Unit 5 Flashcards
How is water added to the body?
Ingestion
Oxidation of CHO
What % of bodyweight is water?
60%
What % of bodyweight is intracellular fluid?
40%
What % of bodyweight is extracellular fluid?
20%
How do plasma and interstitial fluid differ?
Higher protein in plasma
Higher cations in plasma (Donnan effect)
Higher anions in interstitial fluid
Ddx hyponatraemia
Dehydration - adrenal insufficiency, diuretic overuse, v/d
Overhydration - ADH excess, bronchogenic tumours
Ddx hypernatraemia
Dehydration - DI
Overhydration - HAC, hyperaldosteronism
What are the causes of intracellular oedema?
Hyponatraemia
Depression of metabolic systems
Lack of cellular nutrition
Which part of the LOH is the ‘thin’ segment?
Descending and lower end of ascending
Where is the macula densa located?
At the end of the thick, ascending LOH
What are cortical and juxtaglomerular nephrons? How are they different?
Cortical nephron - glomeruli in outer cortex, short LOH than penetrate a short distance into medulla
Juxtaglomerular nephron - glomeruli deeper in cortex, long LOH
JG nephrons have vasa recta
Describe the neuroanatomy of the bladder
Supplied by pelvic nerves via the sacral plexus (S2-3)
Contains sensory + motor fibres
Motor n - parasympathetic fibres
Pudendal nerve - external sphincter (skeletal)
Hypogastric nerves - sympathetic - blood vessels
What innervates the a)detrusor, b)internal sphincter, c)external sphincter
a)pelvic n
b)pelvic n
c)pudendal n
What is the structure of the glomerular capillary membrane?
1 - endothelium
2 - basement membrane
3 - epithelial cells (podocytes)
How does efferent arteriolar constriction affect GFR?
Biphasic
Mild/moderate - slight increase in GFR
Severe - reduces GFR
How does afferent arteriolar constriction affect GFR?
Reduces
What is anatomy of the juxtaglomerular complex?
Macula densa cells in proximal distal tubule
Juxtaglomerular cells in afferent/efferent arteriole
Describe tubuloglomerular feedback
Reduced GRF => slow flow in LOH => increased Na/Cl reabsorption => reduced Na/Cl at macula densa => afferent arteriolar dilation + ^ renin release => efferent arteriolar constriction
What substances are found in higher quantities in plasma than glomerular filtrate?
Albumin
Calcium
Fatty acids
Describe the structure of the glomerular capillary membrane and how they alter filtration
Endothelium (with fenestrate). Endothelial proteins negatively charged - repeals plasma proteins
Basement membrane - mesh of collagen and proteoglycans. PGs negatively charged
Podocytes (with slit pores) - epithelium negatively charged
What conditions are associated with a reduction in glomerular capillary filtration coefficient?
CKD (reduced number of glomerular capillaries)
Systemic hypertension
How if filtration fraction calculated?
FF = GFR/RBF
What factors influence the glomerular capillary colloid osmotic pressure?
Arterial plasma osmotic pressure
Filtration fraction (affected by GFR and RBF)
How does efferent arteriolar constriction affect GFR?
Biphasic
If mild/moderate, slight increase
If severe, decreases (due to increased FF and glomerular colloid oncotic pressure)
How is renal blood flow regulated?
Tubuloglomerular feedback
Myogenic autoregulation
How do dietary protein and hyperglycaemia affect renal blood flow and GFR?
Increase both
Amino acids/glucose reabsorbed with sodium => reduced sodium delivery to macula densa => afferent arteriolar dilation
What are the main primary active transport pumps in the renal tubules?
Na-K ATPase
H+ ATPase
H-K ATPase
Ca ATPase
Describe the renal tubular Na-K ATPase pump
Na exchanged for K at basolateral membrane using ATPase
Na+ passively diffuses across luminal membrane along concentration and electrical gradient
How is the proximal tubule adapted for Na reabsorption?
Brush border - ^ surface area
Carrier proteins for facilitated diffusion
^Mitochondria
Intercellular + basal channels
Describe glucose reabsorption in the proximal tubule
Na-K ATPase in basolateral membrane creates Na concentration gradient
SGLT 1 and 2 in brush border absorb glucose up concentration gradient
Glucose diffuses out of cell using glucose transporters GLUT1 and GLUT2
What are the sodium glucose cotransporters in the proximal tubule and where are they located? Which is more active?
SGLT2 in early PT
SGLT1 in latter PT
90% reabsorbed by SGLT2
What are the glucose transporters in the proximal tubule? Where are they located?
GLUT2 in early PT
GLUT1 in latter PT
What is an example of counter transport?
Na - H+ exchanger in PT
Where are AQO-1 channels found?
Proximal tubule
How does water permeability vary in different parts of the nephron?
PT - high
Descending LOH - high
Ascending LOH - low
Distal tubule, collecting tubules, collecting ducts - low/high (ADH dependent)
How is chloride reabsorbed?
Transported with sodium due to electrical potential, along paracellular pathway
Na reabsorption = H20 reabsorption = ^ Cl concentration = concentration gradient
Secondary active transport - Na-CL cotransporter
How is urea reabsorbed
Na reabsorption = H2O reabsorption = ^ urea concentration
Urea transporters - inner medullary collecting ducts
How much Na/H2O is reabsorbed in the PT?
65%
How is sodium reabsorbed in different regions of the PT?
First half - cotransport with glucose + amino acids
Second half - reabsorbed with Cl-
What is secreted in the PT?
Bile salts, oxalate, urate, catecholamines
PAH
Drugs/toxins
What are the 3 segments of the LOH?
Thin descending
Thin ascending
Thick ascending
How much water is resorbed in the LOH?
20%
How permeable is the LOH to water?
Descending highly permeable
Ascending impermeable
What is the function of the LOH?
Descending - simple diffusion
Thick ascending - active reabsorption of Na/K/Cl
How is sodium reabsorbed in the thick ascending LOH?
Diffusion gradient maintained by Na-K ATPase in basolateral membrane
Na movement mediated by luminal NKCC2 contransporter (Na + K + 2xCl) - drives K+ reabsorption against concentration gradient
What is the site of action of frusemide?
NKCC2 cotransporter
What substances are absorbed/secreted in the thick ascending LOH?
Na, K, Cl reabsorbed vis NKCC2 cotransporter
Na reabsorbed, H+ secreted via Na-H exchanger
Mg, Ca, Na and K - paracellular absorption - encouraged by positive charge in luminal fluid
What is the reason for the positive charge of luminal fluid in the LOH?
Backless of K+ into lumen
How does the distal tubule function?
First portion - macula densa
Second portion - similar function to thick ascending LOH - diluting segment
Second half - principal cells - Na reabsorption/K secretion
Intercalated cells - secrete or reabsorb H+, HCO3, K
How is sodium chloride absorbed in the distal tubule?
Na-Cl cotransporter on luminal surface
Where do thiazide diuretics act?
Na-Cl cotransporter in distal tubule
What is the action of principal cells and where are they located?
Second half distal tubule
Basolateral Na-K ATPase maintains low Na concentration
Na/K channels facilitate diffusion along concentration gradient (Na in, K+ out)
Where does spironolactone act?
Principle cells of distal tubule
Where does amiloride and triamterene act?
Na channel blockers
Block luminal Na channel in principal cells, reduced activity of basolateral Na-K ATPase
What is the function of type A/B intercalated cells?
A - H+ secretion
B - HCO3 secretion
How do type A intercalated cells act?
Secrete H+ into lumen by H-ATPase and H-K ATPase transporter
H+ generated by carbonic anhydrase, liberating HCO3
HCO3 reabsorbed with HCO3-Cl exchanger
K/Cl leave cell via channels (pg 353)
How do type B intercalated cells act?
Secrete HCO3 into lumen using pendrin - HCO3/Cl exchanger
H+ transported across basolateral membrane with H-ATPase or H-K ATPase cotransporter
Which intercalated cells are involved in K+ reabsorption/secretion?
A - reabsorption
B - secretion
Summarise the function of the late distal and cortical collecting tubule
Impermeable to urea
Reabsorb Na in principal cells under aldosterone control
Type A intercalated cells secrete H+ in acidosis
Type B intercalated cells secrete HCO3 in alkalosis
Permeability to water controlled by ADH
Summarise the function of the medullary collecting duct
Permeability to water controlled by ADH
Permeable to urea + urea transporters - important for formation of concentrated urine
Capable of H+ secretion
How is tubular reabsorption regulated?
Glomerulotubular balance
Peritubular capillary and renal interstitial fluid physical forces
Pressure natriuresis/diuresis
Hormonal - aldosterone, angiotensin, ADH, ANP, PTH
SNS
What is glomerulotubular balance?
Proximal tubular reabsorption increased with GFR - percentage of GFR remains stable at approx 65%
Also happens to smaller degree in LOH
Prevents overload of distal segments at high GFR
How do peritubular capillary and renal interstitial fluid physical forces regulate reabsorption?
Increased arterial pressure = increased peritubular capillary pressure = reduced reabsorption
Increased afferent/efferent arteriole resistance = reduced peritubular capillary pressure = increased reabsorption
Osmotic pressure - higher FF = higher osmotic pressure in peritubular capillaries = more reabsorption
Higher interstitial pressure (due to increased capillary hydrostatic or decreased capillary osmotic pressure) = increased backleak
What is pressure diuresis/natriuresis?
Increased ABP =
1) ^GFR
2) v tubular reabsorption (mechanisms not fully understood)
3) v AngII => v Na reabsorption
4) Internalisation of Na transporters
Where does aldosterone exert its effects on tubular reabsorption? What are they?
Collecting tubule/duct
Increased NaCl + H2O reabsorption
Increased K + H secretion
Where does angII exert its effects on tubular reabsorption? What are they?
Proximal tubule, thick ascending LOH, distal tubule, collecting tubule
Increased NaCl + H2O reabsorption
Increased H+ secretion
Where does ADH exert its effects on tubular reabsorption? What are they?
Distal tubule/collecting tubule and duct
Increased H2O reabsorption
Where does ANP exert its effects on tubular reabsorption? What are they?
Distal tubule/collecting tubule and duct
Reduced NaCl reabsorption
Where does PTH exert its effects on tubular reabsorption? What are they?
Reduced PO4- reabsorption
Increased Ca++ reabsorption
On which cells does aldosterone act? How does it act?
Principal cells of collecting duct
Stimulates Na-K ATPase on basolateral membrane + increased Na permeability of luminal membrane by inserting Na channels
What is the main stimulus for aldosterone secretion?
Increased extracellular K+
Increased angII - (usually associated with sodium/volume depletion or low BP)
What is the body’s main Na-retaining hormone?
AngII
What stimulates AngII formation?
Low BP
What are the actions of angII?
Aldosterone secretion
Efferent arteriole constriction - increases reabsorption, raises filtration fraction => further reabsorption
Directly stimulates Na reabsorption in PT, LOH, DT and CT
How does angII act to stimulate Na reabsorption?
Stimulates basolateral Na-K ATPase pump
Stimulates Na-H exchange on luminal surface (especially proximal tubule)
Stimulates basolateral Na-HCO3 cotransport
Where does ADH bind? How does it act?
V2 receptors in late distal tubule, collecting tubules and collecting ducts
Increases formation of CAMP and protein kinase - stimulates movement of AQP-2 to luminal membrane
Where are AQP 1, 2, 3 and 4 found? Which are controlled by ADH?
AQP -1 - proximal tubular lumen, proximal LOH, not ADH controlled
AQP-2 - luminal - ADH controlled
AQP-3/4 - basolateral, not ADH controlled
What are the effects of chronic ADH increase?
Formation of AQP-2 protein through unregulated gene transcription
What stimulates ANP release? What are it’s actions?
Atrial stretch
Inhibits Na/H20 reabsorption + renin secretion
How does the SNS act to control sodium reabsorption?
If severe - constricts arterioles => reduced GFR
Low levels - act on alpha-adrenergic receptors in tubular epithelium => increased Na reabsorption
What is renal clearance?
The volume of plasma cleared of a substance by the kidneys per unit time
What is the main hormone responsible for controlling urine concentration?
ADH
Describe how osmolality of fluid in the renal tubule changes
Proximal tubule - isosmotic (300)
Descending LOH - very hypertonic (600)
Ascending LOH - hypo osmotic (100)
Distal/collecting tubule
- ADH absent - further dilution (50)
- ADH present - concentration (~600)
What is USG? How does it compare to osmolarity?
Measure of weight of solutes in given volume of urine - determined by number and size of molecules
Osmolarity - number of solute molecules
Describe the steps involved in causing a hyper osmotic renal medullary interstitium
Guyton page 369
Where are the urea transporters located?
UT-A1 + UT-A3 - medullary collecting duct
UT-A2 - thin loop of henle
How is plasma osmolarity estimated?
= 2x(Na) + glucose + urea
Describe the osmoreceptor-ADH feedback system
Water deficit => ^extracellular osmolarity
Osmoreceptor cells in anterior hypothalamus shrink => impulse => posterior pituitary => ADH release => reduced water excretion
Where is ADH synthesised?
Hypothalamus (supraoptic/paraventricular nuclei)
What areas detect osmolarity?
Osmoreceptors - anterior hypothalammus
AV3V region - third ventricle
What are the stimuli for ADH release?
Increased osmolarity
Decreased arterial blood pressure
Decreased blood volume
What stimulates thirst?
Increased extracellular fluid osmolarity
Decreased extracellular fluid volume
Angiotensin II
Dry mouth
GI/pharyngeal stimuli
What factors shift K+ into cells?
Insulin
Aldosterone
B-adrenergic stimulation
Alkalosis
What factors shift K+ out of cells?
Diabetes mellitus
Hypoadrenocorticism
B-adrenergic blockade
Acidosis
Cell lysis
Exercise
Increased extracellular fluid osmalality
Why dp patients with hypoadrenocorticism develop hyperkalaemia?
Reduced cellular K+ uptake
Reduced renal excretion
Summarise renal tubular handling of potassium
65% reabsorbed in proximal tubule
25-30% reabsorbed in LOH (especially thick ascending)
Collecting tubules/ducts - variable, depending on intake
Which cells are most important for regulating potassium excretion?
Principal cells
How do the principal cells secrete K+?
Uptake into cell from Na-K ATPase on basolateral membrane
Passive diffusion into tubular fluid via ROMK and BK channels
What cells are involved in potassium reabsorption/secretion in the distal tubule? Do they reabsorb or secrete?
Principal cells - secrete
Intercalated cells - reabsorb or secrete
Which intercalated cells secrete/reabsorb K+?
Type A - reabsorb
Type B - secrete
What acid-base complication can occur secondary to severe prolonged hypokalaemia
Alkalosis
K reabsorption in Type A intercalated celly - H-K ATPase
What factors increase/decrease tubular secretion of K+?
Increase - increased extracellular potassium, increased aldosterone, increased tubular flow rate
Decrease - acidosis
How do increased ECF K+ levels directly stimulate K+ excretion?
1 - stimulates Na K ATPase activity
2 - increased K gradient to interior of epithelial cell
3 - stimulates synthesis of K channels
4 - stimulates aldosterone secretion
How does aldosterone increase K+ secretion?
Activates Na K ATPase on principal cells
Increases K channels
How is normal potassium excretion preserved during increased sodium excretion?
Increased Na excretion = reduced aldosterone secretion + increased tubular flow
Increased tubular flow => K concentration gradient
=> increased BK channels
How is plasma calcium found?
50% ionised
40% protein bound
10% complexed with anions
How does acid-base status influence plasm calcium?
Acidosis - less bound
Alkalosis - more bound
What is the main method of removal of calcium from the body?
Faeces
How does PTH act to increase serum calcium?
Increases bone resorption
Increases activation of vitamin D and intestinal absorption
Increases tubular reabsorption
Where is calcium reabsorbed in the kidneys?
65% PT
25-30% LOH
4-9% distal/collecting tubules
How is calcium absorbed in the proximal tubules?
Mostly paracellular
20% transcellular - flows into cell down electrochemical gradient (cell has slight negative charge)
Exits cell via basolateral Ca ATPase or Ca-3Na countertransporter
How and where is calcium reabsorbed in the LOH and distal tubule?
Thick ascending loop
50% paracellular
50% transcellular - PTH controlled
Distal tubule - all active transport. Similar process to proximal tubule
What regulates active transport of calcium in the LOH and distal tubule?
Mostly PTH
Vitamin D and calcitonin
Direct action of calcium on CSRs in LOH
What factors increase/decrease renal calcium excretion?
PTH - decrease
Extracellular volume expansion/increased arterial pressure - increase
Increased serum phosphate - decrease
Acidosis - increase
How is renal phosphate excretion regulated?
Overflow mechanism - renal transport maximum for excretion
How does PTH effect phosphorus levels?
Promotes bone resorption => increased phosphorus
Reduces reabsorption => decrease phosphorus
What factors increase renal phosphate excretion?
High dietary phosphate
PTH
Acidosis
Hypertension
What factors decrease renal phosphate excretion?
Low dietary phosphate
1, 25 D3
Alkalosis
T4
How is magnesium distributed in the body?
> 50% bones
49% intracellular
<1% in extracellular fluid
> 50% plasma Mg protein bound
Where is Mg reabsorbed in the kidney?
25% proximal tubule
65% LOH
Mechanism of regulation poorly understood
What factors increase Mg excretion?
High extracellular Mg concentration
High extracellular Ca
Low PTH
High extracellular fluid volume
Acidosis
What factors decrease Mg excretion?
Low extracellular Mg concentration
Low extracellular Ca
PTH
Low extracellular fluid volume
Alkalosis
What are the effects of acute and chronic increases in BP on urinary sodium?
Increases
Efficiency increased with chronic due to suppression of renin release
What actions take place following an increase in sodium intake?
Low pressure reflex receptors - inhibit SNS
Suppression of RAAS
ANP
Pressure natriuresis
What 3 systems defend against changes in H+ concentration? Which is the most powerful?
Buffer systems
Respiratory system
Kidneys***
Where is carbonic anhydrase found?
Alveoli and renal tubules
Describe the bicarbonate buffer system
CO2 + H20 <= => H2CO3
Carbonic anhydrase
H2CO3 <= => H+ + HCO3-
+
Na
With regards to acid base - what is K?
Dissociation constant of an acid
When is a buffer system most efficient?
At pH close to it’s pK
Where is the phosphate buffer system most important?
Intracellular fluid and renal tubular fluid
What are the main elements of the phosphate buffer system?
H2PO4- and HPO4–
What are nonvolatile acids?
Not H2CO3
Cannot be removed by lungs
Where does hydrogen iron secretion and HCO3 reabsorption occur?
All parts of the tubules except depending and ascending thin limbs of LOH
Where is the main site of bicarbonate reabsorption?
80-90% in proximal tubule
10% thick ascending LOH
Remainder distal tubule and collecting duct
How is H+ secreted in the early tubular segments?
Na-H counter transport using Na gradient
What is the net change in H/HCO3 in the early tubular segments?
For every H+ secreted one HCO3 reabsorbed
How is bicarbonate reabsorbed in the proximal tubule/LOH/distal tubule/collecting ducts?
Early proximal tubule - HCO3 - Na cotransporter
Late proximal tubule, thick LOH, distal tubule/collecting duct - Cl - HCO3 exchange
Which cells secrete H+ in the distal and collecting tubules? How do they do it?
Type A intercalated cells
Primary active transport - H-ATPase and H-K ATPase
What facilitates excretion of large amounts of H+ in the urine?
Phosphate and ammonia buffer systems
Describe the phosphate buffer system
Once all bicarbonate in tubules reabsorbed, H+ combines with HPO4–
Excreted as NaH2PO4
How does H+ excretion via the phosphate buffer system differ from the bicarbonate buffer system?
Reflects net gain of HCO3-, rather than replacement of filtered HCO3
Net effect of addition of new HCO£-
Describe the ammonia buffer system
Proximal tubule
Glutamine transported into epithelial cells of proximal tubule, metabolised to 2x NH4+ + 2x HCO3-
NH4+ exchanged for sodium on luminal membrane
Collecting duct
H+ actively secreted, combines with NH3 => NH4
What is the dominant mechanism for H+ excretion during chronic acidosis?
Excretion of NH4+
What factors increase H+ secretion and HCO3 reabsorption?
^PCO2
^H+ / v HCO3
v ECFV
^ AngII
^Aldosterone
v K+
What factors decrease H+ secretion and HCO3 reabsorption?
v PCO2
v H+ / ^ HCO3
^ ECFV
v AngII
v Aldosterone
^ K+
What acid-base abnormality is associated with diuretics and why?
Metabolic alkalosis
1 - Diuretics increase flow in distal and collecting tubules => increased sodium reabsorption in exchange for H+
2 - RAAS stimulation
How long does it take for respiratory compensation to an acid-base abnormality?
6-12 hours
How long does it take for metabolic compensation to an acid-base abnormality?
3-5 days
How is AG calculated? What is considered normal?
Na - HCO3 - Cl
8-16
Where do loop diuretics act? How does this increase urine output?
1-Na, 2-Cl, 1-K co-transporter in thick ascending LOH
Increase quantities of solutes delivered to distal nephron
Disrupt countercurrent multiplier system
Where do thiazide diuretics act>
Na Cl cotransporter in early distal tubule
Where does acetylzolamide act?
Carbonic anhydrase inhibitor
Proximal tubule
Where do mineralocorticoid receptor antagonists act?
Collecting tubule/duct
Where does amiloride act?
Na channel blocker
Inhibit sodium reabsorption and potassium secretion in collecting tubules
What are the potassium sparing diuretics?
Spironolactone - MRA
Amiloride - Na channel blocker
Describe the mechanisms behind the development of bone demineralisation in CKD
Reduced renal conversion of vit D into 1,25- vit D = reduced intestinal calcium absorption
Increased serum PO4 => increased binding of PO4 and Ca => reduced serum ionised calcium => ^PTH
How does Fanconi syndrome manifest?
Increased excretion of amino acids, glucose and PO4
In severe cases - metabolic acidosis, increased excretion of K/Ca, NDI
