RENAL VIVAS
Function and Micturition
2010-2
Can you draw a nephron and describe the functions of each part
The nephron:
Glomerulus
Afferent arteriole
Capillary tuft
Efferent arteriole
PCT
Desc. limb of Henle
countercurrent
Prox Asc. Limb of
Asc. limb of Henle
DCT
Macula densa
Collecting duct
Na)
Collecting duct I cells
Function:
Filtration
Contains juxtaglomerular cells
Into Bowman’s capsule
Supplies peritubular capillaries or
descending vasa recta
Reabsorption of most solutes
Na, gluc, aa, HCO3Thin, water permeable –
Thin, NaCl permeable
mechanism
Thick, NaK2Cl co-transporter
NaCl co-tansporter
Juxtaglomerular apparatus
p cells ADH and aldosterone (H2O and
Involved in H+ excretion
Juxtaglomerular apparatus:
Macula densa
Tubuloglomerular feedback
Lacis cells
Contain renin
Juxtaglomerular cells
Contain renin
2007-1
Describe the cell types in the glomerulus and their functions
Capillary endothelial cells
- Afferent arteriole becomes a tuft of capillaries invaginated into Bowman’s capsule
- Endothelium fenestrated with 70-90 nm pores
- Separated from capsule epithelium by basal lamina
Epithelial cells of Bowman’s capsule
- Podocytes possess pseudopodia that interdigitate to form 25 nm wide filtration slits
over capillary endothelium
- Each slit is closed by a thin membrane
Mesangial cells
- Stellate and lie between capillary endothelium and basal lamina
- Involved in regulation of filtration, secretion of various substances and absorption of immune
complexes
What properties of substances in the blood prevent free passage across the glomerular
membrane
Larger diameter > 8 nm
Lack of neutrality (negatively charged prevents)
2011-2
Describe the differences between the ascending and descending loops of Henle
Descending: thin cells, permeable to water due to the presence of aquaporin-1 in both the apical and
basolateral membrane. No active transport of Na
Ascending -proximal (thin): Impermeable to water, very permeable to NaCl, still no active transport
Ascending -distal (thick): thick cells containing many mitochondria, impermeable to water; cotransport of Na+ K+, Cl– out of lumen into interstitium
Describe the changes in the tonicity of tubular fluid as it moves along the loop of Henle
Fluid in the descending limb of the loop of Henle becomes hypertonic as water moves out of the
tubule into the hypertonic interstitium. In the ascending limb it becomes more dilute because of the
active transport of Na+ and Cl– out of the tubular lumen. When fluid reaches the top of the ascending
limb (the diluting segment) it is now hypotonic to plasma.
2010-2, 2008-1, 2006-2
What is the normal renal blood flow
RBF ~ 1250ml/min, 25% CO
How is renal blood flow regulated
1. Neuroendocrine
- Noradrenaline -> constrictor (esp interlobar arteries and afferent arterioles)
- Dopamine -> dilator (and natriuresis)
- Angiotensin II -> constrictor (both afferent and efferent arterioles) at low perfusion pressure
- Prostaglandins -> increase cortical blood flow, decrease medullary blood flow
- Acetylcholine -> dilates
2. Autoregulation - probably vessel wall stretch reflex as occurs in denervated isolated vessels
3. Renal nerves – strong stimulation of sympathetic noradrenergic nerves -> decrease in blood flow
Extra: regional blood flow and O2 consumption
Cortex:
- Function is filtration of high volume of blood (flow 5mL/g/min, c.f. 0.5 for brain)
- Relatively little O2 extracted from the blood in the cortex despite high blood flow (PO 2 = 50mmHg)
Medulla:
- To maintain the osmotic gradient needs low blood flow (2.5mL/g/min in outer, 0.6 in inner)
- Metaboloic demands high in TALH where Na reabsorbed -> PO2 is 15mmHg here and it is more
susceptible to hypoxia
- NO, prostaglandins and cardiovascular peptide in this region function in paracrine fashion to
balance low blood flow and metabolic needs
2008-2, 2006-2
What is normal renal blood flow and how can it be measured
1. Fick principle (amount of a substance taken up per unit time divided by arterio-venous
concentration difference)
2. PAH (para aminohippurate, excreted, not metabolised or stored, doesn’t affect flow) is used to
measure effective renal plasma flow (90% cleared)
ERPF = Clearance of PAH = UV/P = 630 mL/min
3. Actual renal plasma flow = ERPF/0.9 = 700 mL/min
4. Renal blood flow = RPF x 1/1-Hct (Hct = 0.45)
5. Renal blood flow = approx 1250 mL/min
How do blood flow and oxygen extraction vary in different parts of the kidney
1. Cortical flow is high (5 mL/gm of tissue) and oxygen extraction is low
2. Medullary blood flow is low (2.5 mL/gm in outer cortex, 0.6 mL/gm in inner cortex) and oxygen
extraction is higher (more metabolic work done)
3. Medulla is vulnerable to hypoxic damage if flow is reduced (low flow, high oxygen usage)
2006-2, 2004-2
What are the factors that affect renal blood flow?
- Systemic blood pressure (↓ MAP -> ↓ baroreceptor firing -> renal vasoconstriction -> ↓ RBF
- Exercise ↓ RBF
- Renal vascular resistance, which is in turn influenced by:
 Catecholamines (nerves & systemic)
 Angiotensin II (JG cells -> renin)
 Prostaglandins
 Control systems:
 Renal autoregulation (myogenic- stretch response, vasodilator metabolites, ?NO, ?PGs)
2010-1
What general mechanisms are involved in renal tubular reabsorption and secretion
Endocytosis – small proteins and peptide hormones in PT
Passive diffusion – between cells
Facilitated diffusion – through cells, down chemical or electrical gradients
Active transport – against gradients
Especially secondary active transport – aka co-transport, where there is no direct coupling of ATP
and the transport is driven by an electrochemical gradient
Movements is via: ion channels, exchangers, co-transporters and pumps
Note: Active transport systems have a transport maximum: Tm (i.e. can be saturated)
How is sodium reabsorbed in the various parts of the nephron
- see below
2007-2
Describe a method for measuring the GFR
Measure the excretion (i.e. clearance) of a substance which is freely filtered through the glomeruli,
neither secreted, reabsorbed or metabolised and should be non-toxic
- E.g. inulin (creatinine has limitations – it is secreted, but this error is balanced by the measurement
of plasma levels being high due to non-specific chromogens)
GFR = Ux x V / Px (Ux is conc of X in urine, V is urine flow, Px is plasma conc of X)
2007-1
What factors influence clearance of substances by the kidney
1. Amount of substance excreted = amount filtered + net amount transferred
2. Changes in RBF and systemic BP
3. Active transport (primary and secondary)
4. Hormonal (aldosterone, angiotensin, endothelin)
Explain the mechanism of tubuloglomerular feedback
1. Increased GFR -> higher rate of flow and delivery of total Na+ to macula densa
2. Increased Na+/K+ ATPase activity -> increased adenosine -> adenosine A1 receptors -> causing
increased Ca2+ -> efferent vasoconstriction and decreased GFR
3. Means that 3 % Na+ -> DCT/CD remains constant (glomerulotubular balance)
2010-2, 2003-1
What is normal GFR
125ml/min in 70kg male, 10% less in female
What factors affect GFR
GFR = Kf [(PGC - PT) - (GC - T)]
1. Kf is the glomerular ultrafiltration co-efficient = permeability x surface area
2. PGC - PT is the difference in hydrostatic pressure between the glomerular capillary and tubule
3. GC - T is the difference in oncotic pressure between the glomerular capillary and tubule
(tubule = Bownman’s space, and T is negligible, gradient ~ oncotic pressure of the plasma proteins)
1. Hydrostatic pressure and renal blood flow
- Systemic BP (autoregulation)
- Afferent and efferent arteriolar tone
i. Autoregulation
ii. Neuroendocrine (NA, Dopamine, PG’s, ATII, Acetylcholine)
iii. Sympathetic nerve supply
- The GFR will be maintained until systemic BP drops below range of autoregulation
- GFR maintained when efferents constrict more so than afferents (both decreased RBF)
- Tubuloglomerular feedback: the macular densa sense the delivery of NaCl to the DCT
(via Na-2Cl-K) -> increased NaK ATPase -> increased adenosine -> A1 receptors ->
release of Ca2+ -> constriction of afferent arterioles -> reduction in GFR
- Glomerulotubular balance: Increase in GFR -> increase in absorbtion of water and
solutes in PCT -> % of solute reaching the DCT is held relatively constant, partly due to
high oncotic pressure of plasma leaving the efferent arterioles -> peritubular capillaries
- Outlet (ureteric obstruction, oedema in tight renal capsule)
2. Oncotic (colloid osmotic) pressure
- T is negligible, so gradient essentially the oncotic pressure of the plasma proteins
- Thus effected by conc. of plasma proteins: dehydration and hypoproteinaemia (mild effect)
3. Kf - capillary permeability
- About 50x that of skeletal muscle
- Neutral substance <4nm freely filtered, >8nm almost never
- Glomerular wall is negatively charged -> repels negative substances (eg albumin = 7nm)
- Nephritis -> dissipation of negative charge -> albuminuria
Kf - surface area (size of capillary beds)
- Altered by contraction of mesangial cells
- Contraction: Endothelins, ATII, ADH, NA, PAF, PDGF, TXA2, PGF2, leukotrienes,
histamine
- Relaxation: ANP, Dopamine, PGE2, cAMP
As well as filtration, by what other means does the kidney regulate the composition of urine
Secretion and reabsorption
Extra: filtration equilibrium
- GCs hydrostatic pressure very high (45mmHg, short arterioles, high resistance efferents)
- Balanced by oncotic pressure – increases along the GC as fluid leaves the plasma
- Filtration equilibrium may be reached so distal portion of GC may not filter
- Thus exchange is flow-limited (not diffusion limited) -> an increased in renal plasma flow would
increase the distance over which filtration will occur
Extra: filtration fraction
- Ratio of GFR to RPF, normally 0.16 – 0.20
- GFR less variable
- If there is a fall in systemic BP then RPF will drop more and filtration fraction will increase
2011-1, 2010-1, 2009-2, 2009-1
Describe how Na+ is handled by the kidney
- Glomerular filtration 26,000 mEq/day
- 96-99% reabsorbed by active transport out of the tubule in all sections except descending thin
loop of Henle
- Reabsorption of Na (and Cl) major role in electrolyte and water homeostasis
- Transport of Na coupled to H+, glucose, amino acids, organic acids, phosphate and other
electrolytes
60%
none
30%
7%
3% variable
Proximal Tubule
Thin decending loop of Henle
Thick acending loop of Henle
Distal convoluted tuble
Collecting ducts
Na-H exchanger
none
Na-2Cl-K co-transporter (and Na-H)
Na-Cl co-trasnporter
ENaC – aldosterone regulated
60% is via the Na-H exchanger in PT and TALH:
- Via Na-H exchanger: K+ enters, H+ excreted
- Requires carbonic anhydrase (CO2 + H2O -> H2CO3) and then -> H+ and HCO3- The HCO3- diffuses out into the interstitium – bicarbonate is main anion reabsorbed with Na
- Via Na/K ATPase (basement membrane) -> Na actively transported into the interstitium
How does aldosterone influence renal sodium handling
- Increased tubular reabsorption of Na+, with secretion of K+ and H+
- Act principally on the collecting ducts (Principal Cells) to increase number of active epithelial
sodium channels (ENaCs) – via rapid insertion (not clinically relevant) and slower increase in
synthesis
- Latent period of 10 – 30 minutes before effect (time delay due to need to alter protein synthesis
via action on DNA)
List the mechanisms that effect Na reabsorption (2009-2) / reduce Na excretion (2009-1)
Multiple regulatory mechanisms reflecting the importance of Na+ as prime determinant of ECF
volume
1. Factors affecting GFR
- Reduced GFR will ->  Na+ reabsortion via RAS
- Tubuloglomerular feedback (NaCl @ macula densa -> afferent constriction -> GFR)
- Glomerotubular balance (GFR -> pericapillary oncotic pressure -> water/solute
absorbtion in PCT)
2. Factors affecting tubular reabsorption – especially the 3% reaching the CD
- Aldosterone -> ENaC in CD (rapid insertion and slow synthesis) -> Na+ reabsorbtion
- Angiotensin II –> direct effect on PT to increase Na+ reabsorbtion
- Rate of tubular secretion of H+ and K+
Natriuretics
- Natriuretic hormones -> ANP (cGMP) reduces ENaCs (nb reduced atrial stretch also
stimulates aldosterone secretion)
- Oubain blocks Na/K ATPase
- PGE2 (probably blocks N/K ATPase +/- Ca2+ block on ENaC
- IL-1 and endothelin -> probably increases PGE2
2011-2, 2008-2, 2004-2
How does the kidney handle potassium
- Potassium is filtered, reabsorbed and secreted
- K+ is freely filtered at the glomerulus (~600 mEq/day)
- Most is reabsorbed by active transport in the proximal tubule (~560 mEq/day).
- Active reabsorption mostly in PCT (65%) but also 25% in TALoH (NaK2Cl co-transporter) and CD
- 50mmol passively secreted by late DCT and cortical CT cells
- There is no direct exchange of K+ for Na+ in the tubular fluid of the distal nephron. However
reabsorption of Na+ into the tubular cell tends to promote secretion of K+ (or H+) to maintain the
potential difference across the apical membrane.
- With high/low potassium intakes the required extra secretion of K+ achieved by
increased/decreased secretion in DCT/cortical CT
- With extremely low K+ intake, there can be net reabsorbtion of K+ in DCT/cortical CT
- The total K+ excretion is approximately equal to K+ intake (~90 mEq/day) and K+ balance is
maintained.
2008-2, 2004-2
What factors influence this
1. The rate of secretion of K+ is proportional to the rate of flow of tubular fluid through the distal
nephron (via Principal Cells). With rapid flow the concentration of K+ in the fluid remains lower
and secretion continues.
2. In the distal nephron K+ and H+ compete for secretion in association with reabsorption of
Na+. Therefore in acidosis when H+ excretion is increased, K+ secretion is decreased.
3. Aldosterone increases reabsorption of Na+ in the collecting ducts and thereby promotes K+
secretion.
4. Increased delivery of Na+ to the collecting ducts promotes increased secretion of K+ (e.g. thiazide
diuretics).
5. Conversely decreased delivery of Na+ to the collecting ducts -> decreased secretion of K+.
6. Inhibition of K+ absorption in the proximal nephron (e.g. osmotic or loop diuretics) promotes
excretion of K+.
2009-1, 2008-1
Describe the counter-current mechanism in the kidney
- The concentrating mechanism depends on gradient of increasing osmolality along the medullary
pyramids
- This is produced by the loops of Henle as countercurrent multipliers and maintained by the
vasa recta as countercurrent exchangers
- The thin decending loop has hypotonic fluid entering and because it is hightly permeable to H 2O is
diffuses out into the interstitium
- The fluid becomes more hypertonic as it reaches the deepest part at the apex of the loop
- The thin ascending limb is permeable to NaCl (not H2O) and so it will passively diffuse out along
its gradient
- The hypertonic fluid then enters the thick ascending loop and active transport of via the Na-2Cl-K
occurs so the fluid becomes less tonic as it reaches the DCT and is again hypotonic at this point
- Thus an osmotic gradient is established in the interstitium – hypertonic (~1200) at apex and
relatively hypotonic at cortex (~300)
What is the role of the vasa recta
- Peritubular blood vessles from efferent arterioles of JG nephrons run with/along the LoH
- Decending limb is non-fenestrated, ascending limb is fenestrated
- Counter current exchange (a passive process based on the movement of water and NaCl)
- Water diffuses out of the decending limb and enters the ascending limb (also from the CT)
- NaCl (and urea) diffuses out of the ascending limb and enters the decending limb
- The solute remains in the medullary pyramids and the concentration gradient is maintained.
2010-2, 2008-2
Describe the Physiological process of Micturition
Spinal reflex facilitated and inhibited by higher centres
- Initially minimal rise in pressure as bladder fills (Law of Laplace – the radius increases)
- First urge to void at 150ml
- Marked fullness at 400ml (pressure rises quickly as muscle can’t stretch further)
- During micturition, the Detrusor muscle contracts and perineal muscles/external urethral sphincter
relax
- Bladder SM has intrinsic contractile activity
- Post urination, female urethra empties by gravity.
- Male expels by contraction of bulbocavernosus m
Nerve Supply
- Parasympathetic (S2,3,4) afferents respond to stretch receptors in bladder wall to initiate reflex
contraction via parasympathetic efferents
- Pudendal nerve to External Urethral Sphicter causes relaxation
- Spinal reflex integrated in sacral portion of spinal cord
- Sympathetic (L1,2,3) play no role in micturition but only in prevention (cause contraction of
bladder muscle to prevent reflux of semen into bladder during ejaculation)
- EUS and perineal muscles can be controlled voluntary for a period of time but eventually void
reflex overcomes voluntary control
List other factors that stimulate and inhibit micturition
Stimulants
- Stretch/pressure (intravesical volume > 400mls)
- Higher centre input
- Parasympathetics (eg organophosphates)
- Sympathetic inhibiting drug (eg a-blockers)
- Voluntary abdominal muscle contraction augments stream but does not initiate micturition per se
Inhibitors
- Parasympathetic inhibitors (atropine)
- Higher centres
- Sympathomimetics
2007-2
Describe water handling in collecting ducts
- 180L of fluid filtered via glomeruli each day, only ~1L urine/day – i.e. >99% reabsorbed
- 60-70% of the filtered water is reabsorbed in the PCT, via aquaporin-1, along osmotic gradients
set up by the active transport of solutes (60-70% having been reabsorbed) – the fluid leaving the
PCT is isotonic
- The descending limb of the loop of Henle also has aquaporin-1, the ascending limb is
impermeable
- The apex of the loop is in interstitium that is ~4x the tonicity of plasma (1200) so water is drawn
out here
- A further 15% is removed from the descending limb. About 20% will therefore enter the DCT.
- Because of the active reabsorbtion via the Na-K-2Cl in the TALoH the fluid entering the DCT is
hypotonic again
- The DCT continue to remove solute (and is impermeable to water)
Collecting Ducts
- Collecting ducts have 2 portions, a cortical portion and medullary portion
- Changes in the CD volume and osmolality depend on vasopressin (ADH)
- Vasopressin from post. pituitary -> increases the permeability of the CD via aquaporin-2
-
-
Acts on V2 receptors (-> cAMP, protein kinase, cycloskeletal elements)
Aquaporin-2 is stored in vesicles and the VP causes the rapid insertion of these into apical
membrane
Maximal antidiuresis -> fluid in cortical area (isotonic) then fluid -> medullary area (hypertonic, set
up by countercurrent mechanism), removing a further 10%, and urine may be as concentrated as
1400mOsm/kg
With vasopressin absent, the fluid in the CT remains hypotonic with large volume into renal pelvis,
as low as 30mOsm/kg
What is an osmotic diuresis
- Caused by presence of large quantities of unabsorbed solutes in the renal tubules
- Solutes not reabsorbed in the proximal tubules -> osmotic effect and hold water in the tubules
- The concentration gradient for pumping Na+ out is limited (normally movement out of water helps)
- The loop of Henle presented with a large volume of isotonic fluid with low Na+ conc. (but total Na+
is higher than normal)
- Limiting conc. gradient for Na+ reached in the TALoH (Na-2Cl-K pump) -> fall in medullary
hypertonicity -> countercurrent mechanism failure
- So less fluid can be removed in the collecting ducts also
- Result is a marked increased in urine volume containing Na+ and other electrolytes
- The osmolality of the urine approaches that of the plasma
- Produced by administration of mannitol and related polysaccharides, glucose in DM if exceed the
TmG, or infusion of large amounts of NaCl or urea,
- In water diuresis the amount of water absorbed proximally is normal, and the max urine flow is
about 16ml/hr.
Regulation of ECF
2011-2, 2010-2, 2010-1, 2009-2, 2008-2, 2007-2
How does vasopressin act on the kidney
- Vasopressin from post. pituitary -> increases the permeability of H2O in the CD via aquaporin2 -> increased H2O reabsorbtion i.e. renal retention of water -> lower plasma osmolality
- Acts on V2 receptors (-> cAMP, protein kinase, cycloskeletal elements)
- Aquaporin-2 is stored in vesicles/endosome and the VP causes the rapid insertion of these into
apical membrane
What hormonal changes occur after drinking a large amount of water
- Begins about 15 min after ingestion
- Maximum in about 45 min
- The act of drinking produces a small decrease in vasopressin secretion resulting in diuresis
- Most of the inhibition is produced by the decrease in plasma osmolality after the water is
absorbed
2010-2, 2010-1, 2009-2, 2008-2, 2004-2, 2003-2
What stimuli influence vasopressin (ADH) secretion
Vasopressin secretion increased
Increase in plasma osmotic pressure (285mOsm)
Decreased ECF volume
Pain, emotion, “stress”, exercise
Nausea and vomiting
Standing
Clofibrate, carbamazepine
Angiotensin II
Vasopressin secretion decreased
Decreased plasma osmotic pressure
Increased ECF volume
Alcohol
Plasma osmotic pressure
- Via osmoregulators in anterior hypothalamus (OVLT)
- Rate of ADH secretion from post pituitary increased when plasma over 285mOsm/kg
ECF volume
- Inverse relationship between vasopressin release and the rate of discharge of stretch receptors
- Low pressure receptors (great veins, atria, pulmonary vessels) > high pressure (aortic arch,
carotid sinuses
- Exponential increase in vasopressin if BP drops
- ATII reinforces the response to hypovolaemia and hypotension
- Acts via the CVLM
2010-1
What is the normal range of osmolality of ECF
285 - 295mOsm/kg
How is this maintained
 osmolality -> thirst and ADH -> drink and retain the water -> osmolality
 osmolality -> thirst and ADH -> diuresis of free water ->  osmolality
2008-2
Describe the effects of Vasopressin
1. Retention of water (antidiuretic hormone) (V2 receptors)
2. Vasoconstrictor effect (V1A receptors)
3.
4.
5.
6.
Central effect brain (area postrema) to decrease CO (although some effect to increase BP also)
Glycogenolysis in liver (V1A receptors)
Mediate increased ACTH secretion (V1B receptors)
Neurotransmitter in brain and spinal cord
2004-2
What is THIRST, and what causes it
An appetite, under hypothalamic control
1. Increased plasma osmolality
- osmoreceptors in anterior hypothalamus
2. Hypovolaemia
- Renin-angiotensin system
- Baroreceptors in heart and blood vessels
3. Prandial
- Learned or habit response
- Osmolality & GI hormone effects
4. Psychogenic
- Dry pharyngeal mucous membranes
2011-1, 2005-1 (renin), 2004-2 (R-A system), 2003-2 (renin), 2003-1 (response to hypotension)
Describe the factors influencing Angiotensin II production
- Is the effector protein in the renin-angiotensin system: integral to control of volume regulation
- So, principally those that influence renin secretion
- Renin -> increased ATII -> Na and H2O retention and vasoconstriction -> BP
Renin increased by:
- Decreased afferent arteriolar pressure at JG ->  renal baroreceptor mechanism activity
- Inversely proportional to NaCl entering macula densa (in DCT) – increased absorbtion leads
to decreased rennin secretion and visa versa
- Increased sympathetic activity via renal nerves via 1 in JG cells (->cAMP)
- Increased circulating catecholamines
- Increased prostaglandins
Decreased by:
- The opposite of above and…
- Angiotensin II -> negative feedback directly on JG cells
- Vasopressin
Conditions that increase rennin secretion:
Hyponatraemia, diuretics, hypotension, haemorrhage, upright posture, dehydration, cardiac failure,
cirrhoisis, constriction of renal artery/aorta, various psychologic stimuli
What are the physiological effects of Angiotensin II
1. Arteriolar constriction -> rise in BP, it is a potent vasoconstrictor (4-8x more than
norepinephrine), but note decreased activity in Na+ depleted individuals and cirrhotics ->
increased circulating levels and downregulation of ATII receptors in SMC
2. Directly on adrenal cortex to increase aldosterone -> Na+ reabsorbtion
3. Facilitation of norepinephrine secretion at postganglionic sympathetic neurons
4. Contraction of mesangial cells -> reduction in GFR
5. Direct action on renal tubules to increase Na+ resorbtion
6. On brain decrease baroreflex sensitivity (which potentiates the pressor effect)
7. On brain (circumventricular organs) stimulates thirst, secretion of vasopressin and ACTH
2010-2, 2009-2, 2008-2 (Nb renal/endocrine), 2003-2
What is the physiological role of aldosterone
- Causes retention of Na+ (and therefore H2O) expanding the ECF
- Increases absorption of Na+ from urine, sweat, saliva and colon
- On kidney is acts on principal cells in CD -> increase ENaC (rapid insertion and slower synthesis)
-
The increased Na+ will be exchanged for H+ and K+ -> K+ diuresis and acidification of the urine
By expansion of the ECF -> increased renal perfusion -> negative feedback on renin production
Aldosterone is only one of the mechanisms for defense of ECF volume
What conditions increase aldosterone secretion
Primary adrenal disease (Conn syndrome)
- 70% bilateral adrenal hyperplasia
- adrenal adenoma
Secondary hyperaldosteronism
- Overactivity of the RAS
- eg. CCF, cirrhosis & nephrosis
- Renal artery constriction
Describe the typical serum / urine effects in hyperaldosteronism
1. Na/Cl mild ↑, fluid retention (follows Na),
2. ↓K, alkalosis (alkalaemia only if K+ depletes)
3. Urine K+/ H↑
Clinical picture: usually without edema, but weakness, hypertension, tetany, polyuria and
hypokalemic alkalosis
List the stimuli that increase aldosterone secretion
1. Renin from kidney via angiotensin II (diaglycerol and protein kinase C)
2. ACTH from posterior pituitary (cAMP, protein kinase A)
3. Stimulatory effect of rise in plasma K+ conc. on adrenal cortex (Ca2+ via voltage gated channels)
4. Clinical causes: Surgery, haemorrhage, standing, anxiety, physical trauma, high K intake, low
Na+ intake, constriction of IVC in thorax, hyperaldosteronism (eg CCF, cirrhosis, nephrosis)
Describe the feedback regulation of aldosterone secretion
1. Fall in ECF / blood volume -> reflex  in renal nerve discharge &  in renal artery pressure
2. Increase in rennin secretion -> increase -> in angiotensin II -> increase in aldosterone secretion
3. Na+ & water retention -> expanded ECF volume -> decrease in stimulus that initiated renin
secretion
How does aldosterone increase K secretion? 2004-2
1. Increased Na entry into cells
2. Inc pumping out of Na by Na-K pump
3. Inc K uptake into principal cells
4. Inc K conc inc secretion driving force
5. Also inc luminal membrane K channels
2005-1
What hormone systems are involved in the maintenance of Extracellular fluid volume?
Renin, angiotensin, aldosterone/vasopressin
What are the effects of Atrial Naturetic Peptide in response to fluid overload ?
- Increase sodium secretion from the kidneys
- Diuresis
Acidification of the Urine
Sample viva, 2009-2, 2009-1, 2005-1, 2003-1
How does the kidney acidify the urine
Secretion of hydrogen ions
- Maximum H+ gradient which transport mechanisms can cope with = pH of 4.5 (corresponds to
~1000x plasma conc. of H+)
- pH 4.5 is the limiting pH – would be reached quickly if not for buffers in the urine
Binding of the hydrogen ions with buffers
HCO3- -> H2O + CO2 (bicarbonate -> carbonic acid -> water and carbon dioxide)
- In PCT most of the secreted H+ reacts w/ the filtered HCO3- -> H2CO3
- In PCT the brush border has carbonic anhydrase (not in DCT): H2CO3 -> H2O + CO2
- The CO2 then diffuses into the cells and is used to form more H2CO3
- The HCO3- then diffuses back to the interstitial fluid (reabsorbed, although not the same mole the
was initially filtered, but the reabsorbtion is mole for mole)
- The pH of the tubular fluids therefore does not decrease much despite H+ secretion
- HCO3- will only appear in the urine if plasma if ECF volume is expanded (unknown mechanism) or
if plasma HCO3- conc. is above the renal threshold (26-28mEq/L)
- If plasma HCO3- is low the urine will become more acidic with a higher NH4+
HPO42- -> H2PO4- (monohydrogen phosphate -> dihydrogen phosphate)
- Occurs mostly in DCT and CD where HPO42- has become concentrated
NH3 -> NH4+ (ammonia -> ammonium ion)
- Occurs in both PCT and DCT
- pK’ is 9.0 (so ratio at pH 7.0 of NH3 : NH4+ is 1:100)
- NH3 is lipid soluble so diffuses down conc. gradient into intersitial and tubular fluids
- NH4+ remains in the urine
- Most NH4+ is made by metabolism of glutamine -> glutamate
- In chronic acidosis more NH3 will enter the tubular urine (adaptation of secretion, via non-ionic
diffusion) – further enhancing H+ secretion
Is there a difference between the proximal and distal tubules
PCT:
- Na-H exchange via secondary active (co-) transportation
- Na/K ATPase removes Na+ from cell to interstium making intracellular Na+ low
- Na+ is reabsorbed from the lumen as H+ is excreted, driven by this gradient
- The H+ is derived from carbonic anhydrase (CO2 + H2O -> H2CO3)
- The pH doesn’t drop much at this point due to the buffering with filtered HCO3DCT and CD:
- Most of the H+ secretion is independent of Na+
- Via ATP driven proton pump in I (Intercalcated) cells (contain abundant carbonic anhydrase)
- Aldosterone -> increases distal H+ secretion
- Some H+ also via H/K ATPase
What factors increase acid secretion
Factors which increase acid secretion
- ↑ PCO2 (respiratory acidosis -> increased H2CO3)
- ↑ aldosterone
- ↓ K+ (leads to intracellular acidosis even though plasma pH may be elevated)
- ↑ carbonic anhydrase concentration
2011-1, 2010-1
What are the principal buffering systems in the body
Blood:
H2CO3

H+ + HCO3HProt

H+ + ProtHHb

H+ + HbInterstitial fluid:
H2CO3

H+ + HCO3Intracellular fluid: HProt

H+ + ProtH2PO4
H+ + HPO42Urine:
H2CO3

H+ + HCO3H2PO4

H+ + HPO42-
NH4+

H+ + NH3
Outline how the body responds to a metabolic acid load 2010-1, 2003-1
1. Buffering in blood, interstitial and intracellular spaces
- In blood the HCO3-, Prot- and Hb- levels drop
2.
-
Respiratory response
H2CO3 converted to H2O and CO2
CO2 expired via lungs through increased minute ventilation
H+ stimulates resps so the PCO2 will actually drop -> increased pH (respiratory compensation)
3.
-
Renal compensation
Anions that replace HCO3- are filtered at the glomerulus with corresponding cations (mainly Na+)
Renal tubule cells secrete H+ into tubular fluid in exchange for Na+ and HCO3Buffering in the urine gives greater capacity to this system (otherwise limiting pH of 4.5 would stop
further H+ secretion)
Buffering systems include: Bicarbonate(proximal), Phosphate (distal), Ammonia (throughout)
In chronic acidosis glutamine synthesis is liver is increased, using some of the NH4+
The glutamine can be metabolised in the kidneys -> -ketoglutarate + NH4+ (renal adaptation)
The -ketoglutarate can be further metabolised producing HCO3-
-