to pH 4.5 and failure to secrete H+ due to impaired tubular production of NH4+), or in renal tubular acidosis due to inability to acidify urine
- Na+ retention: causes oedema, dependent on cause (acute glomerulonephritis -> decreased Na+ filtration, nephrotic syndrome -> increased aldosterone and decreased plasma protein, or because of concomitant HF)
How is filtration fraction calculated? What are the normal values?
FF = GFR/RPF (note renal plasma flow is different to renal blood flow)
GFR = 125ml/min normally
RPF = 600-700ml/min normally
FF = 0.16-0.20 normally
What is the effect of systemic hypotension on renal plasma flow, GFR and filtration fraction? What is the response in the afferent and efferent arterioles?
Renal plasma flow decreases (more than GFR)
GFR decreases (less than RPF)
Afferent and efferent arterioles constrict (efferent > afferent)
In what form is ammonia secreted into the tubular fluid?
NH3
Outline 5 effects of aldosterone
- Increases basolateral Na/K pump in distal tubule and collecting duct: increases Na+ reabsorption and K+ secretion
- Increases ENaCl: increases Na+ reabsorption
- Increases Cl- reabsorption in conjunction with Na+ (maintains electrochemical balance)
- Stimulates Na+ and water reabsorption from gut, salivary and sweat glands in exchange for K+
- Aldosterone stimulates secretion of H+ in exchange for Na+ in intercalated cells of cortical collecting tubules to regulate HCO3- levels and acid/base balance
