Giles Kisby
GE Y1 Renal
Renal:
Spring Term:
LECTURES:
Learning Outcomes – Year 1 (2014)
Spring Term:
Exam questions will be set in standard SBA (single best answer) and EMQ (extended matching
question) formats. The SBA and EMQ formats will be well known to you, and further details are
provided on Blackboard.
LECTURES
Lecture 1: Kidney structure and histology
Lecture 2: Approaches to assessing kidney function
Lecture 3: Renal blood flow and regulation
Lecture 4: Renin Angiotensin system
Lecture 5: Water loading states
Lecture 6: The lone Englishman lost in the Sahara
Lecture 7: Acid base balance – physiology
Lecture 8: Acid base balance – illustrations from the
critically ill patient’s physiology
Lecture 9: Renal causes of hypertension
Lecture 10: Erythropoetin
Lecture 11: Sodium and potassium handling
Lecture 12: Clinical scenarios (electrolytes)
Lecture 13: When the kidneys are lost
Lecture 14: Clinical demonstration: video and meeting with
a renal patient
Lecture 15: Renal physiology scenarios
Lecture 16: Overview of kidney function and dysfunction
Lecture 17: Predict the consequences of loss of endocrine
functions of the kidney
Lecture 18: Control of calcium and phosphate; vitamin D, PTH
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and the kidney
The main goal of this course is to help you develop a sound understanding of how the renal
system achieves the vital functions of controlling fluid and electrolyte balance, its role in control of
blood pressure and as part of the endocrine system - and how these functions are perturbed in
disease. The course has been designed to develop and present core material from a clinical
perspective. The primary goal is to equip you with the knowledge base to apply basic renal
science to clinical practice in the later years of your course, recognizing that the practice of renal
medicine, and fluid and biochemical management in all patients, is integrally related to the
physiological processes you will cover over this term. We also hope to instill a finer appreciation
of the scientific intricacies of the renal system.
The course is structured in three overlapping themes: Theme one covers functional anatomy and
histology. In the second theme, the essentials of fluid and electrolyte balance are understood
through lectures on physiology and illustrations from clinical pathology. Theme three explores the
consequences to normal physiology ‘when things go wrong’ in disease states.
At the end of the course, you will be able to:
1) Describe the structural organisation of the kidneys and urinary tract at the system and
cellular levels.
2) Explain the physiological mechanisms by which the various components of the kidney
produce and regulate the composition of urine.
a) Define Renal Clearance and Glomerular Filtration Rate and explain in principle how
these may be measured in patients
3) Understand the principal renal mechanisms responsible for homeostasis of water,
electrolytes, pH, glucose and urea in the extracellular fluid.
a) Appreciate the centrality of water in the control of cell volume, blood pressure and
metabolism
b) Understand the physiological implications of dehydration and how the body responds to
it
c) Understand the physiological implications of water loading states and how the body
responds to them
d) Understand the intracellular and extracellular balance of sodium and potassium ions
including how and why the gradients are maintained.
e) Understand why maintenance of appropriate pH is important physiologically
4) Understand how renal mechanisms contribute to the control of blood pressure.
5) Describe the sites and mechanism of action of the main classes of diuretics.
6) Use the knowledge of kidney function and roles to:
a) Understand how the body responds to overload and deficiencies of sodium and
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potassium, including the pathological features found in each situation.
b) Determine the implications of sodium and potassium abnormalities in a number of
different clinical scenarios.
c) Identify several clinical scenarios in which acid-base balance is disrupted.
d) Describe how the body deals with acid-base abnormalities in a number of different
situations. - 2 7) Outline the principal causes of acute and chronic renal failure.
a) Show awareness of the clinical features people may develop in acute and renal failure.
b) Outline the possible ways of managing these patients.
c) Show awareness of the different modalities of renal replacement therapy.
LECTURES
Lecture 1: Kidney Structure and Histology
Dr Ruth Tarzi, (r.tarzitiimperial.ac.uk)
relations to other structures
• To understand the purpose of the medical renal biopsy
• To be able to recognise in a renal biopsy some of the possible deviations from the norm
Lecture 2: Approaches to assessing renal function
Dr Peter Hill (peter.hill4tinhs.net)
ion rate
Lecture 3: Renal blood flow and regulation
Dr Nish Arulkumaran, (n.arulkumarantiimperial.ac.uk)
about the anatomical and physiological concepts underlying the renal
vasculature and perfusion,
renal blood flow
gain understanding on pathophysiology of renal vascular impairmen
Lecture 4: Renin-angiotensin system and control of blood pressure
Dr Nish Arulkumaran (n.arulkumarantiimperial.ac.uk)
how do we measure it
- components and roles, therapeutic targets
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GE Y1 Renal
Lecture 5: Drinking yourself to death: water loading states
Dr Ruth Tarzi (r.tarzitiimperial.ac.uk)
he principal mechanisms responsible for the homeostasis of serum sodium,
osmolality and total body water content.
to
it. - 4 syndrome of inappropriate ADH secretion, primary polydipsia, secondary
hyperaldosteronism.
Lecture 6: The lone Englishman lost in the Sahara Desert.
Dr Jeremy Levy (j.levytiimperial.ac.uk)
To understand how the body handles water and what can go wrong. To understand how to
interpret blood results in this context and how disorders of water balance might be managed.
Much of the body is water. Water allows solutes to remain dissolved, and changes in body water
can cause changes in solute concentrations. Physiological processes require tight control of
solute concentrations, and hence water distribution is also tightly regulated.
Control of body water is mainly through the kidneys. The proximal tubule reabsorbs 70% of water
filtered together with salt, but cannot change the concentration of urine (iso-osmolar
reabsorption). The loop of Henlé in the kidney allows humans to make dilute urine, while the
distal tubule and collecting ducts act to make concentrated urine, through the action of ADH (or
Vasopressin). Humans can change the concentration of their urine over a very wide range. ADH
is the key hormone controlling water balance, but many others affect water homeostasis via
actions on salt and water (eg cortisol, thyroxine, atrial natriuretic peptide).
Excess water leads to solute dilution (eg hyponatraemia) whilst water deprivation leads to solute
concentration (eg hypernatraemia). Both these states can cause severe problems. Both can also
be caused by bad doctoring, as well as by hormone dysfunction, drugs, behaviour etc.
Dehydration (in its true form loss of water only) leads to increased concentration of solutes, and
reduction of both extracellular and intracellular volume. Dehydration is a very potent stimulus to
ADH release, which should minimise further water loss through the kidneys by increasing the
reabsorption of water in the distal tubules – less water is excreted in the urine. If this does not
happen and water loss is not corrected, dehydration leads to death. Under- or over-activity of the
hormone systems controlling water balance can lead to over or under-hydration, and various
electrolyte disturbances. Excess ADH leads to water retention and hyponatraemia, while too little
ADH leads to diabetes insipidus and dehydration. The rennin-angiotensin system is also crucial
in control of water balance via the effects of angiotensin II and aldosterone on sodium handling
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GE Y1 Renal
and vasoconstriction.
It is important to identify the cause of disturbance in patients physiology in order that the correct
action can be taken to remedy the situation – if water is missing, water needs replacing alone; if
salt is lost, salt needs replacing.
Lecture 7: Acid-Base balance – physiology
Dr Doris Doberenz (doris.doberenztiimperial.nhs.uk)
articles will be made available on Blackboard
Lecture 8: Acid Base Balance – illustrations from the critically ill patient’s physiology
Dr Doris Doberenz (doris.doberenztiimperial.nhs.uk)
-5Lecture 9: Renal causes of hypertension
Dr Peter Hill (peter.hill4tinhs.net)
hypertension
Lecture 10: Erythropoeitin
Dr Peter Hill (peter.hill4tinhs.net)
understand the approach to managing anaemia in renal disease
Lecture 11: Sodium and potassium handling
Dr Elaine Clutterbuck (Elaine.clutterbucktiimperial.nhs.uk)
a) the levels are regulated, and the role of the kidneys
b) that there is a close relationship between – sodium and water homeostasis,
and between potassium and hydrogen ion balance.
/ potassium
a) their symptoms, signs and immediate management
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Lecture 12: Discussion of clinical scenarios
Dr Damien Ashby (d.ashbytiimperial.ac.uk)
Lecture 13: When the kidneys are lost
Dr Damien Ashby (damien.ashbytiimperial.nhs.uk)
he pathophysiology and treatment of end stage renal disease
Lecture 14: Clinical demonstration : video and meeting with renal patient
Dr Liz Lightstone (l.lightstonetiimperial.ac.uk)
rstand the practicalities involved in dialysis and transplantation
Lecture 15: Renal Physiology – clinical scenarios
Dr Jeremy Levy (j.levytiimperial.ac.uk)
-directed learning will be made available on Blackboard
Lecture 16: Overview of kidney function and dysfunction with respect to learning
objectives of the course
Dr Damien Ashby (damien.ashbytiimperial.nhs.uk)
Lecture 17*: Predict the consequences of loss of endocrine functions of the kidney
Professor Karim Meeran (k.meerantiimperial.ac.uk)
-6Lecture 18*: Control of calcium and phosphate: vitamin D, PTH and the kidney; Professor
Karim Meeran (k.meerantiimperial.ac.uk)
* These two lectures will be given in the Pathology (Part 2) Course where they sit more
appropriately.
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GE Y1 Renal
LECTURES:
07/01/14: Introduction to the kidney: anatomy and
histology: Ruth Tarzi
Los (from booklet):
rstand the basic structure of the glomerulus at a cellular level
understand the sampling and handling issues related to taking a medical renal biopsy
• To understand the purpose of the medical renal biopsy
• To be able to recognise in a renal biopsy some of the possible deviations from the norm
Los (from Slides):
o
o
o
o
o
o
To understand the gross anatomy of the kidney
To be aware of its principal relations to other structures
To understand the basic structure of the glomerulus
To appreciate how this structure controls its filtering function
To know the component parts of the nephron
To understand the role of the renal biopsy in diagnosis of kidney disease
Notes:
-
Basic anatomy:
o Kidneys are at T11-L2 on left; kidneys are T12-L3 on right
o Kidneys are 11-13cm long
o Pathway of urine after kidney:
 Urine collects in central portion (pelvis)
 By the time it reaches this point, urine is in its final state
 Drains into ureters (on on each side)
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o
o
o
 Collects in bladder
 Excreted by (single) urethra
Renal parenchyma = Cortex and medulla
Approximately 1 million filtering units; the nephrons
Glomerulus: the network of capillaries at the filtering site:
 Blood enters a capillary tuft by afferent arteriole
 Under high pressure, cells and proteins retained within capillary lumen
 Much of fluid phase pushed out of blood vessel across specialised filtration
structure
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

o
o
o
o
 Endothelial cell layer with pores
 Glomerular basement membrane
 Epithelial cells (= podocytes) with slit membranes
Blood leaves glomerulus by efferent arteriole
Filtrate passes into Bowman’s capsule
Bowman's capsule: surrounds the glomerulus and performs the first filtration step
Nephron: Nephron is the basic structural and functional unit of the kidney; ie
includes the blood vessels as well as the bowman’s capsule etc of each unit
Glomeruli are in cortex with the loop of henle travelling into the medulla; ie
glomeruli are a part of the nephron
The Bowman's capsule is a cup-like sac at the beginning of the tubular component of
a nephron in the mammalian kidney that performs the first step in the filtration of
blood to form urine. A glomerulus is enclosed in the sac. Fluids from blood in the
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o
o
-
glomerulus are collected in the Bowman's capsule (i.e., glomerular filtrate) and
further processed along the nephron to form urine.
Nephrons join collecting ducts to take urine out through medulla into pelvis
Mesangial cells regulate blood flow through the capillaries and contribute towards
the support of the capillaries
 Ie capillaries held together by mesangial cells with podocytes on the other
surfaces of the capillaries to mediate filtration (holding back large molecules
such as proteins, and passing through small molecules such as water, salts,
and sugar) out to the filtered region (bowman’s space)
The nephron:
o 1. Afferent arteriole:
 ANP increases flow
 ATII, sympa, ADH decrease blood flow
o 2. Glomerulus:
 Small molecules (HCO3-, Cl-, Na+, K+, etc) and water exit; proteins kept in
blood (podocyte damage can therefore give proteinurea and
hypoalbuminaemia)
 Endothelium has large pores: fluid, dissolved solutes, and plasma proteins all
are filtered across this layer of the glomerular capillary barrier. On the other
hand, the pores are not so large that blood cells can be filtered.
 Basement memb: The multilayered basement membrane does not permit
filtration of plasma proteins and, therefore, constitutes the most significant
barrier of the glomerular capillary.
 Podocytes: Because of the relatively small size of the filtration slits formed by
the podocytes, the epithelial layer (in addition to the basement membrane)
also is considered an important barrier to filtration.
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GE Y1 Renal

o
o
o
o
Another feature of the glomerular barrier is the presence of negatively
charged glycoproteins. These fixed negative charges are present throughout
the barrier: on the endothelium, basement membrane, on the podocytes /
epithelium.
 Nb Regardless of their charge, small solutes are freely filtered across
the glomerular barrier. However, for large solutes such as plasma
proteins, the charge does affect filtration.
3. Proximal convoluted tubule: [the major reabsorbtion site]
 2/3 water and 2/3 Na ions passing are reabsorbed [both same rate so
remains isotonic]; brush border cell microvilli aid water resorbtion
 100% AAs and gluc reabsorbed (unless undiagnosed diabetic; the
transporters can become saturated if v. high gluc conc) [secondary active
transport]
4. Descending loop of henle: [concentration occurs]
 Permeable to water but not NaCl and urea
 Decends to medulla
 At bottom osmolarity equalised with surrounding medullary interstitum:
however tubular fluid mainly NaCl whereas medullary interstitum mainly
urea
5. Ascending Limbs of the loop of henle:
 Thin asc limb
 Impermeable to water, permeable to NaCl and urea: NaCl moves
out, urea moves in
 Volume and osmolarity unchanged
 Thick asc limb:
 Impermeable to water AND urea; NaCl actively reabsorbed into the
interstitum so tubular fluid hyposmotic by the end of the limb
6. Distal convoluted tubule:
 At early part: Aldosterone acts here to increase NaCl reabsorbtion; at late
part: ADH is able to act; in ADH absence will just give further dilution making
further hypoosmotic but in ADH presence water exits too
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
o
o
Impermeable to water unless ADH present (ie ADH inserts porins).
Impermeable to urea; NaCl actively reabsorbed into the interstitum so
tubular fluid increasingly hyposmotic
 Aldosterone acts here to increase NaCl reabsorbtion
 Juxtaglomerular cells in the afferent arteriole at the region of the Distal
convoluted tubule secrete RENIN (ie then its downstream effects etc) in
response to:
 (1) Renal hypoperfusion,
 (2) Sympathetic nerve stimulation
 (3) Reduced NaCl delivery to tubule lumen at macula densa
(caused by reduced GFR/filtrate volume)
 macula densa: an area of closely packed specialized cells lining the wall of
the distal convoluted tubule which form a part of the juxtaglomerular
apparatus (sensitive to NaCl)
7. Collecting ducts:
 Cortical collecting duct acts exactly as the Distal convoluted tubule
 Medullary collecting duct reabsorbs NaCl actively as prev but is slightly more
permeable to water and urea, even without ADH present (small amount of
urea enters tubular fluid, small amount of water reabsorbed)
 ADH affects water permeability and is required for sufficient water
reabsorbtion
 ADH also affects urea permeability here; will give knock on effect of allowing
greater water reabsorbtion via changing the osmotic gradient; the urea will
ultimately re-enter the tubule at the thin asc limb again but via this mech
greater concentration is facilitated
8. Efferent arteriole: [ie from glomerulus]
 Proteins not filtered so high conc protein here; this allows for the extensive
water reabsorbtion that occurs as prev described
 Mechanical pressure difference also occurs due to blood having slowed at
glomerulus therefore via starling equation any water reabsorbtion will be
encouraged compared to otherwise
 Constriction of efferent arterioles gives increased glomerular filtration rate
due to increased pressure at glomerular capillaries; eg ATII constricts
efferent more than afferent arteriole so inc GFR (efferent arteriole more
sensitive to ATII; serves to maintain GFR when ATII is constricting the
afferent arteriole)
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-
The nephron
o Modulates the contents of filtrate
o Depending on body’s needs varies
 Volume of fluid excreted
 Amount of salt excreted
o Major points of control
 Glomerular filtration
 Counter-current multiplier (Loop of Henle)
 Anti-diuretic hormone’s effects (water reabsorption)
 Renin-angiotensin-aldosterone system (salt retention)
-
The renal biopsy
o For patient:
 Provide the cause of the patient’s disease
 Indicate what treatment the patient requires
 Provide information on likely outcome eg. recovery of renal function vs need
for long term dialysis
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o
Sample fixed in paraffin and sections taken for inspection
 Light microscopy
 Need to examine the biopsy at multiple levels for thorough
assessment
 Immunohistology
 Often stain for antibody components to demonstrate areas of
immune activity
 Immunofluorescence
o Performed by applying fluorescent labelled antibodies to
frozen sections
o Visualised on a fluorescence microscope
 Immunoperoxidase
o Uses paraffin sections
o Primary antibodies are identified using an antibody
amplification step with a coloured end product
 Electron microscopy
 May show
o Deposition of immune complexes
o Deposition of other abnormal substances e.g. amyloid
[amyloidosis refers to a variety of conditions wherein
normally soluble proteins become insoluble and are
deposited in the extracellular space of various organs or
tissues, disrupting normal function]
o Abnormalities of intrinsic glomerular structure eg the
thickening of diabetes
Pathologies:
- Glomeruli
o
o
o
o
o
Inflammation
Scarring
Infiltration
Major manifestations are due to either:
 Failure to filter an adequate amount of blood so that waste products are
not excreted
 Failure to maintain barrier function leading to loss of protein and/or
blood cells in the urine
Many glomerular diseases are caused by deposition of immunoglobulins in the
glomerulus
 Therefore biopsies are stained for IgA, IgG, IgM and complement
 Immune complexes are composed of a lattice-work of antibody and
antigen
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


May become deposited in the glomerulus and lead to an inflammatory
response
 Deposition at subendothelial sites will give greatest inflam due
to close proximity to blood and therefore are worst location;
 also can occur at mesangial cells (eg IgA nephropathy)
 or at subepithelial cells (ie on the podocyte side not the
mesangial side)
 Antigens in immune complexes may be:
 endogenous (autoantigens) – e.g. lupus
 exogenous e.g. derived from response to infective organisms
Microscopic Haematuria
 Most patients will have either:
o IgA nephropathy
 Mesangial proliferation
 IgA deposition at the mesangial cells
 Mesangial electron dense deposits (ie the immune
complexes)
o Thin membrane disease
 Normal glomeruli by light and immunomicroscopy
 Thin membranes on electron microscopy [thinning
of the basement membrane (ie the blood/tubular
fluid interface) of the glomeruli in the kidneys]
Nephrotic syndrome
 the 'filters' in the kidney become 'leaky' and large amounts of
protein leak from your blood into your urine
 Caused by breakdown of the normal glomerular filtration barrier;
Barrier depends on the integrity of the glomerular basement
membrane and podocytes; possible causes of breakdown of barrier:
o Damage to podocyte
 focal / segmental glomerulosclerosis
 minimal change disease
 loss of podocyte foot processes,
vacuolation, and the appearance of
microvilli.
o Immune deposits
 membranous nephropathy
 light chain deposition disease
o Others
 advanced diabetic nephropathy [Marked thickening
of basement membrane (and mesangial increase) in
diabetes]
 renal amyloid deposition
 Symptoms:
o Severe proteinuria
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GE Y1 Renal
o
o
o
-
Hypoalbuminaemia
Oedema (due to effect of low blood prot on starling
equation)
Hyperlipidaemia (the low blood prot causes inhibition of
certain enzymes that would otherwise lower blood lipid
levels)
Tubules
- Acute tubular necrosis
o Inflammation
o Scarring
o Acute lesions: acute tubular necrosis / injury: one of the below stimuli
 gives loss of polarity of tubule cells
 apoptosis&necrosis and sloughing into lumen to give lumen obstruction
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o
-
Interstitium
o
o
-
 result is cause failure of glomerular filtration
if insult removed the tubules recover [dedifferentiation  prolif 
differentiation]
 Ischaemic
 eg hypovolaemic shock
 Toxic
 (drugs, eg cisplatin, myoglobin in rhabdomyolysis)
 Immunological
 eg secondary to glomerulonephritis
Chronic lesions: tubular atrophy
 Due to imflam at tubules or secondary to imflam elsewhere in kidneys
 tubular atrophy is an Indication of permanent nephron loss; correlates
with irreversible loss of function
Acute examples
 Oedema
 Inflammatory cell infiltration
 Haemorrhage
Chronic:
 interstitial fibrosis
Vessels
o
o
Narrowing
Inflammation
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GE Y1 Renal
08/01/14: Approaches to assessing renal function: Dr Peter
Hill
Los (from booklet):
Lecture 2: Approaches to assessing renal function
Dr Peter Hill (peter.hill4@nhs.net)
n can be measured
Notes:
-
Overview:
o Review of anatomy and physiological functions of the kidney
o How to measure kidney function
o Measuring glomerular filtration
 GFR assessments and introduction to CKD
o Assessing the urine
o Applying renal function tests in renal disease
-
Kidney Functions
o Filtration and excretion of waste products
o Electrolyte homeostasis
o Hormone production
 Erythropoietin
 For red blood cell production
 1,25 Calcitriol [ie activation of vit D via providing the 2nd hydroxylation]
 For calcium, phosphate and bone metabolism
o Blood pressure control
 via renin/angiotensin/aldosterone axis prostagladins and bradykinin
o Acid Base homeostasis
-
Nephron diagram:
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-
Glomerulus:
o 20% of cardiac output reaches the kidney (1200ml/min)
o Allows filtration of small and molecules but acts of a barrier to larger molecules.
o Also limits filtration based on charge with cations filtered more freely
o Creates ultra-filtrate:
 Ultrafiltrate is made by pressure differences between the afferent and
efferent arterioles.
 By increasing vasoconstriction of efferent arteriole there is an increase in
upstream pressure and thus increases UF
o To exit the blood components must pass through the three layers of cells within a
glomerulus:
 Endothelial Cells with fenestrations
 Glomerular Basement Membrane
 Epithelial Cells/Podocytes
 The epithelial cells are attached to the GBM by discrete foot
processes.
 The pores between the foot processes (slit pores) are closed by a
thin membrane called the slit diaphragm, which functions as a
modified adherens junction
o Other functions include
 Phagocytosis
 Endocrine
 Synthesis of vasoactive and inflammatory meditiators
-
Proximal Convoluted Tubule
o Main function is reabsorbtion
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o
-
-
Most of the volume of the fitrate solution is reabsorped here; 55-60% of filtrate is
reabsorbed here
 70% of filtered sodium chloride and water
 90% of filtered bicarbonate
 Excretes Ammonia
 Resorption of amino acids and glucose (100% unless untreated diabetic;
system overwealmed)
o Three steps:
 entry into the cell across the luminal membrane,
 movement across the basolateral membrane into the intercellular space,
 and uptake by the peritubular capillary.
Loop of Henle
o Concentrating machinery: max concentration at bottom of the loop then begins to
become less concentrated again as NaCl resorbed]
o The term "counter-current" is also used in descriptions of the Loop of Henle - and
refers to the tubular fluid flowing in opposite directions along the descending and
ascending limbs
o Descending limb
 Permeable to water
 Less permeable to Na+ and Cl Ie water moves out
o Thin Ascending Limb
 Impermeable to water
 Highly permeable to Na and Cl, and somewhat permeable to urea
 loss of NaCl from the tubular fluid greatly exceeds the gain in urea
[ie as ascends the conc of the fluid starts to fall from its peak at the
bottom]
 Ie Na and Cl are resorbed
o Thick Ascending Limb
 Reabsorbs NaCl from the tubular fluid via a different transport process from
that of the thin ascending limb of Henle.
 Acts in similar way to Distal Convoluted Tubule.
 Where furosemide = frusemide acts (Na-K Cl symporter is inhibited)
Distal Tubule
o Ie DCT and Collecting duct
o Fine tuning occurs
o Some Na and Cl resorption
o Urinary acidification
o Calcium excretion: dep on PTH
o Ongoing urine concentrating
o Potassium Secretion: dep on electrochem grad
o ADH acts here to increase salt and water resorption
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o
-
Thiazides act here
Measuring Kidney Function
1. Glomerular Filtration
2. Tubular Reabsorption
3. Tubular Secretion
4. Hormone production (EPO and vitamin D)
5. Urine Production.
o
Glomerular Filtration
 Most common test of kidney function
 Determines the clearance of a substance from the plasma
 Does not determine the cause for kidney disease
 Glomerular Filtration Rate
 Sum of the filtrate rates of all functioning nephrons
 Normal 120-130ml/min/1.73m2
 Depends on age, sex and body size
 Variable between nephrons and between people
 Reduced GFR means loss of filtering capacity and accumulation of
waste products
 No direct measurement
 Estimated from urinary clearance of an ideal filtration marker from
the plasma per unit time
o Clearance =
U*V
P
P = plasma concentration of marker
U = urinary concentration of marker
V = urine flow rate
o Inulin – best molecule we have so far
 Fructose polymer
 Freely filtered solute
 Non-toxic
 Not secreted or reabsorped by the kidney
 Not metabolised by the kidney
 Infuse inulin, then collect regular blood and urine
samples over several hours for GFR assessment [ie
to gain U, V, P readings]; BUT IMPRACTICAL SO
RARELY USED
o Creatinine
 best endogenous substance so far
 Product of metabolism of creatine and
phosphocreatine in skeletal muscle
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




Usually constant muscle turnover for an individual
[BUT a person with more muscle will have a higher
baseline creatine level] [nb heavier means prob has
more muscle]
Freely filtered and not reabsorped but there is
tubular secretion
 tends to over estimate GFR because of
tubular secretion
CON: Creatine level poorly sensitive to GFR: spike in
endogenous production of Creatinine (thus
allowing its use to measure GFR) only comes when
there is established kidney failure!! (actually want
sensitivity at start of kidney damage instead!)
Alternatively: Cystatin C; an endogenous cysteine
protease inhibitor
Basic equation:


Creatine variables other than kidney damage:
muscle mass, age, sex, race; these variables can be
added to make more complex equations: [give
accurate predictions]
 Cockcroft Gault eq
 MDRD - Modified Diet in Renal Disease
Equations
o Urea: [less good]
 Product of nitrogen metabolism
 Small molecule freely filtered by kidney
 Variable production rate
 depending on protein intake, liver function, tissue
breakdown
 Approx 50% may be reabsorped by the tubules
Alternatively: measure using radioisotopic methods:
23
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o
o
o
o
o
o
o
-
Closely correlate with inulin clearance
Given as a single bolus
Measure decay in serial blood test
BUT:
 Expensive
 Radioactivity used
Eg radiolabelled EDTA (51 Cr labelled
diethylenediaminetetra-acetate)
 used widely in clinical practice (Transplant donors,
to accurately assess GFR when administering
chemotherapy
Eg Iothalamate;
eg Iohexol
Other renal function tests
o urine
 Appearance
 If supernatant is clear but urine looked red at the outset likely
haematuria
 Red / Brown
o – myoglobinuria or haemoglobinuria
o – food dyes or beetroot ingestion
o – porphyria
o – rifampicin
 White
o – pyuria [white cells in urine], phosphate crystals, chyluria
 Black
o due to hemoglobinuria , alkaptonuria,
 Microscopy
 An undervalued but useful resource
 Infection [RBCs stacked up can indicate nephritis] rouleaux
 Crystals [antifreeze crystals in attempted suicide]
 Casts [granular protein casts in nephrotic syndrome]
 Urinalysis – dipstick analysis
 Concentration [taken early morning so not diet/drinking dependant]
 pH
 Glucose
 Proteinuria
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o

o
Indicates glomerular permeability or lose of reabsorption of
filtered proteins
o But can be a benign variant (Orthostatic proteinuria)
o Primarily detects albumin but not other proteins eg
immunoglobulin light chains.
o Highly specific, but not very sensitive for the detection of
proteinuria; it becomes positive only when protein excretion
exceeds 300 to 500 mg/day.
o Can be used to detect microalbuminuria, the earliest clinical
manifestation of diabetic nephropathy
o Likely to reflect some underlying glomerular disease
 Primary renal lesion (focal glomerulosclerosis or
membranous nephropathy or another
glomerulonephritis)
 secondary (diabetic nephropathy or myeloma)
 secondary to a systemic disorder such as congestive
heart failure.
Haematuria
o Macroscopic vs microscopic
o Bleeding anywhere in renal tract – glomerulus to external
urethral meatus
o Common causes
 Infection
 Stones
 Malignancy
 Glomerulonephritis
 Myoglobinuria
Blood:



Low Ca level of blood would indicate poor hydroxylation of vit D by
kidney
Anaemia can be due to Erythropoietin Deficiency from kidney
o In anaemia the kidney is more hypoxic than otherwise so
HIFs generated at kidney leading to greater erythropoietin
(EPO) production to lead to replacement RBCs being
synthesised
o [nb also:, transfusions will give high Fe levels which can
cause kidney failure]
Poor kidney function can give acidosis as the tubular fluid is more
acidic than blood (ie so if not removed the blood will be more acidic)
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Renal Failure (GFR used to follow/investigate)
o Renal Failure definitions
 Acute – rapid loss of GFR and tubular function over hours to days
 Chronic – sustained loss of GFR and tubular function over longer period –
months.
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08/01/14: Renal blood flow and regulation: Nish
Arulkumaran
Los (from booklet):
learn about the anatomical and physiological concepts underlying the renal
vasculature and perfusion,
c and extrinsic mechanisms involved in regulation of
renal blood flow
gy of renal vascular impairment
Notes:
-
Pressure and Flow are required to perfuse organs
o • Pressure is determined by:
 the volume of blood within the vascular bed (regulated by kidneys)
 and the compliance of the vessel wall (regulated by kidneys)
o • Flow is determined by
 heart rate and contractility
 and blood volume (regulated by kidneys)
-
The kidney Controls blood volume & composition:
o 1. Controls Red blood cell production
 – Secretion Of the hormone erythropoietin
o 2. Maintains Volume of the circulation
 – Excretion Of sodium and water
o 3. Maintains Tonicity and composition of plasma
 – Excretion Of acid and other electrolytes/substances
-
Kidney blood flow:
o Only tissue to have arterioles either side of a capillary bed
o Afferent: high pressure; main control of blood flow occurs here
o Efferent arterioles: low pressure; constriction allows GFR to be maintained even if
OVR RPF is decreased (ie even if wanting to excrete less still want to maintain
filtering; events elsewhere will change amount of fluid reabsorbed/lost)
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o
o
o
>20% of cardiac output goes to kidney; any blood loss etc therefore will give major
disruption at the kidney
 Cortex 90%, Medulla 10%
 To ensure:
 1. Adequate Blood filtration
 2. Effective other renal processes: (absorption, secretion, excretion)
Blood flow regulation is achieved mainly by alterations in vessel diameter (poiseuille
eq shows this is the most effective method)
Regulation of renal blood flow [in addition myogenic stretch feedback occurs]
 1. Autocrine and paracrine [extensive autoregulation occurs - cf ]
 • Nitric Oxide
o Produced by endothelium
o • Causes vasodilation: decreases vascular resistance
o • Systemically: reduces blood pressure
o • Locally: Maintains renal blood flow
o • Maintains basal state of vasodilatation in health
o • Lost in presence of vascular inflammatory diseases
 – Smoking
 – Hypertension
 – Hypercholesterolemia
 – Diabetes
 – Systemic inflammatory conditions
 – Reactive oxygen species production
 • Adenosine
o The macula densa signals via adenosine – cf
 • Prostaglandins
o Vasoactive autocoids synthesized from fatty acids by
Cyclooxygenase
o Inhibited by NSAIDs
o Most are vasodilators
o Important role in haemorrhage: production stimulated to
counter the sympa and ATII effects which would otherwise
give a damaging decrease in RPF and GFR
o PGE2 and PGI2 produced locally at the kidney
 Dopamine
o At low levels gives dilation at renal arterioles thus serving
similar function to prostaglandins
 • bradykinin
o Peptide which stimulates NO and prostaglandin production
o – Broken down by angiotensin converting enzyme (ACE)
 • endothelin
o Vasoconstrictor – important in acute BP changes
 2. Neural
 • Sympathetic tone
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o
o
More alpha1 receptors on afferent arterioles than efferent
so gives decrease in RPF and GFR.
Ie in hypotension the cardiovascular system with attempt to
raise systemic BP even at the cost of blood flow to the
kidneys

o
3. Hormonal
 • Angiotensin II
o Low levels: high RPF
o High levels: decrease in RPF but GFR maintained
o In the kidneys, ATII constricts glomerular arterioles, having a
greater effect on efferent arterioles than afferent.
o As with most other capillary beds in the body, the
constriction of afferent arterioles increases the arteriolar
resistance, raising systemic arterial blood pressure and
decreasing the blood flow.
o However, the kidneys must continue to filter enough blood
despite this drop in blood flow, necessitating mechanisms to
keep glomerular blood pressure up.
o To do this, angiotensin II constricts efferent arterioles, which
forces blood to build up in the glomerulus, increasing
glomerular pressure.
o The glomerular filtration rate(GFR) is thus maintained, and
blood filtration can continue despite lowered overall kidney
blood flow.
o Because the filtration fraction has increased, there is less
plasma fluid in the downstream peritubular capillaries. This
in turn leads to a decreased hydrostatic pressure and
increased oncotic pressure (due to unfiltered plasma
proteins) in the peritubular capillaries. The effect of
decreased hydrostatic pressure and increased oncotic
pressure in the peritubular capillaries will facilitate increased
reabsorption of tubular fluid.
o There is actually some contradictions with Costanzo saying
Low levels: increase in GFR; (& prob tiny dec to RPF); High
levels: decrease in GFR and RPF.
 • Vasopressin
 • Catecholamines
o Noradrenaline, adrenaline
o Parallel sympathetic activation
 ADH and Atrial/Brain Natriuretic Peptides released in response to
changes in blood volume
Changes in blood flow are sensed by juxtaglomerular apparatus
 Modulates release of renin and vasoactive substances which act locally and
systemically
 – Vascular tone (especially afferent and efferent arterioles)
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o
-
 – Renal salt and water retention
Note the proximity of the glomeruli and juxtaglomerular apparatus inc ascending
limb of loop of henle/start of distal convoluted tubules where the macula densa is
Renal autoregulation: Autoregulation protects glomeruli from changes in BP; preserves RBF
and circulating volume given changes to systemic BP; simultaneously preserves renal
excretion/GFR
o 1. Myogenic hypothesis:
 Inc arterial pressure stretches the blood vessels
 This gives reflex contraction of smooth muscle in the walls of the vessels;
stretch activated Ca channels are activated
 Increased resistance to bloodflow results thus preventing a rise to RPF
o Tubuloglomerular feedback
 Increased renal arterial pressure gives inc RPF and GFR
 Due to starling equation there will be a greater delivery of solute and water
to the tubules
 Macula densa is sensitive to the NaCl concentration (ie elevated once the
water has left; will also be raised if there is a problem with sodium reuptake)
and signals for vasoconstriction of the afferent arterioles
 RPF and GFR then will return to normal
 Specifically:
 Apical Na-K-2Cl cotransporters move sodium into the cells of the
macula densa.
 The macula densa cells do not have enough basolateral Na/K
ATPases to excrete the sodium, so the cell's osmolarity increases.
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



-
Water flows into the cell to bring the osmolarity back down, causing
the cell to swell.
When the cell swells, a stretch-activated non-selective anion channel
is opened on the basolateral surface. [pannexin channels]; ATP
escapes through this channel and is subsequently converted to
adenosine.
Adenosine vasoconstricts the afferent arteriole via A1 receptors and
vasodilates (to a lesser degree) efferent arterioles via A2 receptors,
which decreases GFR.
Also, adenosine inhibits renin release in JG cells via A2 receptors on
JG cells using a Gi pathway.
If renal perfusion drops:
 Systemic responses:
 Control of systemic blood volume [RAS – cf]
o Salt and water retention
 Systemic Vascular responses [RAS – cf]
o Inc Perfusion pressure
 Autoregulation:
 the myogenic and tubuloglomerular feedback will shut off to inc
perfusion
 Local vascular responses
 Renal arteriolar vasodilation: prostaglandins give vasodilation at
afferent arterioles [eg PG synthesis stimulated at kidneys if
hypotension/haemorrhage; note that the same stimuli trigger
sympa, PG synth and ATII]
 ATII at low level so gives vasoconstriction mainly at efferent
arteriole
 OVR result is GFR being maintained
 Drugs may interfere with this local regulation:
o Eg NSAIDs counter prostaglandin action and ACEi counters
ATII action
o Dangerous in low pressure states eg:
 – Dehydration
 – Heart failure
 – Sepsis
 – Postoperative recovery
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
At very low pressures a threshold is reached and renal regulation is
insufficient to maintain blood pressure; this threshold can be increased (ie
bad) in various disease states to give normotensive renal failure
[note: here are talking of autoregulation (ie the myogenic and
tubuloglomerular feedback will shut off to inc perfusion) but is actually
including the other mechanisms eg local proastaglandin and ATII effects that
also will try to raise the pressure]
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o
-
If renal perfusion rises: [systemic hypertension]:
 Pressure diauresis can occur: increased salt and water loss due to increase in
RPF
 Autoregulatiory systems give return to baseline: Renal blood flow constant
across physiological range of hydration and blood pressure
Note that autoregulation for preservation of GFR occurs in the healthy state but in disease
eg haemorrhage the SNS may signal for dec GFR to prevent loss of fluid (at the cost of
filtration; therefore creatinine levels will increase). Prostaglandins help to reduce the
magnitude of any such drop. ATII acts to reduce RPF without reducing GFR.
33
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34
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08/01/14: Blood pressure & the Renin-Angiotensin System:
Nish Arulkumaran
Los (from booklet):
learn about the blood pressure: what it does to/for the body, how do we measure it
- components and roles, therapeutic targets
Notes:
-
-
-
Highly compliant arteries give accumulation of potential energy (and therefore lower systolic
pressure) and then release of the potential pressure during diastole (and therefore
increased diastolic pressure than otherwise)
Low compliance arteries ie stiff arteries will give systolic hypertension and a wide pulse
pressure (due to both an increased systolic pressure and decreased diastolic pressure).
o Diabetes, hypertension, atherosclerosis and renal failure all result in arteries
becoming calcified and therefore less compliant
o The low pressure in diastole is bad as it is this period in which the heart gets its
blood supply
Hypertension:
o Retinopathy: haemorrhage/edema in eye
o LV hypertrophy: working against high resistance; will give poorer filling
o Vessel hypertrophy: impaired kidney flow / renal artery stenosis; kidney will
interpret as hypotension and so give damaging feedback responses; renal failure
may occur
o Increases stroke risk: prob via causing intracranial haemorrages and shear stresses in
vessels
o
o
o
RAS activation due to renovascular disease is the primary mechanism for
hypertension
is most effectively treated with RAS blockade
 WILL RESULT IN SHORT TERM REDUCTION OF GFR
 – If renal function very poor may lead to renal failure
 – Better long term renal outcomes if tolerated
Patients with heart failure, hypertension or renal disease (especially diabetes)
should be on ACEIs / ARBs unless contraindicated
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o
o
Essential hypertension is the form of hypertension that by definition, has no
identifiable cause [contributors: Genetic – Diet (Salt) – BMI – Exercise – alcohol –
Age – Smoking]
Secondary hypertension is a type of hypertension which by definition is caused by an
identifiable underlying secondary cause [Renal disease is the commonest cause]
-
RAS is activated when renal perfusion/function is impaired
o – Shock
o – Renal artery stenosis
o – Intrinsic renal diseases: diabetes, glomerulonephritis
-
The three cellular components of the JGA are the:
o 1. Macula densa of the distal convoluted tubule
 Senses any increase in the NaCl concentration in the distal tubule and
secretes a locally active vasopressor (adenosine) which acts on the adjacent
afferent arteriole to decrease glomerular filtration rate (GFR).
 Nb this signalling was detailed prev
o 2. smooth muscle cells of the afferent arteriole known as juxtaglomerular cells
(=granular cells)
 They secrete renin in response to:
 – Beta1 adrenergic stimulation
 – Decrease in renal perfusion pressure (detected directly by the granular
cells)
 – Decrease in NaCl concentration at the macula densa as signalled via PGs
(not via adenosine for RAS stim)
o 3. extraglomerular mesengial cells
 Produce EPO (erythropoietin)
36
Giles Kisby
-
Renin is secreted by at least 2 cellular pathways:
o A constitutive pathway for the secretion of prorenin
o A regulated pathway for the secretion of mature renin
-
Angiotensinogen
GE Y1 Renal
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• No enzymatic activity
• Produced constitutively by the liver and released into the circulation
• Substrate for cleavage by RENIN to give ANGIOTENSIN I (the N-terminal 12 amino
acids)
-
Angiotensin I
• 12 amino acid peptide
– Produced by cleavage of angiotensinogen by renin
• No intrinsic activity
• Substrate for ANGIOTENSIN CONVERTING ENZYME (ACE)
• ACE is made by the pulmonary and renal endothelium
• Cleavage by ACE produces the 10--‐amino acid peptide ANGIOTENSIN II; The active
hormone
• ACE also breaks down bradykinin
-
Angiotensin II
• 10 amino acid peptide
• Host of actions
• All tend to INCREASE blood pressure
• Systemic Vasoconstriction
– Increases blood pressure
• Renal vasoconstriction
– Efferent>afferent arteriole
– Protects glomerular filtration pressure
– Reduces medullary blood flow thereby reducing hydrostatic
pressure in pericapillary tubules (therefore increased reabsorbtion)
• Salt retention
– Stimulates proximal tubular Na+/H+ exchange
– Stimulates aldosterone release from adrenal gland
• Water retention and thirst
– Stimulates release of ADH from pituitary
• Cleaved by angiotensinases located in red blood cells to form less active cleavage
products
• Half life is ~30s in the circulation
-
Angiotensin III
• Angiotensin III has 40% of the pressor activity of angiotensin II but has 100% of
the aldosterone producing activity
-
Aldosterone
• Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex
• Aldosterone is produced in response to an increase in the plasma concentration of
Angiotensin III, angiotensin II, ACTH (Adrenocorticotropic hormone), and K+
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• Aldosterone exerts its effects via the mineralocorticoidreceptor (MR) and the
resultant activation of specific amiloride-sensitive sodium channels (ENaC) and the
Na/K ATPase pump.
 Acting on the nuclear mineralocorticoid receptors (MR) within the principal
cells of the distal tubule and the collecting duct of the kidney nephron, it
upregulates and activates the basolateral Na+/K+ pumps, which pumps
three sodium ions out of the cell and two potassium ions into the cell.
 This results in reabsorption of sodium (Na+) ions and water (which follows
sodium) into the blood, and secreting potassium (K+) ions into the urine
(lumen of collecting duct).
 Aldosterone upregulates epithelial sodium channels (ENaCs), increasing
apical membrane permeability for Na+
• This results in reabsorption of sodium (Na+) ions and water (which follows sodium)
into the blood, and secreting potassium (K+) ions into the urine (lumen of collecting
duct).
-
RAS system acts to maximise glomerular filtration pressure
– Vasoconstriction: Systemic and renal (efferent>afferent arterioles)
– Proximal sodium resorption (ATII)
– Distal sodium resorption (aldosterone)
– Water resorption and thirst (ADH)
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GE Y1 Renal
• β blockers (usually end in --‐olol)
– Renin release is increased by sympathetic stimulation
• Renin inhibitor (Aliskiren)
cleavage of angiotensinogen by renin
• Angiotensin Converting Enzyme Inhibitors (ACEIs)
– End in “--‐pril”
– Block production of angiotensin II
– Also inhibit breakdown of bradykinin (dry cough; bradykinin sensitises pulmonary
receptors)
• Angiotensin II receptor blockers
– End in “--‐sartan”
– Block vasoconstriction and release of aldosterone/ADH
• Spironolactone
– Antagonises aldosterone
–ie downstream of RAS
When to block RAS
• Hypertension from any cause
• Heart failure
• Intrinsic renal disease (PROTEINURIA)
– Commonly associated with intraglomerular hypertension
– All proteinuric patients should be on ACEI/ARB unless contraindicated
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• Renovascular disease (~ renal artery stenosis: but don’t use ACEi)
When NOT to block RAS
• Acute illness/haemodynamic stress
– GFR critically dependent on RAS when haemodynamics are compromised (ie
w
after heavy bleed etc)
• RAS Blockade will reduce GFR by up to 15%
– If renal function very poor RAS blockade can precipitate need for dialysis
• Hyperkalaemia
– Reduced aldosterone will impair K+ excretion
• Persistent cough with ACEI --‐> ARB
41
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14/01/14: Water and dehydration: Jeremy Levy
Los (from booklet: are in the below format there!):
“To understand how the body handles water and what can go wrong. To understand how to
interpret blood results in this context and how disorders of water balance might be managed.
Much of the body is water. Water allows solutes to remain dissolved, and changes in body water can
cause changes in solute concentrations. Physiological processes require tight control of solute
concentrations, and hence water distribution is also tightly regulated.
Control of body water is mainly through the kidneys. The proximal tubule reabsorbs 70% of water
filtered together with salt, but cannot change the concentration of urine (iso-osmolar reabsorption).
The loop of Henlé in the kidney allows humans to make dilute urine, while the distal tubule
[assuming ADH absence; otherwise further dilution of urine occurs here] and collecting ducts act to
make concentrated urine, through the action of ADH (Vasopressin). Humans can change the
concentration of their urine over a very wide range. ADH is the key hormone controlling water
balance, but many others affect water homeostasis via actions on salt and water (eg cortisol [inc
A/NA sensitivity for a1 & b1 signalling at kidney], thyroxine [increases GFR; prob via inc cardiac
output], atrial natriuretic peptide).
Excess water leads to solute dilution (eg hyponatraemia) whilst water deprivation leads to solute
concentration (eg hypernatraemia). Both these states can cause severe problems. Both can also be
caused by bad doctoring, as well as by hormone dysfunction, drugs, behaviour etc.
Dehydration (in its true form loss of water only) leads to increased concentration of solutes, and
reduction of both extracellular and intracellular volume. Dehydration is a very potent stimulus to
ADH release, which should minimise further water loss through the kidneys by increasing the
reabsorption of water in the distal tubules – less water is excreted in the urine. If this does not
happen and water loss is not corrected, dehydration leads to death.
Under- or over-activity of the hormone systems controlling water balance can lead to over or underhydration, and various electrolyte disturbances. Excess ADH leads to water retention and
hyponatraemia, while too little ADH leads to diabetes insipidus (see below) and dehydration. The
rennin-angiotensin system is also crucial in control of water balance via the effects of angiotensin II
and aldosterone on sodium handling and vasoconstriction.
It is important to identify the cause of disturbance in patients physiology in order that the correct
action can be taken to remedy the situation – if water is missing, water needs replacing alone; if
salt is lost, salt needs replacing.”
From slides:
• To understand the physiological control of water and circulating blood volume.
• To understand how this can go wrong
• To be able to interpret blood biochemistry correctly and manage states of dehydration
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Notes:
-
Solute distribution:
o OVR osmolarity inside and out of cells will be the same and is typically 290mmol/l [is
very tightly controlled; little variance]
 K is the main contributor inside cells
 Na is the main contributor outside cells
o By comparison urine osmolarity varies greatly: 50-1500mmol/L
-
What would happen if ..
o You give a person intravenous hypertonic saline?
 Blood pressure increases due to both the fluid itself and the movement of
water out of cells
 Through time bp returns to normal as kidneys etc respond
o You give intravenous normal saline?
 BP increases due to the fluid vol added
 Through time bp returns to normal as kidneys etc respond
 Detailed answer (see next lec for some explaination):
  isotonic fluid ingestion, no change in osmolarity
  intravascular volume
  baroreceptor stimulation and  macula densa sodium   renin
secretion   renal sodium loss
  ANP and BNP secretion  renal sodium and water loss
o You give intravenous 5% dextrose solution?
 Is the closest thing to pure water that can be added; pure water would give
cell bursting at area of entry and of RBCs, dextrose is quickly metabolised
but at least gives a small delay/buffer to allow for fluid to move out of blood
not at a dangerous rate
43
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
BP will inc but quickly fall as fluid exits to cells; later kidneys start removing
the fluid altogether
-
Furosemide:
o Blocks NaKCl2 pump of thick ascending limb
o therefore reduced resorbtion of Na to kidney medulla [nb loop makes urine dilute
by reabsorbing salt; then distal tubule and collecting ducts act to make
concentrated urine]
o therefore Na gradient is not established which would otherwise allow for extensive
concentration of the urine / resorbtion of water later in the tubules (also drives the
water resorbtion that is occurring on the descending limb of the loop too)
o therefore acts as a diauretic (is a loop diauretic)
-
Ie: The loop of Henlé in the kidney allows humans to make dilute urine, while the distal
tubule [assuming ADH absence; otherwise further dilution of urine occurs here] and
collecting ducts act to make concentrated urine, through the action of ADH (Vasopressin).
o Distal Tubule [here are assuming ADH not present]
 Active solute reabsorption – last 2 – 3 %
 Urine maximally dilute (50 mosmol/kg)
o Collecting Duct
 ADH sensitive; If no ADH – CD is water insensitive hence dilute urine
 In presence of ADH – water is reabsorbed
44
Giles Kisby
-
GE Y1 Renal
AVP = ADH = vasopressin = arginine vasopressin
o Nonapeptide (9 aas) synthesised by hypothalamus and secreted from posterior
pituitary
o Effects:
 Direct vasoconstrictor
 NaCl reabsorption in TAL loop of Henle
 Water retention in collecting ducts
 Receptor binding activates cAMP which stimulates water channel (aquaporin
2) incorporation into apical membrane
o Osmoceptors (at hypothalamus) sense change in serum osmolality NOT Na
o Osmoceptors are sensitive:
 1%  ECF osmolality  ADH release (eg fluid deprivation) and thirst
 1%  ECF osmolality  ADH release (eg water ingestion) and thirst
supression
o Non-osmotic stimuli for ADH release include:
[eg in surgery body may retain fluid even if serum is very dilute]
 stress,
 hypoxia,
 pain,
 volume depletion
 [also: MDMA = ecstasy - cf]
45
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GE Y1 Renal
Renin-angiotensin-aldosterone system:
apopt
[nb therefore if are on such drugs and are dehydrated will be unable to vasoconstrict to
restore kidney perfusion (and also unable to inc blood pressure of any blood still going to
kidney)]
-
ANP
o
Polypeptide released from cardiac myocytes (mainly the atria) [small amount from
other body areas entirely!]
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o
o
o
o
Increases urinary excretion of Na and water [increases flow at afferent arteriole and
decreases it at efferent arteriole]
Inhibits Na resorption by collecting duct by inhibiting ENaC
Inhibits renin production and aldosterone secretion
Vascular smooth muscle relaxation is stimulated
-
Dehydration causes:
o Burns
o Cholera
o Diarrhoea
o Heat/exercise
o Diauretic use
o Untreated Diabetes insipidus
o Untreated Diabetes mellitus [nb Hyperglycaemia causes severe dehydration;
Glucose is a potent osmolite]
-
Dehydration effects:
o 1% weight loss
 – thirst
o 2% weight loss
 – more thirst, vague discomfort, loss of appetite
o 3-4% weight loss
 – increased blood red cell concentration, lethargy, apathy, nausea,
emotional instability
o 6% weight loss
 – tingling limbs, heat exhaustion, increased body temp
o 8% weight loss
 – dizziness, confusion, delerium
o 20% weight loss
 – death
-
Clinical features of dehydration
o Postural hypotension,
o Tachycardia [heart struggling to find enough blood to pump around body]
o low skin turgor,
 To determine skin turgor, the health care provider grasps the skin on the
back of the hand, lower arm, or abdomen between two fingers so that it is
tented up. The skin is held for a few seconds then released.
 Skin with normal turgor snaps rapidly back to its normal position. Skin with
decreased turgor remains elevated and returns slowly to its normal position
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o
o
o
sunken eyes,
dry mouth,
thirst
-
Biochemical features of dehydration
o Serum osmolality high
o Serum Na usually high
o Serum K / Mg / Ca – high/low or normal
o Serum urea high
o Hb high
-
Treatment:
o Give back the lost fluid
– if true dehydration – water !
– if salt and water – saline!
-
Diabetes insipidus (DI)
o Is a condition characterized by excessive thirst and excretion of large amounts of
severely diluted urine, with reduction of fluid intake having no effect on the
concentration of the urine.
o Dilute urine despite elevated serum osmolality; Patients may produce 10 –15 litres
urine per day
o Central (lack of secretion) or nephrogenic (failure to respond) to ADH (AVP)
o Differential diagnosis is psychogenic polydipsia
 Any of a range of mental disorders leading to obsessive / over-drinking
-
Diabetes mellitus
o Glucose is a potent osmolite
o Hyperglycaemia causes severe dehydration
o Typical diabetic readings:
 Low Na: normal mass diluted by the glucose
drawing water out of cells
 High K: ketoacidosis is pushing K+ out of cells and
lack of insulin pushing K+ into cells!!
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 Urea
15 mmol/l
[high because of increased
renal reabsorption of urea mediated by ADH in
turn triggered by high blood osmolarity]
 Glucose 50 mmol/l
diabetes]
[high directly because of the
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14/01/14: Water loading states: Dr Ruth Tarzi
Los (from booklet):
osmolality and total body water content.
Understand the physiological implications of water loading and how the body responds to
it.
syndrome of inappropriate ADH secretion, primary polydipsia, secondary
hyperaldosteronism.
Notes:
-
Summary:
o Water Balance is a critical homeostatic function.
o Movement of water between compartments is regulated by osmotic pressure
provided by solutes.
o Plasma osmolarity is tightly regulated by thirst and the secretion of ADH leading to
renal water reabsorption.
o Sodium balance is maintained by the renin/angiotensin aldosterone system and
ANP/BNP.
-
MDMA = ecstasy effects:
o Sympathomimetic
 Tachycardia
 Sweating
 Pyrexia
o Induces Serotonin release
 Psychological effects
o Also:
 Hyper-pyrexia: abnormally high fever
 Rhabdomyolysis causing Acute Renal Failure
 Ie breakdown of muscle fibers that leads to the release of muscle
fiber contents (myoglobin) into the bloodstream  kidney problems
 Disseminated Intravascular Coagulation
 Long term pyschopathology associated with degeneration of serotoninergic
neurones
o Secretion of ADH is caused by ecstasy:
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

-
Is a form of syndrome of inappropriate antidiuretic hormone secretion
or SIADH
 ie failure to excrete water
If associated with very high fluid intake too then:
 Water overload
 Diluted serum (hyponatraemia)
 Cerebral Oedema
o Acute hyponatraemia: With rapid hyponatremia, water
moves down osmotic gradient into the CSF and brain
causing cerebral oedema.
o Chronic hyponatraemia: brain volume expansion leads to
loss of water and osmolytes from brain and new equilibrium
with lower extracellular sodium concentration.
[but may die before the solutes have been able to exit the
brain]
Water/osmolarity balance
o Water accounts for 50-60% total body weight;
[Total body water is controlled to within <1-2%]
 2/3 total body water is intracellular
 1/3 total body water is extracellular
o Osmolarity vs Osmolality
 Osmolarity = measure of solute concentration per volume (mOsm/litre of
solution).
 Osmolality = measure of solute concentration per kg of solvent (mOsm/kg).
 For our purposes these are virtually the same.
o Calculating plasma osmolality
 Calculated plasma osmolality = (2 x Na) + glucose + urea = about 290
mOsmoles/l.
 True osmolarity can be measured in the biochemistry lab and usually does
not deviate more than +2 to -2 from the calculated.
 Causes of an osmolal gap – difference between calculated and true
osmolality:
o With metabolic acidosis
 Ethanol
 Ketones
 Lactic acids
 Renal failure
 Ethylene glycol (antifreeze)
 Paraldehydes
o Without metabolic acidosis
 Ethanol
 Mannitol or sobitol infusion
o Regulation:
 OSMORECEPTORS in the hypothalamus;
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
-
ADH
o
o
o
o
 Can sense changes in plasma Osmolarity of <1%
 Sensing possible due to absent BBB at hypothalamus
a. After water load (ie drinking), plasma osmolarity falls
b. Detected by Hypothalamic osmoreceptors
c. Reduced thirst
d. Reduced ADH secretion
BARORECEPTORS of circulatory system:
 respond to hypovolaemia 8-10% change; ie much less sensitive than
the osmoreceoptors
 Control levels of:
– Angiotensin II [gives inc level]
– Relaxin [gives inc level]
– ANP [gives dec level]
nonopeptide
Synthesized in the supraoptic nucleus of the hypothalamus.
Secretory granules migrate down the suprahypophyseal tract and are stored in the
posterior pituitary from where they are secreted.
Stimuli for secretion:
 (1) OSMOTIC REGULATION: Increasing Plasma Osmolarity detected by
hypothalamic osmoreceptors (linear relationship; sensitive)
 Effects: ADH secretion and thirst:
o Basal ADH receptors exist to detect ADH (ie blood side)
o Aquaporin-2 inserted into the luminal surface
o Long term effect: increased Aquaporin 2 synthesis too
o RESULT: Reabsorption of water from filtrate
 (2) VOLUME REGULATION: Decreased intravascular volume (non-linear
relationship; less sensitive)
 Sensors:
o Pressure receptors in carotid sinus and left atrium
(baroreceptors), and afferent arteriole (juxta glomerular
apparatus).
 Effectors:
o Renin-Angiotensin System
 (retain sodium; ie used if vol dec)
o Atrial and ‘Brain’ Natriuretic Peptides
 (lose sodium; ie used if vol inc)
o RESULT: This system principally functions to regulate renal
sodium excretion; ie then the water will follow the Na to
give the required volume change
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-
Example: Man on a marathon in humid climate; not drinking; will lose both water and salt
so osmoreceptors will not be triggered but the baroreceptors will be:
o (1) REDUCED carotid sinus baroreceptor stimulation leading to reduced
parasympathetic tone (tachycardia and vasoconstriction).
o (2) Reduced NaCl delivery to the macula densa and reduced stretch in the afferent
arteriole, leading to INCREASED renin secretion.
o (3) Reduced atrial stretch – reduced ANP secretion.
o (4) NB ADH will only be released if plasma osmolarity goes up or severe
hypovolaemia (8-10%).
-
Example: Eating crisps and drinking beer in a bar: INCREASED circulating volume
o Carotid and atrial baroreceptor stimulation induces INCREASED atrial natriuretic
peptide secretion
o Natriuretic peptides oppose the renin-angiotensin system
 Induce renal sodium loss
 Reduces plasma renin activity
o Natriuresis results in loss of body water
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
-
Ie have to bring the Na back to body to regain the water but are trying to get
rid of the Na
Water Overloaded States
o (1)Inability to secrete excess water
 - Syndrome of inappropriate ADH secretion
 Non-physiological (ie abnormal) release of ADH
 Water retention
 Reduced plasma osmolarity [ie must have this on test readings for it
to be SIADH [if not given this directly can still work it out by the
equation: Plasma osmolarity = 2 x (Na) + urea + glucose]
 Ecstasy induced ADH secretion may be fatal because of the speed of
secretion and amount of water drunk.
 Causes of SIADH: (see also endo notes)
o CNS Disorders
o Drugs eg MDMA ie ecstasy
o Pulmonary Disorders: pneumonia
o Cancer
 Treatment of SIADH
o Treatment (and diagnosis) of the underlying precipitant
o Treatment of the effects of ADH
 Treat quickly if effects of ADH excess arose quickly
 Treat slowly if effects of ADH excess arose slowly
 Rapidly correcting hyponatraemia in chronic
situations risks demyelinating brain injury
as water leaves the brain down an osmotic
gradient.
[Brain adapts to chronic hyponatraemia by
loss of salts. Over-rapid correction of serum
sodium leads to loss of water and brain
shrinkage]
 Most cases, and if in doubt, treat slowly
with fluid restriction
 - Primary polydipsia
 Inappropriate ingestion of water (10-20L per day!)
 Results in reduced plasma osmolarity
 Usually associated with psychiatric conditions
 Kidney has a high capacity to excrete urine but if this is exhausted
then hyponatraemia will occur.
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o
-
(2) Primary Renal Salt Retention and Secondary Water Retention [all will prob
result in oedematous states; Inability to secrete excess water won’t give edema as
RAS not activated and proteins remain in blood]
 - Renal Failure
 Inabilty to excrete salt and water loads due to reduced GFR.
 - Nephrotic syndrome [can lead to RAAS activation]
 In nephrotic syndrome serum albumin is low because it is able to
exit at nephrons and leave the body; this leads to low plasma
oncotic pressure, giving fluid leakage into tissues and in turn
inappropriate activation of RAS due to low BP [actually have plenty
of fluid, just is in the wrong place]
 [ie sufficient filtering at kidney is occurring, is just that protein is also
leaving]
 - Heart Failure [can lead to RAAS activation]
 (1) reduced cardiac output increases venous pressure, so increased
hydrostatic pressure pushing fluid out of vessels, reducing circ vol
and activates RAS;
 (2) reduced renal perfusion also activates RAS
 - Liver Failure [can lead to RAAS activation]
 Liver cirrhosis increases portal venous pressure so favouring fluid
moving into ascites rather than travel through liver and circ system
 RAS activation
 Liver failure reduces serum albumin, reduces oncotic pressure so
fluid not retained in capillary, so effective circulating volume
reduced, activates RAS
Example: lung cancer
o
Inappropriate ADH secretion from his Ca lung. His urine osmolarity is higher than the
plasma osmolarity, even though he is hyponatraemic. His reduced level of
consiousness is due to cerebral oedema.
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Example: prostate cancer
o
o
o
Although he is hyponatraemic, he does not have SIADH as his osmolarity is HIGH.
He is appropriately concentrating his urine.
He has renal failure secondary to bladder outflow obstruction (prostate cancer),
leading to primary salt retention and a high urea. His concentrated plasma and low
potassium are likely due to diuretic use.
30/01/14: Acid-Base Balance: Doris Doberenz
Los (from booklet):
Lecture 7: Acid-Base balance – physiology
Dr Doris Doberenz (doris.doberenztiimperial.nhs.uk)
• Lecture and relevant articles will be made available on Blackboard
Los (from slides):
•
•
•
•
•
•
Homeostatic principles:
• maintenance of hydrogen ion concentration and electric neutrality
Different conceptual principles of explaining acid base abnormalities:
• Traditional: H+ and Bicarbonate (Henderson-Hasselbalch) vs. physicochemical
(Stewart)
Physiological consequences of acidosis and alkalosis for the whole body
Principles of acid-base production, buffering, transport, elimination and compensation
Definition of pH, Standard Bicarbonate, Base excess and deficit
Common acid base disturbances and causes
• Metabolic acidosis:
• Hyperkalaemia
56
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•
•
•
•
•
•
•
•
Lactic acidosis (shock and liver failure)
Ketoacidosis
• Starvation
• Diabetes
Loss/decrease of Sodium Bicarbonate
• gut (diarrhoea)
• kidneys: RF
• hyperchloraemia
Metabolic alkalosis
• common association with: hypochloraemia, hypokalaemia
Respiratory acidosis:
high production and/or reduced respiratory elimination of CO2
Causes of reduced ventilation
• airways, lungs
• Brain
• Nervous system and neuromuscular junction
• Muscle
Respiratory alkalosis:
• reduced production of CO2 and/or
• Hyperventilation
• hypoxia, high altitude
• Mechanical (over)ventilation
Systematic approach to evaluating acid base abnormalities:
• History, drugs, fluids
• Examination
• Blood pH ?acidosis/?alkalosis
• pCO2: ?respiratory cause or compensation
• Bicarbonate/base excess/deficit: ?metabolic cause/compensation
• Other blood and urine tests (Na, K, Cl, renal and liver function, lactate,
ketones, urine dipsticks
Notes:
-
Acid-Base Balance: important homeostatic and physico-chemical principles
o Maintenance of normal hydrogen ion concentration/pH
 For optimal cellular function
 (enzymatic reactions, transmembrane ion transport pumps etc)
 Acidaemia effects:
 Systemic vasodilation [tissue autoregulation]
 Sympathoadrenal activation: tachycardia, increased cardiac output
[“reflex tachy”]
 More O2 release from Hb / Increased tissue O2 delivery
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
o
High blood potassium as it moves out of cells in exchange for H+
ions moving into cells [  hyperkalemia gives cardiac dysarrthmias
and cardiac arrest]
o Bradycardia risk (K+ is outside the cell so hyperpolarised
membrane)
o Tall T waves
o smaller P waves
o widening of the QRS complex
 Direct negative inotropic effect (“K+ will dec ionotropy as it is by
blocking K+ site that Dijoxin increases ionotrophy”)
 Insulin resistance [ diabetes] (“insulin prob triggered to
encourage K+ uptake by cells as this is one of its functions”)
 Alkalaemia effects:
 Systemic + cerebral vasoconstriction (“brain etc assumes O2 is
high”)
 Reduced cardiac output (prob due to arrhythmias)
 Less O2 release from Hb / Decreased O2 delivery
 Low blood potassium as it moves into cells in exchange for H+ ions
moving out of cells: hypokalemia:
o Tachycardia risk (K+ in the cell so less negative memb
potential BUT repolarisation will take longer)
o Arrhythmias
o flattened or inverted T waves,
o ST depression
o wide PR interval
o prolonged QT interval
 Ionized hypocalcaemia, as calcium binding to plasma proteins
increased
 Traditional Henderson-Hasselbalch relevant here: (focus: pH control)
 Bicarbonate and pCO2 govern acid/base balance
 Henderson-Hasselbalch equation:
 pH = 6.1 + log [HCO3-]
paCO2 x SCO2
 [ie paCO2 x SCO2 = PP * solubility = [H2CO3]]
Maintenance of electrical neutrality (positive ions = negative ions)
 In any watery solution, and in any body compartment the sum of all
positively charged ions must equal the sum of all negatively charged ions
 e.g. [Na+] + [H+] = [Cl-] + [OH-]
 Strong cations (eg Na+ in blood) drive H+ out and OH- in (to blood)
 Strong anions (eg Cl- in blood) drive H+ in and OH- out (of blood)
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
[ie the H+ and OH- fill the gap in charge as above]
 A more complete equation:
o [SID] + [H+] – [WA-] - [HCO3-] – [CO32-] – [OH-] = 0
o Where SID = strong ion difference
 Ie (Na+ + K+ + Ca++ + Mg++) – (Cl- + SO42- + Lactate-)
 Normally 40 – 44 meq(+)
o Also: WA = Weak acids/bases (~buffers):
 mainly albumin and phosphoric acid/phosphate
Stewart’s approach relavant here:
 new quantitative/ physico-chemical approach
 Focus on Electroneutrality
 Dissociation of water and concentration of H+ (pH) and HCO3- (=OH+ CO2) are dependent variables of:
o pCO2
o Strong ion difference (in plasma/ECF mainly [Na+] – [Cl-])
o [weak acids] (mainly proteins, eg albumin and phosphate)
o Ie HCO3- resorption will be upregulated if Cl- or HCO3- level
falls and downregulated if Cl- or HCO3- level rises as a
means to keep anion level constant
-
Note:
o Red meat and cheese contribute to acidic conditions in body: one of the effects of
academia is insulin resistance therefore such foods may contribute to diabetes
o Most acid-base disorders are treated by reversal of the cause
-
Physiologic acids
o Cellular metabolism constantly produces:
 ‘Volatile’ acid (13–15 000 mEq/d)
 = CO2 (CO2 + H2O  H2CO3  HCO3- + H+)
 from aerobic metabolism/cellular respiration (Krebs cycle)
 ‘Non-volatile’ acids (20 – 70 mEq/day)
 Lactic acid (anaerobic glucose metabolism)
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

-
Sulphuric, phosporic and and uric acid from protein and nucleic acid
metabolism
Free fatty acids, ketoacids (fat metabolism)
How does the body deal with acid-base challenges and maintain homeostasis?
o 1. Buffering
o 2. Transport (often by buffers!)
 Blood proteins (Haemoglobin, Albumin)
 Carbonic-acid- + H+)
[early PCT]
o
o
3. Elimination:
 pulmonary (CO2)
 renal (H+), coupled with generation of HCO34. Compensation
 Respiratory / metabolic, mainly (but not only) via Carbonic-acid-bicarbonate
system:
 [Pulmonary elimination]
 (CO2 + H2O   H2CO3  HCO3- + H+) 
[Renal elimination/generation]
 = Metabolic-respiratory link
 In a state of dynamic balance
 Maintenance of normal physiological pH ~ 7.4 requires maintenance
of 20:1 relationship between bicarbonate and carbon dioxide
component as can be proven via the HH equation
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


-
Lungs
o In metabolic acidosis: inc CO2 removal by hyperventilation
o In metabolic alkalosis: dec CO2 removal by hypoventilation
Kidney
o In metab. or resp. acidosis:
 inc excretion of H+ (& Cl-) [nb excretion of H+ is
coupled to retention of HCO3-] and inc generation
HCO3o In metab. or resp. alkalosis:
 dec excretion of H+; this gives inc net urinary loss of
filtered HCO3- instead
 and dec Generation of HCO3o Lactate metabolism
 to CO2 and H2O using H+ and
 generating HCO3o Glutamine metabolism
 NH4+ excretion
 HCO3- generation
o Nb the strong control of blood pH by kidney means that
there is a wide urine pH range as these compensations are
made:
 Urine pH range: 4.5 – 8.5
Liver
o Lactate metabolism:
 gluconeogenesis using H+ and generating HCO3- for
titration of peripheral H+ from lactic acid
o Urea formation generating H+:
 titrating HCO3- from metabolism of neutral and
alkaline amino acids
 BUT excess H+ from acid amino acids; ie generating
H+
 Ie therefore this is decreased in acidosis
 CO2+2NH4  CO(NH2)2 + H2O + 2 H+ + Urea
o Glutamine generation
 using H+ (increased in acidosis)
pH
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o
o
o
o
o
pH change by 1 = [H+] change x 10
Small decimal changes in pH mean relatively large changes in [H+]
pH range compatible with life: 6.8 – 7.8
normal range: 7.37 - 7.45
veins are more acidic than arteries
-
Standard bicarbonate
o Concentration of bicarbonate in a sample of blood under ‘standard’ conditions:
 Temp 37˚
 pCO2 of 5.3 kPa (= 40 mmHg)
o i.e. normalized respiratory conditions, to eliminate changes in bicarbonate resulting
from patient respiration; thus assessing only the metabolic component of acid-base
balance
o Normal range 21 – 27 mmol/l
 < 21 mmol/l: metabolic acidosis
 > 27 mmol/l: metabolic alkalosis
-
Base excess and deficit
o more accurate assessment of metabolic component of acid-base status than
standard bicarbonate
o Compared to Standard Bicarbonate, takes not only carbonic-acid-bicarbonate but
also other blood buffer systems into account (haemoglobin, albumin and phosphate;
often abnormal in sick patients)
o Base excess: Amount of strong acid that would have to be added to produce normal
pH 7.4 in sample
 Base excess > + 2 mmol/l: metabolic alkalosis
o Base deficit: Amount of strong base that would have to be added to produce normal
pH 7.4 in sample
 Base deficit more negative than - 2 mmol/l: metabolic acidosis
-
Lactate
o Normal <2mmol/l
-
Metabolic acidosis: common causes
o 1.Addition of acid
 (overwhelming buffers and metabolic elimination)
 OR (addition of acid anions leading to rise in H+ to maintain electric
neutrality)
 Lactic acidosis / ketoacidosis etc
 Examples:
 Diabetes mellitus
 Starvation (including hospital starvation!)
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
o
o
o
o
Poisoning with external acid substances and their metabolites:
o Salicylate
o Ethylenglycol (anti-freeze)
o Methanol
o Ethanol (formic acid as metabolite)
2. Sodium Bicarbonate loss
 Gastrointestinal (diarrhoea, fistulae)
 Renal: renal tubular acidosis: failure of the kidneys to appropriately acidify
the urine; HCO3- will be lost instead (see also kidney failure below)
4. Hyperchloraemia
 As blood chloride rises, blood hydrogen ion rises and bicarbonate falls (to
maintain electric neutrality)
 Eg can cause by giving (‘Normal’ Saline, containing 154 mmol/l Cl!; v high)
5. Renal failure:
 Decreased elimination of ‘fixed renal acid anions Sulphate (SO42-) and
Phosphate (PO43-)
 Reduced net renal H+ removal and HCO3- regeneration
Hyperkalaemia
-
Metabolic acidosis investigations:
o Blood lactate
o Blood chloride
o Urinanalysis (dipstick)
 ?Ketoacidosis (starvation or diabetes)
 Ketones (can also be measured in blood)
 Glucose (high in diabetes, absent in starvation; therefore can be
used to distinguish the two)
 ?Renal failure
 Blood creatinine (and creatinine clearance)
 Urine pH (with acid blood urine pH should be < 5)
 Specific gravity (low as failing kidney can’t concentrate urine)
 Protein, Blood
-
Metabolic Alkalosis
o Raised pH from raised HCO3- [though as below seems to also encompass other
causes]
o Causes:
 H+ loss
 Loss of gastric acid (and Na+) from severe vomiting or excessive
gastric tube drainage
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
o
Increased HCO3 commonly due to hypochloraemia from diuretics (loss of Clcompensated by increased Bicarbonate anion to maintain electric
neutrality
 Bicarbonate administration
 H+ shift into cells
 Ie A rise in the serum pH (decrease in H+ concentration) will result in
a shift of H+ out of the cell and potassium into the cell. 
Hypokalaemia
 Low chloride
 commonly due to renal chloride loss from diuretics  metabolic
alkalosis
Compensation: Pulmonary CO2 retention by hypoventilation (gain in volatile acid)
 (maintenance of ~20:1 relationship between HCO3- and CO2)
-
Respiratory Acidosis
o Increase in CO2 (volatile acid) [ie as below is not just due to breathing issues; is any
mech via CO2 changes:
 tissue acidosis
 increased production (sepsis, hyperthermia/fever,
hyperalimentation)
 decreased removal by perfusion
 blood acidosis/acidaemia
 decreased removal by ventilation
o due to pathology in:
 Central nervous system (brain, spinal cord)
 Peripheral nervous system/neuromuscular junction
 Respiratory muscles
 Airways
 Lungs/cardiorespiratory system
o Due to:
 too little mechanical ventilation
o Metabolic/renal compensation:
 Increased excretion of H+ (e.g. as NH4+Cl-)
 retention/production of HCO3-
-
Respiratory Alkalaemia/Alkalosis
o Increased pH from excessive respiratory loss of CO2 (volatile acid) (hyperventilation)
o Causes;
 Primary:
 anxiety, pain, stress
 Response to hypoxia,
 eg. high altitude, pathological hypoxia
 Mechanical hyperventilation
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o
Compensation: Increased renal HCO3- excretion and H+ retention (gain of metabolic
acid), i.e. reduced standard bicarbonate and base deficit  (maintenance of ~20:1
relationship between HCO3- and CO2)
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30/01/14: Acid-Base Balance Clinical Cases: Doris Doberenz
Los (from booklet):
Lecture 8: Acid Base Balance – illustrations from the critically ill patient’s physiology
Dr Doris Doberenz (doris.doberenztiimperial.nhs.uk)
• Cases will be provided on the day of the lectures
Los (from slides):
[no Los]
Notes: [use these cases/examples on slides as rev test: ie
understand all the example numbers]
-
Misc:
o
o
o
o
o
o
o
o
'drip and suck' - consisting of a IV fluids (drip) and nasogastric tube to decompress
the bowel (suck) [gastric aspiration]
Drugs for asthma can give heart effects  cardiac arrest
Case 1: abdominal pain & acidosis:
 Was thought to be due to gut ischaemia but was just starving
Case 2: COPD, acidosis:
 metabolic acidosis exacerbation by too little mechanical ventilation
[patient requires a high RR]
Case 3: asthma:
 Drugs for asthma can give heart effects  cardiac arrest  BOTH resp and
metabolic (due to ischaemia) acidosis
Case 4:
 Persistent vomiting, unable to tolerate food  metabolic alkylosis
 Very anxious/nervous, breathing fast  resp alkylosis
Case 5:
 heavy smoking and chronic lung disease  resp acidosis
 previous stroke, associated with fits  lactic acidosis
 low blood glucose (1 mmol/l)  ketoacidosis
Case 6:
 In Intensive Care on mechanical ventilation with aim to keep arterial
carbon dioxide low normal (to help control brain blood volume and brain
pressure: ie brain constricts as thinks there is high O2 availability)  resp
alkylosis
 Then given intravenous Normal Saline  strong acidosis exaserbated by
low HCO3 from the prev situation
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Giles Kisby
GE Y1 Renal
06/02/14: Clinical scenarios (electrolytes): Dr Damien Ashby
Los:
-
THERE ARE NO LOS; THIS LEC IS PROB JUST FOR PRACTICE / REINFORCEMENT OF INFO
COVERED ELSEWHERE ON THE COURSE
Notes:
-
Normal Na = 135 – 145
Normal K = 3.5 – 5.5
o Ie this dilute K+ in serum means that K+ is relatively unaffected by addition of
water to the ECF (will stay in normal range) whereas the Na level will be more
significantly reduced in terms of magnitude of reduction so hyponatremia can occur
-
Conc of Na determines the amount of water in the extracellular space:
o ADH ~ ICF
 Ie are moving water which is then mostly distributed to the intracellular
spaces (because have not changed Na level)
 However will be some expansion of ECF too thus a hyponatremia is
observed (see below ectopic ADH); hypokalemia will not be caused for the
reason given above
o Aldosterone ~ ECF
 Ie are moving water and Na so the water will be retained in the ECF because
are not changing the Na conc so there will not be a reason for shift to ICF
 Note that aldosterone is not only regulated by RAS system but by the K+
level too: Aldosterone stimulated by:
 potassium levels going too high,
 if there is less blood flow to your kidneys,
 or if your blood pressure falls
-
Note that cerebral edema is a problem with high ICF whereas all other edemas are a
problem with high ECF
o Ie ADH hypersecretion can cause cerebral edema but not peripheral edema
Note that can be ECF depleted and poor renal perfusion but with high blood pressure; ie the
high BP is trying to correct the renal perfusion
Note dextrose water replaces ICF and saline replaces ECF
-
-
Case 1
o Low BP, dirrhoea, oligourea
o = ECF depletion; give Na rich fluid
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Giles Kisby
GE Y1 Renal
-
Case 2
o Edema, Heart attack recently, high BP
o = Ras activation due to low renal perfusion pressure caused by the low cardiac
output due to the heart attack
-
Case 3:
o Lung mass, head problems (prob encephalopathy), low Na
o = ADH secreting lung tumour giving hyponatremia (but not hypokalemia for the
reason given prev) and cerebral edema (an ICF edema)
-
Case 4
o Vomiting, high K, pigmented skin
o = NOT CAUSED BY THE VOMITING; THIS IS IN FACT A SYMPTOM
o = Addisons: low aldosterone so low K+ excretion. Vomiting / nausea is a symptom of
Addisons (specifically of hyperkalemia). Skin pigmentation caused by the high ACTH
-
Case 5
o Patient on loop diauretic, stroke, high BP, high Na
o = must have been on floor a while before found so is dehydrated giving
hypernatremia, exacerbated by the frusimide. High BP as when you do not drink
adequate water the body will compensate by retaining sodium but at same time
the persistent dehydration will lead the body to gradually ‘close' some of the
capillary beds. This leads to increased pressure places on arteries and a rise in
blood pressure.
-
Case 6
o High Na, skull fracture, confused, seizures, polyuric
o = fracture gives pituitary damage and therefore loss of ADH release. Low ADH
(Diabetes insipidus) gives the polyuria and therefore H2O depletion causing cerebral
contraction; symptoms of which include confusion and seizures
o Give fluid with high water content (eg 5% dextrose) [ie dextrose water replaces ICF]
-
Case 7:
o Collapse, high K+, low BP, oligourea, pelvic mass, low pulse
o = renal failure due to bladder blockage causing urinary retention (the mass) and
giving reduced K+ excretion (unresponsive to aldosterone). High K+ give the low
pulse and low BP due to disruption at heart
69
Giles Kisby
GE Y1 Renal
06/02/14: When the kidneys are lost: Dr Damien Ashby
Los (from booklet):
-
Understand the pathophysiology and treatment of end stage renal disease
Notes:
Azotemia is a medical condition characterized by abnormally high levels of nitrogen-containing
compounds (such as urea, creatinine, various body waste compounds, and other nitrogen-rich
compounds) in the blood. [ie all of which occurs in renal failure]
In turn results in inflammation of the visceral and parietal pericardium [ie pericarditis]
Note that creatine does not increase proportionately with kidney failure; only high for
extreme failure
-
Kidney failure effects:
o Oedema [ie kidneys fail to remove excess fluid from body: DON’T PUT RF PATIENTS
ON A DRIP!]
o high K [reduced K+ excretion (unresponsive to aldosterone!)]
 tall T waves
 loss of P waves
 broad QRS
 bradycardia
 acidosis
o nausea [hyperkalemia gives nausea]
o pericarditis [see above]
o encephalopathy [due to the high levels of toxins in the blood]
o anaemia: are not making EPO; therefore administer synthetic EPO
o bone damage: A build-up of phosphates in the blood that diseased kidneys cannot
filter out may cause Bone damage
o Altered cardiovascular disease risks:
 Raised risks of arterial calcification disease
 higher cholesterol levels associated with improved CV disease risk
-
Treatment: [which favoured depends on personal aspects of that patient / preference and
whether are young enough for the temporary inc in mortality rate exhibited by transplant op
to be worth the risk]
o Dialysis:
[Associated with high mortality rates even in the young]
 Peritoneal dialysis
 Fill peritoneal space with fluid; leave for diffusion exchange to occur
then keep replacing
 Hemodialysis
70
Giles Kisby
GE Y1 Renal



o
Either via fistula [vein/artery shunt that gives a high flow vessel that
is suitable for the frequent needle penertations for dialysis]
Or a line: flexible tube, which is put into one of the veins just below
the neck, and held securely in place by a cuff under the skin. Ie used
repeatedly without removal between dialysis events
Fluid accumulates in interval between dialysis events so follow
weight changes and correct at dialysis
Transplant
 raised demand but constant donation levels; long waiting times; tissue
typing
 immune suppression
 corticosteroids
 calcineurin inhibitors
o eg cyclosporine
 antiproliferative agents
o eg azathioprine
 monoclonal antibodies
 complications - early
 vein thrombosis
 ureteric obstruction
 rejection
 complications - late
 opportunistic infections
o CMV
o fungal
 cancers: inc risk;
o skin
o lymphoma
 chronic graft failure
71
Giles Kisby
GE Y1 Renal
06/02/14: Sodium and Potassium Handling: Dr E. J.
Clutterbuck
Los (from slides/booklet):
-
-
To understand
o the factors affecting sodium and potassium balance
o How the levels are regulated, and the role of the kidneys
o that there is a close relationship between
 sodium and water homeostasis,
 potassium and hydrogen ion balance.
To outline some of the clinical conditions associated with an imbalance of sodium /
potassium
o Their symptoms, signs and immediate management.
Notes:
Sodium:
-
Sodium handling: Summary
o Sodium and water homeostasis are interlinked
o Potassium and Hydrogen take part in exchange
o Fluid distribution between cells and ECF
 depends on osmotic differences
 which are usually due to sodium concentration
o Aldosterone
 is most important factor in Na regulation
 controlled by RAS - responds to renal blood flow
-
Na is mainly regulated by kidney ie kidney = regulator of ECF volume
Sodium loss
o GI Tract
 Potent source of Na loss if vomit / diarrhoea: ~100-130mmol/litre
o Skin
 insensible losses = sweat: ~30mmol Na/day
o Urine
 Wide regulation but relatively non-existant losses when necessary;
Na excretion regulates Na balance: 3-200mmol/day
 [ie If sodium-free diet - urine losses can reduce to 3mmol/day]
Sites of sodium reabsorption
-
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GE Y1 Renal
o
Proximal tubule 65%
 Basolateral membrane Active Na / K exchange pump Pumps Na out of cell
in exchange for K; Keeps intracellular [Na] low
 Then Na in tubular lumen can enter cell passively down concentration
gradient
 Other mechanisms for Na entry through lumen side:
o Co-transport - amino acids, glucose, PO4
o Exchange transport - Na / H antiporter
 In this way Na reabsorbtion is coupled to HCO3
reabsorption: The H+ once in lumen gives CO2 from
HCO3 which can then diffuse into the tubule cell and
reform HCO3 for transport to blood and H+ for the
cycle to repeat


o
Subsequently water follows.
As other solutes and water leave the lumen, Chloride concentration rises;
Chloride moves down conc gradient via paracellular pathway
Loop of Henle: Thick Ascending Limb: 25%
 Cl=rate limiting; Loop diuretics compete Cl (eg frusemide)
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Giles Kisby
GE Y1 Renal
o
Distal tubule and collecting duct 9-10%
 Distal convoluted tubule
 Basolateral Na/K pump
o provides energy
o keeps cell [Na] low for Na / Cl co-transport on lumen side
 Thiazide diuretics inhibit NaCl reabsorption

Cortical collecting duct
 Here is the main point of regulation; ie is via aldosterone level
 basolateral active Na pump
o Na entry via lumen channels creates -ve lumen potential
o This drives K secretion and /or Cl paracellular reabsorption
 Aldosterone generated by renin release from JGA on stimulation by:
74
Giles Kisby
GE Y1 Renal
o

stretch receptors in afferent arteriole wall (ie blood volume
low renin release)
o cardiac/arterial baroreceptors: adrenergic nerves
o fall in lumen Cl in macula densa
aldosterone
o increases tubular sodium reabsorption
 increases number of Na channels
 Drives the Na pump
 Increases K influx to cell on blood side
 Increases K efflux into lumen [ie can cause
hypokalaemia & alkalosis]
-
Non-aldosterone factors affecting sodium excretion
o Changes in glomerular filtration rate
 V Low GFR decreases Na excretion
 Low GFR reduces sodium presented to prox tubule ie Nearly all reabsorbed
o Changes in renal blood flow
 Low tubular flow increases prox tubule reabsorption
o Changes in plasma oncotic pressure in tubule blood vessels
 Haemoconcentration increases prox tubule reabsorption
-
Hypernatraemia (high [Na])
o Usually water deficit - NOT sodium excess
o Cellular dehydration
 thirst, confusion, coma
o Other causes:
 Inappropriate secretion of excess aldosterone
75
Giles Kisby
GE Y1 Renal


-
Primary aldosteronism (Conn’s syndrome)
 benign adenoma of adrenal cortex
 water excess, high BP, hypokalaemia, high plasma bicarbonate
 early: low urinary sodium; late: tubular damage  rise urinary Na
Secondary aldosteronism
 liver disease, Nephrotic, Protein malnutrition
 reduced renal blood flow: hypertension, renal artery stenosis
 cardiac failure
Hyponatraemia (low [Na])
o Usually water overload - NOT sodium loss: must assess volume status first
o Subtypes:
 1) GI Fluid loss with water replacement [ie Sodium losses usually isotonic
(GI Tract) then replaced by water
 diarrhoea, vomit, sweat, burns – then drink water
 iatrogenic - excess dextrose replacement fluids
 2) Failure of homeostasis
 Addisons disease (absence of aldosterone)
 Kidney tubule dysfunction
o pyelonephritis, analgesic nephropathy
o recovery from Acute tubular necrosis (ATN), postobstructive uropathy
o Results in cellular overhydration: Effects:
 headache, nausea/vomit, cramps, confusion, fits
o Pseudo-hyponatraemia:
 other osmotic agents attract water and therefore dilute sodium
 eg diabetic : glucose
 eg renal failure: urea
o Factitious hyponatraemia:
 Sodium measured mmol / l plasma
 hyperlipidaemia / hyperproteinaemia replaces plasma water [though if just
serum looked at then the Na level will be fine]
o Treatment; [Never correct more than 6mmol/l in 6hrs; Vaptans often overcorrect]
 Hypovolaemic Hyponatraemia:
 Replace salt and water; but not too suddenly: (increase
[Na]<6mm/l/day)
o Normal saline (140mm/l)
o Dioralyte (60mm/l Na, 20mm/l K, 90mm/l glucose)
 Normovolaemic Hyponatraemia:
 SIADH: treat the disease
 Hypervolaemic Hyponatraemia :
 diuretics (to remove extracellular sodium),
 water restrict (1l), ACEI
76
Giles Kisby
-
GE Y1 Renal
Na and volume loss (ie is not hyponatremia)
o plasma volume reduced - dizzy, faint, tachycardia, low BP (postural drop)
o reduced interstitial volume
 thirsty, nausea
 no oedema, sunken eyes, dry mucosa
77
Giles Kisby
GE Y1 Renal
Regulation of Potassium
-
Potassium handling: Summary
o Mainly intracellular
o Regulated by kidney
 degree of re-secretion by distal tubular cells
 subservient to control of body Na and hydrogen
 aldosterone
o Changes usually due to
 changes in total body K
 shift between ICF and ECF
o Hypo- / Hyper-kalaemia can be life-threatening
-
[K] change due to change in total body K or shift in K in / out of large intracellular pool
Longterm K homeostasis controlled by renal K excretion governed by aldosterone
Things that inc K+ uptake at body cells:
o Insulin,
o b antagonists
o shift potassium into cells
Things that dec K+ uptake at body cells:
o Acidosis,
o hyperosmolarity,
o cell lysis
o shift potassium out of cells
Effects of inc ECF [K]:
o Fall in membrane potential, lower threshold for excitation (nerve, muscles)
Intake - foods: 60-80mmol / day
o Output
o colonic fluid (rich in K) 10 mmol
o sweat
10 mmol
o ie output is therefore primarily urine [regulated by aldosterone] ~ 60 mmol / day
 Urine losses depend upon:
 amount of Na available for exchange
 amount of H and K in distal tubule / coll ducts
(H competes with K)
 aldosterone level (causes Na retention / K loss)
Movement at kidney:
o Glomerular filtrate
700 mmol / day
-
-
-
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Giles Kisby
GE Y1 Renal
o
o
proximal tubule
~100% reabsorption
distal tubule - principle cells
re-secreted (ie via Na exchange)
 Na/K ATPase
 maintains high ICF K  K diffusion to lumen
 Na diffusion from lumen  negative lumen potential/gradient gives
further K diffusion to lumen
 Aldosterone (stimulated by [K] rise)
 increases Na and K channels
 drives Na/K ATPase
o
medullary collecting duct - intercalated cells
 Acidify urine; Pump H against conc gradient out of cells to lumen (& makes
fresh bicarbonate for release to blood)) [ie H pumped out by intercalated
cells diminishes the negative gradient so K+ not secreted]
 Luminal Active K pump reabsorbs K
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Giles Kisby
GE Y1 Renal
-
Ie K secretion is determined by:
o priority of Na reabsorption [at principle cells]; and H secretion [at intercalated cells]
o although: [K] stimulates aldosterone  K secretion
-
Hypokalaemia
o Loss of total body K
 GI losses
 vomit, diarrhoea, surgical fistula
 Kidney
 diuretics, renal disease, Cushings syndrome / steroids [MR receptor
overlap], increased aldosterone production
o Shift from ECF into cells
 primary alkalosis (H leaves cells to correct alkalosis, K shifts into cells in
exchange)
 use of insulin (drives glucose into cells, takes K)
o Symptoms:
 weakness, tetany (alkalosis reduces Ca ionisation) ecg changes: ST
depression, flat T; arrhythmia, acid urine, high plasma bicarbonate (may lag
behind a few days)
o Therapeutic Potassium Repletion
 Don’t overshoot
 Not too fast (arrhythmias) no more than 40mmol per hour
 If not fluid overloaded / normal kidney function
 give in normal saline 20-40mmol KClper litre
 NB correcting acidosis - will induce hypokalaemia
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Giles Kisby
GE Y1 Renal


-
ie remember to consider K replacement
diabetic ketoacidosis: fluids/insulin : K falls
Hyperkalaemia
o False hyperkalaemia:
 Taken from vein being infused with potassium
 Haemolysis / Cell breakdown
 small needle, traumatic puncture
 delayed analysis /prolonged storage
 high platelets, high leucocytes
 Lab error
 Familial pseudohyperkalaemia (uncommon genetic disorder)
o Increased total body K
 increased intake - food, drugs, IV fluids
 renal disease (unable to secrete eGFR<15-20ml/min / Aldosterone
deficiency
 adrenal dysfunction (addisons disease +volume depletion )
 low renin due to JGA damage- DM
 Blockage of renin - angiotensin stimulus to aldosterone
o ACEInhibitors; ARBlockers; Aliskiren
 Inhibition of action on distal tubule
o Competitive inhibitor: Spironolactone
 Inhibition of Na transport in distal tubule
o Amiloride , triamterene
o Increased total body K
o Shift of K from Cells to ECF
 severe systemic metabolic acidosis
 K exchanges for H
 insulin deficiency (reduced uptake by cells)
 cellular damage (release of K)
 Rhabdomyolysis, tumour lysis syndrome, severe burns
 Drugs – succinylcholine,Bblockers, digoxin toxicity
o May be multifactorial
 Diabetic, hypertensive, heart failure, renal failure
 Drugs: ACEinhibitors, ARblockers, spironolactone
o
Drugs causing Hyperkalaemia
 Alter transmembrane potassium movement
 B blockers, digoxin, mannitol, glucoose
 Potassium containing agents
 Iv K fluids, salt substitutes, herbal meds, blood,
 Reduce aldosterone secretion
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Giles Kisby
GE Y1 Renal



o
o
ACEI, ARB, NSAIds, heparins, antifungals (fluconazole), CNI:
Cyclosporin / tacrolimus
Block aldosterone bind to mineralocorticoid R
 Spironolactone, epleronone
Inhibit epithelial sodium channel
 Amiloride, triamterene, trimethoprim, pentamidine
Hyperkalaemia potentially Life-threatening:
 weak, irritable, paraesthesiae
 ecg changes K>6.5 (tall T, flat P, wide QRS)
 arrythmia- cardiac arrest if >7.5-8mmol/l
Treatment
 Stabilise membrane potential:
 Achieve using iv Calcium
 Shift into cells: iv Glucose / insulin
 Nb 10u actrapid WITH 50ml glucose 50% [ie doctors often get this
wrong]
 Correct acidosis:
 Ie use Sodium Bicarbonate
 Chelate:
 Use Calcium resonium
 Diuretics / If Renal failure - call dialysis unit!
82
Giles Kisby
GE Y1 Renal
13/02/14: Renal Physiology – clinical scenarios: Dr Jeremy
Levy
Los (from slides/booklet): No actual Los and said in class not
examinable (prob as is quite clinical) but worth doing
scenarios as brings knowledge together and the pattern
recog will prob be useful for the exams:
Notes:
-
Normal:
o Na: 135-145
o Osmolality: 280-295
-
You foolishly decide to take part in the Marathon des Sables – running 150 km across the
Sahara in 6 days, carrying your food and emergency kit weighing 9 Kg. On the third day you
lose you water bottle soon after starting, but continue running all day. You crawl into camp
that afternoon rather the worse for wear.
= Hyperosmotic volume contraction
-
-
-
Serum sodium and osmolality:
 Loss of water greater than loss of salt (amount of salt in sweat is less than in
blood : sweat is a hypotonic solution)
 Higher than norm: eg Na might be 150-160 mmol/l and osmolality 300-310
mosm/mol (Normal= 280-295)
 Note that high salt is due to both the net loss of water in sweat and
the increased Na reabsorbtion at kidneys to try to hold onto what
water body still has
 Water and salt are lost from the serum (intravascularly) so water then
moves from cells to the blood and is further lost. Leading to total body
water depletion.
blood pressure:
 For moderate dehydration BP remains normal but in very severe/prolonged
cases such as this the homeostatic systems are overwealmed and BP drops
(once BP systems maximally active the BP falls with volume)
 If is normal will likely be sensitive to stresses; eg postural hypotension; if
stand up vasoconstriction etc is usually required to maintain the BP but is
already maximal so BP falls (and person may also faint)
physiological processes that have kept you more or less alive:
83
Giles Kisby
GE Y1 Renal


o
-
Dehydration  ADH release from posterior pituitary  stimulates
reabsorption of water + vasoconstricts
 Mech of Dehydration  ADH release:
o Secretion in response to reduced plasma volume is activated
by pressure receptors in the veins, atria, and carotids.
o Secretion in response to increases in plasma osmotic
pressure is mediated by osmoreceptors in the
hypothalamus.
o Secretion in response to increases in plasma CCK is
mediated by an unknown pathway.
o JGA  Angiotensin II stimulates AVP secretion, in keeping
with its general pressor and pro-volumic effects on the
body.
 Aside: ADH secretion inhibitors:
o Ethanol (alcohol) reduces the secretion of AVP
o Atrial natriuretic peptide inhibits AVP secretion
Kidneys produce renin  angiotensin II  powerful vasoconstrictor and
stimulates production of aldosterone which increases water reabsorption
(and ADH as mentioned above)
Inhibition of ANP

Urine:
 low urine sodium, (as want to retain Na to allow retention of water)
 high osmolality (as still must get rid of waste products to a degree but low
water excretion)
 low urine volume / low micturition: will lead to an increase in waste
products in blood (eg urea reabsorbtion somewhat increased to help retain
H2O) but is NOT renal failure as is fully reversible; but may progress to ATN /
RF with continued low perfusion etc. Note that creatinine is still cleared;
serum Cre only inc at late RF (reduced clearance and inc production due to
ischaemia)
A 25 year old woman is admitted to hospital for the birth of her first baby. After a prolonged
labour she requires a caesarian section, and the baby is safely delivered. Blood test on the
next day show:
= Hyperosmotic volume contraction



o
Serum Na
Serum potassium
Serum urea
149 mmol/l (135-145) [High]
5.0 mmol/l (3.5-5) [slightly high]
8 mmol/l (2.5 – 6.7) [high]
Results analysis:
 Dehydration due to hard labour / sweat, blood loss  high sodium, high
urea
 potassium hard to interpret:
 is concentrated due to the dehydration but also excreted in
exchange for Na to greater degree at kidney as high Na wanted to
retain the H2O
 therefore K+ doesn’t generally change unless severely dehydrated
84
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GE Y1 Renal

-
Give IV dextrose solution to replace volume
48 hours later she is noted to be semi conscious, barely rousable, with a new divergent
squint of her eyes. Blood tests show:



o
o
o
Serum Na
Serum potassium
Serum urea
105 mmol/l (135-145) – very low
3 mmol/l (3.5-5)
3 mmol/l (2.5 – 6.7)
Explanation:
Water overloaded:
 encouraged to drink lots
 given too much fluids by IV
 Pain gives central ADH stim ( sympa  ADH secretion) and via kidney (
sympa  JGA  renin/RAS  ADH secretion)
 Analgesics (opiates) give central ADH stim
Rapid fall in Na has led to central pontine myelinolysis
 Occurs when dehydrated then overhydrated
 Nerve demylination at pons area (only) occurs
 potentially fatal
 mech not clear; seems to be due to the rapid Na shifts either way across
memb as Na moves in when dehydrated then out when overhydrated
causing the demylination
-
Distinguish between a patient with primary polydipsia (drinking too much from psychiatric
illness) causing polyuria, and a patient with true polyuria from diabetes insipidus.
o Fluid deprivation test: fluid deprive and those with DI will not be able to concentrate
their urine but polydipsic individuals will
o Include hourly weight and urine volume / Na / osmolality:
 Eg polydipsic gives conc urine and maintains weight
 Eg cheating poydypsic would give dilute urine instead of concentrated but
would not lose weight!
o Note that no treatments are really available to help vs nephrogenic DI in terms of
cure; can only give thiazide diuretics
-
Cholera
-
How does cholera cause diarrhoea?
 Bacteria which releases a toxin that binds irreversibly to small bowel
epithelium.
 Toxin taken up into cells and stimulates cAMP production.
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GE Y1 Renal


-
-
-
-
Inhibits absorption of NaCl in villus cells,
stimulates chloride secretion in crypt cells
leading to massive loss of isotonic electrolyte solution.
 Improves in a few days as gut replenishes and bacteria are lost but must
maintain hydration of patients: water, NaCl until infection passes
Why do people die from dehydration? What actually kills them?
 Intravascular water loss  hypovolaemia  loss of perfusion to major
organs
 Concentrated intravascular solution dehydrates cells: shrink and contract
 Loss of perfusion to muscles increases lactic acid production  acidotic:
enzymes do not work
 Brain shrinks: attached to the inside of the skull stretches  venous sinus
bleeding
Why do patients with dehydration sometimes get renal failure?
 Blood pressure falls reducing blood flow to the kidneys and hence their
ability to function. Recovers with hydration, but over too long will lead to
ATN / RF
A 21 year old woman has become tired and lethargic and gone to her GP. She is found to
have a BP of 110/60 and weighs 50 Kg. She has weak muscles globally (due to low
potassium).
Some investigations show:
Serum Na
Serum K
Serum Urea
138 mmol/l [normal]
2.2 mmol/l [low]
10 mmol/l [high]
-
How would you decide if she was intravascular volume depleted?; BP is low but may be
normal for her!:
o Test for postural hypotension. If volume depleted will not be able to compensate
when stands vasoconstriction is maximally activated
o look for weak pulse but tachy
o look for low JVP
o Skin turgor [Decreased skin turgor/elasticity is a late sign in dehydration]
o dry mouth
-
Possible causes of this scenario:
o Diuretic abuse fits perfectly; look for diauretic presence in urine
o Possibly vomiting (e.g. bulimia)
 potassium wouldn’t likely drop so much but is possible due to alkylosis
giving H+ movement out of cells in exchange for K+ and dehydration giving
RAS stim for inc Na retention at cost of K+ at kidney via aldosterone
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o
o
o
Not Conn’s [aldosterone-producing adenoma]: causes hypokalaemia but
hypertension not hypotension!
Not Simmond’s syndrome = Sheehan syndrome: pituitary infarct;
panhypopituitarism; would not be walking into the GP
Severe diarrhoea; This can cause either a metabolic acidosis or a metabolic alkalosis:
 Metabolic acidosis tends to be associated with acute infective diarrhoea eg
cholera. The problem is an excessive loss of bicarbonate in the diarrhoeal
fluid.
 Diarrhoeas which are caused by predominantly colonic pathology may cause
a metabolic alkalosis: this includes chronic diarrhoeas due to ulcerative
colitis, colonic Crohn’s disease and chronic laxative abuse.
[ie these latter examples could be the solution due to alkylosis giving H+
movement out of cells in exchange for K+ and dehydration giving RAS stim
for inc Na retention at cost of K+ at kidney via aldosterone]
nb
-
Bulimia: vomiting
Anorexia: not eating
-
Irbesartan is an angiotensin receptor blocker
Losartan is an angiotensin receptor blocker
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13/02/14: Overview of kidney function and dysfunction
with respect to learning objectives of the course Dr Damien
Ashby
Los (from slides/booklet):
Notes:
See requested slides to practice with
-
-
-
-
Steroid drugs  adrenals stop making steroids so if drug removed will get addison’s (low
aldosterone) etc
Septic shock  low BP  low flow causing lactic acidosis
Nb Ti/Tii RF as possible causes of electrolyte imbalances
Pulmonary embolism does not show up on CXR esp if acute
o Gives cough and chest pain
o Gives type I resp failure  hyperventilation  acute resp alkylosis
o [nb there are many other causes for hyperventilation than anxiety!]
Too high heparin/warfarin can give blood in stools (nb they are cleared renally so RF  high
circ conc  blood in stools!]
Renovascular disease = renal artery stenosis:
o lack of bloodflow will cause the kidney to shrink
o the kidney will activate RAS dueto its low blood flow!
RRT = renal replacement therapy = dialysis of transplantation
RF gives nausea due to electrolyte imbalance / toxin buildup  loss of appetite  may then
explain further disruptions
Cachexia (wasting syndrome) is long term result of anorexia
“BM” = blood glucose test! (was just the name of the company making the tests)
Normal anion gap <12; abnormal if lactate / ketones etc
o = ([Na+] + [K+]) − ([Cl−] + [HCO3−])
Reasons for normal anion gap but metabolic acidosis:
o Surgical urinary diversion to gut (urine Cl absorbed in bowel  excrete HCO3 to
compensate  acidosis) (creat low)
o RF (creat high)
o Overcompensated Na replacement (consider if known Dr input)
Renal cysts show on Xray; are benign
Calyces shrink and contract through time randomly; benign; seen on x ray
Hyperkalemia: bradycardia, flat p waves, broad QRS, tall T waves
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28/02/14: CONTROL OF CALCIUM AND PHOSPHATE:
VITAMIN D, PTH AND THE KIDNEY: Prof Karim Meeran
Los (from Booklet):
All of the below:
1. Predict the consequences of loss of endocrine functions of the kidney
2. Control of calcium and phosphate: vitamin D, PTH and the kidney
mportance of a fixed calcium level on nerve and muscle function
ocalcaemia
*Please note that this topic can be examined in either
exam, as it forms part of both the Renal course and the
Pathology course.
Notes: [nb netters images/book may be useful]
-
Vitamin D:
o Animal products / supplements / from our skin: Vitamin D3 cholecalciferol;
 not hydroxylated at 1 or 25 position; only at inherent 3 position
o Plant products / supplements: Vitamin D2 ergocalciferol;
 not hydroxylated at 1 or 25 position; only at inherent 3 position
o 25 – vit D
 Generated by vit D - 25 hydroxylase in the liver
 100% of any absorbed vitamin D from gut is hydroxylated
 This is the stored and measured form of vitamin D
o 1,25 – vit D
 Generated by 1 alpha hydroxylase in kidney
 Rarely, this enzyme can be expressed in lung cells of sarcoid tissue
 Called calcitriol as now has three OH groups
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Calcium:
o Parathyroid hormone
 when calcium low, PTH rises.
 PTH causes:
 movement of calcium from bone  increased calcium
 activation of renal 1 alpha hydroxylase  increased calcium via vit D
o this is the rate determining step in activation of vit D and
therefore is the step that needs to be regulated
o Causes of hypercalcaemia
 Primary hyperparathyroidism (ie high PTH giving high Calcium in the
plasma):
 Bones: pain / fractures
 Extra calcium gets stuck in kidneys  nephrocalcinosis and Kidney
stones
 Causes psychiatric symptoms ie moans
 Causes abdominal pain and constipation ie groans
 Cancer with bone metastases
 Distinguish from primary hyperparathyroidism by PTH level; cf
 Overactive active vitamin D production
 Eg due to sarcoidosis:
o A disease involving abnormal collections of inflammatory
cells (granulomas) that can form as nodules in multiple
organs.
o Frequently causes an increase in vitamin D production
outside the kidney, namely inside the immune cells found in
the granulomas the condition produces
 Check vitD level
o Investigations of high calcium
 Serum calcium
 Serum PTH (high or normal suggest hyperparathyroidism; Low PTH suggests
cancer)
 Vitamin D levels
 CXR (sarcoidosis; ie frequently causes an increase in vitamin D production
outside the kidney, namely inside the immune cells found in the granulomas
the condition produces)
o Hypoparathyroidism:
 Eg no parathyroid glands
 Give calcitriol to allow gut Ca uptake but must also give Ca supplements as
will still not get the physiological release of Ca from bones that occurs in
normal person
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o
CLINICAL SIGNS of a low calcium
 [Chronic calcium deficiency results in loss of calcium from bone in order to
maintain circulating calcium]
 Trousseau’s sign (~ carpopedal spasm)
 Chvostek’s sigh
 Convulsions
 Laryngeal spasm
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Metabolic bone disease (don’t confuse these with osteoarthritis):
o Osteoporosis [= things that will affect all aspects of bone (so not vit D deficiency!!)]
 Normal serum calcium and phosphate and PTH, ALP may be raised esp if one
of the sudden causes
 Bone slowly lost after age 20
 Residual bone normal in structure; is just loss of bone mass ie the bones just
become thinner (bone loss but with a normal calcium)
 Causes of osteoporosis:
 Bed bound
 Space: weightlessness
 Low testosterone / oestrogen for any reason (inc Menopause)
 Hyperthyroidism
 Cushing’s
 Malnutrition
 Old age
 Cirrhosis (due to the harmful effects of substances such as bilirubin
and bile acids or the toxic effect of alcohol or iron on osteoblasts)
 Ketoacidosis (the acidosis thins the bones)
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o
Osteomalacia = secondary hyperparathyroidism (“due to low vit D or diet / preg /
other tumours(!)”)
 Bone is demineralized; ie Ca:protein ratio in bone will decrease
 Low serum calcium and phosphate
 Caused by lack of Ca:
 Diet:
o Lack of Ca in diet
 vitamin D deficiency giving failure to gain Ca from diet:
o Renal failure; hydroxylation function lost
o Anticonvulsants induce breakdown of vitamin D
o Lack of sunlight
o Chappatis (phytic acid); in Asian diet, chelates vit D in gut

Pregnancy:
o
PTHrP: Physiological role at bone is in causing sacrifice of
mother’s bone via paracrine mech to provide Ca for building
child skeleton during pregnancy

Case history:
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



Low calcium, low phosphate
High PTH
High alkaline phosphatase (a marker of bone breakdown/turnover;
is generated in osteoblasts)
= OSTEOMALACIA!
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o
Paget’s disease
 Bone has increased turnover
 ie Increased osteoblasts (synth) and osteoclasts (deg)
 ie high breakdown and high synth; initially is net thinning then net
thickening
 Bone pain
 High alkaline phosphatase
 Normal serum calcium and phosphate and PTH
 Case history:
 Very high alkaline phosphatase and bone pain
 = Paget’s disease!
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26/03/14: Renal causes of hypertension: Dr Peter Hill
Los (from Booklet):

Lecture 9: Renal causes of hypertension
Dr Peter Hill (peter.hill4@nhs.net)
rtension
Notes:
-
Nb the majority of studies have reported a higher prevalence and significantly higher mean
blood pressure levels among both Afro-Caribbean populations
-
Hypertension is a risk factor for:
o Stroke
o Cardiovascular Disease [ie MI / angina]
o Heart Failure
o Left Ventricular Hypertrophy
-
Clinical values:
o OPTIMAL
 120/80 or less
o NORMAL
 120-129/80-84
o HIGH NORMAL
 130-139/85-89
o HYPTENSION
 140+/90+
 Nb diurnal variation in BP is lost in hypertension too
-
Primary vs Secondary hypertension:
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o
o
Primary = essential hypertension = no specific individual cause
 The vast majority of cases
 Contributing factors:
 – Familial
 – overweight
 – Increased salt intake
 – high alcohol intake
 – black population.
Secondary = Hypertension with a discernable cause
 Secondary causes:
 Renal [reduced filtration/excretion will give hypertension]
o – Intrinsic Renal disease eg Glomerulonephritis
o – Chronic kidney disease
o NB ACEi/ARB CAN be used in these patients: these drugs
help by giving just a small drop in GFR (ie in this situation
the GFR is not highly reliant on RAS system) thereby
reducing the workload on the kidneys and therefore helping
avoid ischaemic effects by reducing oxygen demands
 Renovascular Disease = RAS [gives hypertension due to RAAS
activation]
o Renal Bruit on auscultation
 bruit ("rushing" sound) on affected side due to renal
artery stenosis
o Creatinine rise after starting ACEi or ARB: DO NOT USE
THESE IN THESE PATIENTS: use CCBs or stent the RAS
o Unequal sized kidneys: kidney with RAS is smaller
o RAS caused by:
 Atherosclerosis
 May be widespread through body or just at
renal artery
 Often associated with peripheral vascular
disease (PVD): obstruction of large arteries
not within the coronary, aortic arch
vasculature, or brain.
 Fibromuscular dysplasia
 Affects young women
 non-atherosclerotic, non-inflammatory
vascular disease that causes abnormal
growth within the wall of an artery; tight
loops of vessel obstruct flow
 Can affect any arterial bed: here are
referring to renal artery effects
 Causes hypertension, transient ischemic
attack and stroke
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




-
Hypertension
 Via smooth muscle hypertrophy (nb
myogenic theory)
o Doesn’t just cause hypertension: Ischaemic Atrophy or
Ischaemic glomerulopathy of the kidneys
Vascular Disease
o – Coarctation: ie narrowing of arteries in peripheral
vasculature to give increase to blood pressure
Endocrine causes
o – Cushings disease
o – Conn’s syndrome/ Hyperaldosteronism
 Low Potassium, high sodium values
 Sudden onset pulmonary oedema due to the water
retention]
o – Phaeochromocytoma
Drugs
o – Alcohol
o – Nasal decongestant (adrenaline is active agent)
o – Cocaine
o – OCP
o – NSAIDS
o – Corticosteroids
Sleep Apnoea  hypertension
o Thought to be due to nocturnal hypoxia or hypercapnia
provoking responses to give daytime hypertension
Imaging modalities to investigate renovascular hypertension:
o Digital subtraction angiography: is Xray and contrast based
o Magnetic Resonance Angiography: is MRI
 Gadolinium contrast:
 Gives toxicity if patient has renal failure; ie poor clearance gives
Nephrogenic systemic fibrosis (NSF), also known as nephrogenic
fibrosing dermopathy (NFD) [is a disease of fibrosis of the skin and
internal organs caused by gadolinium exposure]
 Can’t see Fibromuscular Dysplasia very well
o CT Angiography
 Not as good as Magnetic Resonance Angiography: Less good resolution
 Very good at picking up fibromuscular dysplasia
o Doppler Ultrasound
 Compare systolic velocities in aorta and renal artery
o Captopril Renogram
 Use a maker of glomerular filtration
 Compare images before and after captopril (an ACEi): in renal artery stenosis
see fall in GFR in stenosed kidney due to its dependence on the RAS system
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Hypertension treatments: [secondary has lower NICE target BP than does essential
hypertension]
o Life Style changes:
 Weight loss
 Regular exercise
 Avoidance of excess alcohol
 salt
 smoking
 caffeine
o Drugs:
 Young (<55yrs)
 ACEi/ARB is first line
 Older (>55yrs) or afro-Caribbean
 CCB or thiazide is first line
 BUT NOT ABLE TO USE ACEi/ARB IF RENAL ARTERY STENOSIS
 Alpha blockers (doxazocin) if urinary symptoms [will aid relaxation of the
bladder as well as drop the BP]
o Surgery:
 Angioplasty alone / Angioplasty with sten>ng
 Eg if treatment not working
 Eg if malignant hypertension (eg haemorrages being caused in eyes or brain)
 Eg if want to be able to use ACEi to treat another disease
 Eg effective at straightening the loops of Fibromuscular dysplasia
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26/03/14: Erythropoeitin: Dr Peter Hill
Los (from Booklet):

Lecture 10: Erythropoeitin
Dr Peter Hill (peter.hill4@nhs.net)
understand the consequences of dysregulation of the HIF axis
Notes:
-
HIF = Hypoxia Inducible Factor
o Is a transcription factor
o EPO gene HRE = hypoxic response element binds HIF to upregulate EPO
o Is constitutionally expressed but is inactivated in normoxia due to the presence of
O2 AND Fe allowing hydroxylation  which gives ubiquitination  which gives
degradation of the HIF
o Effects:
 Angiogenesis / Vascular endothelial growth
 VEGF, iNOS, HO-1
 pH regulation
 Carbonic anhydrase production [ie prob to counter any acidity]
 Cell Proliferation, differentiation & Viability
 IGF-2
 TGF-β3
 Blood Cell Production
 EPO
 Iron metabolism
 Transferrin production [is a iron-binding blood plasma glycoprotein]
 Glucose metabolism
 Glucose Transporters
 Glycolytic Enzymes
o Pathology: ALL THESE GIVE INC ERYTHROCYTOSIS
 Loss of HIF Hydroxylase enzyme leads to increased erythrocytosis [“Chuvash
Polycythaemia”]
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

-
EPO
o
o
o
Mutation in HIF2 alpha subunit gives increased erythrocytosis with
pulmonary hypertension
von Hippel Lindau Syndrome: failure of the degradation pathway: result is a
cancer syndrome predisposing to a variety of malignant and benign tumors
of the eye, brain, spinal cord, kidney, pancreas, and adrenal glands
Is a glycoprotein growth factor with Fe cofactor
Produced in the kidney (>90%) and liver (<10%)
 Made by fibroblasts in kidney
 produced by interstitial fibroblasts in the kidney in close
association with peritubular capillary and tubular epithelial tubule
= from Juxtatubular Interstitial Cells = from extraglomerular
mesangial cells
 Made by stellate cells in the liver
Stimulates erythropoiesis:
 Acts via JAK / STAT signalling at erythropoietin receptor (EpoR)
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
o
o
o
o
Promotes red blood cell survival by protecting immature RBC cells from
apoptosis.
 EPO uses iron as a co‐factor so need to ensure adequate stores: nb renal
pateints have poor storage capacity of Fe so must really iron overload them
Other effects:
 vasoconstriction and hypertension
 stimulating angiogenesis
 proliferation of smooth muscle fibers
EPO synth is stimulated by renal hypoxia: Anaemia stimulates EPO production by
acting as a hypoxic stimulus
Kidney is a relatively hypoxic environment making it ideal to be the regulator of EPO
level
Clinical use:
 Has replaced transfusions as a means of maintaining RBC / Hb level in
dialysis patients [ie renal patients that are not making the EPO themselves
so will have low RBC / Hb]
 Transfusions gave viral diseases such as Hepatitis B, decreased
transplant success due to sensitisation of the patient to possible
kidney transplants and Iron Overload Syndromes
o However is useful to give EPO immediately with a new
transplant to help protect against ischaemic injury
 Slows progression of renal failure: prob via countering renal hypoxia
without giving inc workload of increase Fe clearance requirement
 In fact EPO varients are often used instead called ESA’s =
erythropoiesis stimulating agents, which act for longer period at
the EPO receptor: eg Darbepoeitin, Micera
 Note that less drug used than would give normalisation because has
been shown to give increase CVD / stroke risk though the exact
mechanism is not clear
 Use in cancer:
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

Cancer patients often have low RBC levels but use of EPO in such
cases has been shown to enhance the oncogenic progression in the
body
Unwanted events:
 ESA use can stimulate the production of antibodies vs the EPO
receptor thereby making the patient transfusion dependant for new
RBC source
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Tutorial notes:
-
EMQ ans: Countercurrent in loop of henle has steep longitudinal gradient and shallow
transverse gradient
-
Kidney is NOT erythropoietic!
ADH acts at collecting duct not DCT
UTA1 protein performs the urea reabsorbtion at collecting duct in response to ADH
- Na2ClK cotransporter is secondary active transport
-
-
-
ADH and oxytocin differ by 2x AA
Lack of FVIII gives haemophillia A therefore can give people ADH to help stimulate FVIII
production
Nb if there is an “all of the above” option then if two of the others are true then that MUST
be the correct answer regardless of the other options
THIAZIDES HAVE A VASODILATION EFFECT; IS ARGUEABLY MORE IMPORTANT THAN THEIR
EFFECT ON REDUCING SALT REUPTAKE IN LOWERING BLOOD PRESSURE
K+ sparing diuretics have diuretic effect but key action is in inducing hyperkalemia to help
counter effect of coadministered diurectics
Loop diuretics give hypocalcaemia
Differentials (all some similarities): DM vs diuretic vs lithium poisoning vs primary polydipsia
vs DI
Kf is the rate constant for the GFR equation: is affected by:
o Surface area at glomerulus
o Integrity of glomerulus
o The negative charge of albumin in blood (esp for cations)
Adenosine vasoconstricts the afferent arteriole via A1 receptors in response to macula densa
sensing high Na in tubules
Causes of glomerulonephritis:
o SLE
o Goodpasture’s
o Streptococcal infection leading to macrophage activation at kidney
o Berger’s disease = “IgA nephropathy”
 deposition of the IgA antibody in the glomerulus
o UTI
o Alport
Fanconi’s syndrome
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o
-
-
-
-
-
Disturbance of PCT function (glucose, amino acids, bicarbonate etc are passed into
the urine)
o Will present with hypokalemia (prob due to changed electrochem gradient)
Bartter syndrome
o Autosomal recessive
o Na2ClK cotransporter is mutated
o Hypokalemia and alkylosis will result with risk of hypotension
Addisons
o Low Na high K
Liddle’s Syndrome
o Activating ENaC mutation
o Hypertension is the result
o Nb ENaC = epithelial sodium channel upregulated by aldosterone and inhibited by
amiloride
Conn’s
o Primary hyperaldosteronism
o High Na, low K, low renin
RAS
o Secondary hyperaldosteronism
o High Na, low K, high renin
Alport
o A renal disease that is associated with deafness
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Constanzo notes:
-
the cells of the proximal convoluted tubule are unique in having an extensive development
of microvilli, called a brush border, on their luminal side.
-
The superficial cortical nephrons have their glomeruli in the outer cortex. These nephrons
have relatively short loops of Henle, which descend only into the outer medulla. The
juxtamedullary nephrons have their glomeruli near the corticomedullary border.
The glomeruli of the juxtamedullary nephrons are larger than those of the superficial
cortical nephrons and, accordingly, have higher glomerular filtration rates. The
juxtamedullary nephrons are characterized by long loops of Henle that descend deep into
the inner medulla and papilla and are essential for the concentration of urine.
renal artery  segmental arteries  interlobar arteries  arcuate arteries  interlobular
arteries  the first set of arterioles, the afferent arterioles  the first capillary network, the
glomerular capillaries, ultrafiltration occurs  second set of arterioles, the efferent
arterioles,  peritubular capillaries, (mainly juxtamedullary nephrons: vasa recta present:
solutes and water are reabsorbed, a few solutes are secreted), (mainly superficial cortical
nephrons: kidney epithelial cells are supplied with blood)  small veins  renal vein.
-
-
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Water accounts for 60% of body weight
Approximately two-thirds of total body water is in the ICF, and about one-third is in the ECF
(plasma + interstitial fluid).
60% of body weight is water, 40% of body weight is ICF, and 20% of body weight is ECF.
The percent of blood volume occupied by red blood cells is called the hematocrit, which
averages 0.45 or 45% and is higher in males (0.48) than in females (0.42).
volumes of the body fluid compartments are measured by the dilution method:
o mannitol cannot cross cell membranes, and it will be distributed in ECF but not in
ICF. Thus, mannitol is a marker for ECF volume.
o Isotopic water (e.g., D2O) will be distributed everywhere that water is distributed,
and thus isotopic water is used as a marker for total body water
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The volume of a body fluid compartment:
o Depends on the amount of solute it contains.
o For example, the volume of the ECF is determined by its total Na (and its
accompanying anions which together with it will form NaCl and NaHCO3
The normal value for osmolarity of the body fluids is 290 mOsm/L
Solutes such as NaCl and NaHCO3 and large sugars such as mannitol are assumed to be
confined to the ECF compartment because they do not readily cross cell membranes.
o For example, if a person ingests a large quantity of NaCl, that NaCl will be added
only to the ECF compartment and the total solute content of the ECF will be
increased.
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Disturbances:
o Isosmotic volume contraction
 Diarrhea
 burn
o Hyperosmotic volume contraction = more water lost than salt = hyperosmotic ECF is
left at end = no change to haemocrit
 Sweating
 fever
 diabetes insipidus
o Hypoosmotic volume contraction = less water lost than salt = hypoosmotic ECF is left
at end = ICF will increase!!
 Adrenal insufficiency
o Isosmotic volume expansion
 Infusion of isotonic NaCl
o Hyperosmotic volume expansion
 High NaCl intake
o Hyposmotic volume expansion = no change to haemocrit
 SIADH; For example, if an extra 3 L of water is reabsorbed by the collecting
ducts, 1 L will be added to the ECF and 2 L will be added to the ICF (because
ECF constitutes one-third and ICF constitutes two-thirds of the total body
water).
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Clearance:
o By definition, renal clearance is the volume of plasma completely cleared of a
substance by the kidneys per unit time
o the units of clearance are volume per unit time (e.g., mL/min; L/hour; L/day)
o renal clearance is the ratio of urinary excretion ([U]x * V ) to plasma concentration
(ie have to account for both amount removed but also the amount remaining to
know how many units of volume have been completely cleared by having removed
that volume of the substance):
o
o
renal clearance of albumin is approximately zero because, normally, albumin is not
filtered across the glomerular capillaries
renal clearance of glucose is also zero as Glucose is filtered and then completely
reabsorbed
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o
Inulin, a fructose polymer, is freely filtered across the glomerular capillaries, but it is
neither reabsorbed nor secreted; therefore, its clearance measures the glomerular
filtration rate (GFR).
o
Filtration fraction:
 The filtration fraction is that fraction of the RPF that is filtered across the
glomerular capillaries. The value for the filtration fraction is normally about
0.20, or 20%. That is, 20% of the RPF is filtered, and 80% is not filtered.
o
Net Resorbtion vs net Secretion:
RBF: The kidneys receive about 25% of the cardiac output
o RBF follows Q = ΔP/R.
o The major mechanism for changing blood flow (RBF; eg in response to
haemorrhage) is by changing arteriolar resistance. (nb here are wanting to change
RBF; below will later see autoregulation which keeps RBF constant with
physiological systemic pressure changes)
o Resistance is provided mainly by the arterioles, however, there are two sets of
arterioles, the afferent and the efferent. Therefore in the kidney changing blood
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o
o
o
flow can be accomplished by changing afferent arteriolar resistance and/or efferent
arteriolar resistance
Sympathetic nervous system and circulating catecholamines.
 Both afferent and efferent arterioles are innervated by sympathetic nerve
fibers that produce vasoconstriction by activating a1 receptors.
 However, because there are far more a1 receptors on afferent arterioles,
increased sympathetic nerve activity causes a decrease in both RBF and
GFR.
 Thus, the cardiovascular system will attempt to raise arterial pressure even
at the expense of blood flow to the kidneys.
Angiotensin II.
 Angiotensin II is a potent vasoconstrictor of both afferent and efferent
arterioles.
 However, the efferent arteriole is more sensitive to angiotensin II than the
afferent arteriole
 Low levels of angiotensin II produce an increase in GFR by constricting
efferent arterioles (ie think of as for mild / severe haemorrhage will need to
reduce RBF to send blood elsewhere but want to maintain GFR if possible to
avoid toxicity),
 This protective effect of ATII in maintaining BP and GFR in
haemorrhage is lost in ACEi use so a bleed not only gives low BP to
rest of body but at kidney will get low BP/RBP without
maintenance of a normal GFR
 high levels of angiotensin II produce a decrease in GFR by constricting both
afferent and efferent arterioles (ie just think of as for very serious
haemorrhage will want to lower the GFR to maintain every bit of fluid
possible).
 The juxtaglomerular cells secrete renin in response to:
 Beta-1 adrenergic stimulation
 Decrease in renal perfusion pressure (detected directly by the
granular cells)
 Decrease in NaCl concentration at the macula densa (ie is sensing
the tubule lumen), often due to a decrease in glomerular filtration
rate, resulting in slower filtrate movement through the proximal
tubule and, thus, more time for reabsorption. [here the signalling is
via adenosine which will also give some direct vasoconstriction]
 Gives increased reabsorbtion at the proximal tubule [acts at the Na/H
exchanger]
Prostaglandins.
 Several prostaglandins (e.g., prostaglandin E2 and prostaglandin I2) are
produced locally in the kidneys and cause vasodilation of both afferent and
efferent arterioles.
 The same stimuli that activate the sympathetic nervous system and increase
angiotensin II levels in hemorrhage also activate local renal prostaglandin
production.
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

Thus, prostaglandins modulate the vasoconstriction produced by the
sympathetic nervous system and angiotensin II (Unopposed, this
vasoconstrictioncan cause a profound reduction in RBF, resulting in renal
failure.)
Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit synthesis of
prostaglandins and, therefore, interfere with the protective effects of
prostaglandins on renal function following a hemorrhage.
-
Autoregulation (Renal arterial pressure can vary from 80 to 200 mm Hg, yet RBF will be kept
constant; nb as prev in haemorrhage if drops v low then changes to RBF may need to be
made to save body at cost of kidney)
o Myogenic hypothesis.
 The myogenic hypothesis states that increased arterial pressure stretches
the blood vessels, which causes reflex contraction of smooth muscle in the
blood vessel walls and consequently increased resistance to blood flow
o Tubuloglomerular feedback.
 Tubuloglomerular feedback is also a mechanism for autoregulation
explained as follows: When renal arterial pressure increases, both RBF and
GFR increase.
 The macula densa uses the composition of the tubular fluid as an indicator
of GFR. A large sodium chloride concentration is indicative of an elevated
GFR, while low sodium chloride concentration indicates a depressed GFR.
 Sodium chloride is sensed by the macula densa by an apical Na-K-2Cl
cotransporter. Detection of elevated sodium chloride levels triggers the
basolateral release of ATP from the macula densa cells, causing a drop in
GFR, mediated by constriction of the afferent arteriole.
-
Ultrafiltration: (also neg glycoproteins throughout help to repel proteins)
o Endothelium: no real barrier to filtration
 All but cells can pass through
o Basement membrane:
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o
o
 Proteins cannot pass through
Epithelial cells = podocytes; attached to basement membrane by foot processes:
 Also some prot blocking
Starling equation:
 The oncotic pressure of Bowman’s space, which is analogous to interstitial
fluid, is considered to be zero, since filtration of protein is negligible.
 The only pressure that changes along the afferent arteriole is πGC, the
oncotic pressure of glomerular capillary blood. As fluid is filtered out of the
glomerular capillary, protein is left behind, and the protein concentration
and pGC increase. By the end of the glomerular capillary, pGC has increased
to the point where the net ultrafiltration pressure becomes zero.
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
Causes of low GFR:
 ACEi (see prev)
 Changes in πGC are produced by changes in plasma protein
concentration.
o Thus, increases in plasma protein concentration produce
increases in πGC, which decrease both the net
ultrafiltration pressure and GFR.
o On the other hand, decreases in plasma protein
concentration (e.g., nephrotic syndrome, in which large
amounts of protein are lost in urine) produce decreases in
πGC, which increase both net ultrafiltration pressure and
GFR.
 Changes in PBS can be produced by obstructing urine flow (e.g.,
ureteral stone or constriction of a ureter).
o For example, if the ureter is constricted, urine cannot flow
through that ureter to the bladder, causing urine to back up
in the kidney. Consequently, hydrostatic pressure in the
nephrons will increase as far back as Bowman’s space,
producing an increase in PBS. An increase in PBS decreases
the net ultrafiltration pressure, thereby decreasing GFR.
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Glucose:
- Glucose moves from tubular fluid into the cell on the Na+/glucose cotransporter (called
SGLT; sodium-glucose linked transporter; is secondary active transport) in the luminal
membrane. Two Na ions and one glucose bind to the cotransport protein.
- On the basolateral side GLUT 1 and GLUT 2 mediate the transfer of glucose by facilitated
diffusion
-
-
PAH: EXAMPLE OF SECRETION
o para-aminohippurate
o the substance used to measure RPF.
o PAH is an organic acid that is both filtered across glomerular capillaries and secreted
from peritubular capillary blood into tubular fluid.
Urea: EXAMPLE OF PASSIVE REABSORBTION:
o Urea is freely filtered across the glomerular capillaries, and the concentration in the
initial filtrate is identical to that in blood (i.e., initially, there is no concentration
difference or driving force for urea reabsorption). However, as water is reabsorbed
along the nephron, the urea concentration in tubular fluid increases, creating a
driving force for passive urea reabsorption
o The urea from the collecting duct passively enters the medullary interstial fluid and
diffuses into the loop of henle. As it passes back up the ascending limb of the loop
of henle and reabsorption of other ions occurs the urea becomes even more
concentrated. This recirculation can occur several times and steadily increases urea
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concentration in the medullary tissue until equilibrium is reached. The overall aim of
this recirculation is to excrete a high concentration of urea in very little water.
WEAK ACIDS AND BASES—Example of NON-IONIC DIFFUSION
o Eg salicylic acid (HA) and its conjugate base, salicylate (A)
 At acidic urine pH, HA predominates, there is more “back-diffusion =
resorbtion” from urine into blood, and the excretion (and clearance) of
salicylate is decreased.
 At alkaline urine pH, A- predominates, there is less “back-diffusion =
resorbtion” from urine to blood, and the excretion (and clearance) of
salicylate is increased.
o Ie recall pharma aspirin (salicylic acid is the active metabolite of aspirin) can make
urine alkaline to increase excretion
[ie y axis is just clearance but given per unit GFR here as this would also affect OVR
clearance]
-
Sites of Na reabsorbtion:
o See image below: this is the reason for the potency order being loop>thiazide>K
sparing
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Sites of K+ resorption:
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PROXIMAL CONVOLUTED TUBULE
o PTH inhibits Na/phosphate cotransport [recall from endo notes that PTH inhibits
Na/phosphate cotransport PROXIMAL CONVOLUTED TUBULE: ie at NaPi IIa]
o Angiotensin II stimulates Na-H exchanger on lumen side [ie stimulates Na
reabsorption and H excretion which is coupled to bicarbonate reabsorption]
o Ie as below the Na/H exchanger and HCO3- transport are reflecting carbonic
anhydrase activity on lumen side (to give CO2 passage inside) and CA activity
inside the cell to give H & HCO3- for these transport events
o Note that once Na passes out Cl- will follow via paracellular mech as lumen becomes
more negatively charged; see below pic
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[ie whole carbonic anhydrase system is at early PCT]
-
Thick Ascending Limb
o Note that ADH stimulates Na-K-2Cl cotransport out of tubules but prob is a minor
effect as should be equating ADH effects as movements of H2O only
o loop diuretics
 are anions that attach to the Cl-binding site of the Na -K-2Cl cotransporter
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



-
as on prev diagram loop diauretics will therefore have the capacity to block
up to 25% of Na reabsorption
Na is extruded from the cell by the Na-K ATPase
Cl and K diffuse through channels in the basolateral membrane, down their
respective electrochemical gradients.
Small amount of K recycles back to lumen to make the system electrogenic;
helps drive Ca and K reabsorption further down lumen
Early Distal tubule:
o Is the site of Ca reabsorption stimulated by PTH
o Thiazide diuretics bind to the Cl site of the electroneutral Na –Cl cotransporter
o Cl diffuses through channels in the basolateral membrane
[ie NaCl entry!!]
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Late distal tubule and collecting ducts:
o The principal cells
 are involved in water and urea reabsorption (stimulated by ADH ie at
principal cells)
 are involved in Na reabsorption (stimulated by aldosterone) and K
secretion (stimulated by aldosterone)
 The K permeability and the size of the electrochemical gradient for K
are higher in the luminal membrane; therefore, most of the K
diffuses across the luminal membrane rather than being recycled
across the basolateral membrane into the blood.
 The single most important principle for understanding the factors
that alter K+ secretion is that the magnitude of K secretion is
determined by the size of the electrochemical gradient for K across
the luminal membrane.
 Effect of diet (&visa versa): high K+ diet: The ingested K enters the
cells (aided by the insulin response to a meal) and raises the
electrochemical driving force for K secretion across the luminal
membrane and so the ingested K is excreted into the urine.
 Aldosterone: increases electrochemical gradient to favour K+ exit to
urine via increasing NA/K pump activity
 Acid-base disturbances: alkalosis increases K secretion, and acidosis
decreases K secretion (ie due to the universal H/K exchanger on cells
including at principal cells
 Diuretics: [is by increasing the intracellular K concentration and by
decreasing the luminal K concentration]
o Loop diuretics and thiazide diuretics inhibit Na reabsorption
“upstream” to the site of K secretion (in the thick ascending
limb and in the early distal tubule, respectively), thereby
delivering more Na to the principal cells. When more Na is
delivered to the principal cells, more Na enters the cells
across the luminal membrane, and more Na is extruded
from the cells by the Na-K ATPase. Simultaneously, more K
is pumped into the cells, which increases the intracellular K
concentration and increases the electrochemical driving
force for K secretion.
o A second factor contributing to the increased K secretion is
the increased flow rate produced by these diuretics. When
the flow rate through the late distal tubule and collecting
duct increases, the luminal K concentration is diluted, which
increases the driving force for K secretion.
o Loop diuretics (but not thiazide diuretics) also cause
increased K excretion by inhibiting Na-K-2Cl cotransport
and, as a result, K reabsorption in the thick ascending limb
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
o
Luminal anions. The presence of large anions (e.g., sulfate and
HCO3) in the lumen of the distal tubule and collecting duct increases
K secretion. Such nonreabsorbable anions increase the
electronegativity of the lumen, thereby increasing the
electrochemical driving force for K secretion
 ARE NOT WHRE THIAZIDES ACT
 K–sparing diuretics (ie counter aldosterone K+ loss to compensate for K+
loss caused by diauretics acting elsewhere):
 Amiloride and triamterene bind to the luminal membrane Na
channels and inhibit the aldosterone induced increase in Na
reabsorption.
 Spironolactone (aldosterone-antagonist but can also be classed as a
potassium-sparing diuretic), prevents aldosterone (also is steroidbased) from entering the nucleus of the principal cells
The α-intercalated cells
 are involved in K reabsorption in exchange for H+ in the condition of a low
K diet (prob a minor physiological event)
 at separate transporter the cells are involved in H+ secretion driven by
aldosterone
o
The principal cells:
o
The α-intercalated cells:
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Na regulation:
o Sympathetic nerve activity (inc filtering)
 Sympathetic activity is activated by the baroreceptor mechanism in
response to a decrease in arterial pressure
 Causes:
 vasoconstriction of afferent arterioles and therefore reduced GFR
( inc Na retained)
 increased proximal tubule Na reabsorption due to the slower flow in
the tubules ( inc Na retained)
o Atriopeptin (ANP) [and brain natriuretic peptide (BNP)] (inc filtering)
 ANP is secreted by the atria in response to an increase in ECF volume
 Causes:
 vasodilation of afferent arterioles,
 vasoconstriction of efferent arterioles,
 increased GFR ie greater gross Na/H2O filtered; subsequent
reabsorbtions are just percentages so greater OVR gross losses
 decreased Na reabsorption in the late distal tubule and collecting
ducts (prob due to the reduced RBF giving reduced refreshing of
blood)
o Starling forces in peritubular capillaries (dec reuptake)
 increases in ECF volume dilute πc (ie reduced oncotic pressure) and
therefore inhibit proximal tubule Na reabsorption
o Renin-angiotensin-aldosterone system (dec reuptake)
 Activated in response to decreased arterial pressure
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Potassium regulation:
o Causes of K+ Shift Out of Cells / Hyperkalemia
 Insulin deficiency (due to acidosis and because insulin usually directly stim K
uptake due to having just had meal)
 b2-Adrenergic antagonists (dec K/Na pump action)
 a-Adrenergic agonists (just learn)
 Acidosis / Exercise (H/K exchanger at all cells)
 Cell lysis: K+ is an intracellular ion!
 Hyperosmolarity (ie of ECF)
 If the osmolarity of ECF is increased, water will flow from ICF to ECF
because of the osmotic gradient. As water leaves the cells, the
intracellular K concentration increases, which then drives the
diffusion of K from ICF to ECF.
 (A simpler way of visualizing the mechanism is to think of water flow
from ICF to ECF as “dragging” K with it.)
o Causes of K+ Shift into Cells / Hypokalemia
 Insulin
 b2-Adrenergic agonists (inc K/Na pump action)
 a-Adrenergic antagonists (just learn)
 Alkalosis (H/K exchanger at all cells)
 Hyposmolarity
 Reverse mech to above; water moving into cells will dilute the K+
present there thereby setting up grad for more to move in
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-
Phosphate regulation:
o Only Phos unbound to plasma proteins is ultrafiltrateable
o reabsorption is accomplished by an Na-phosphate cotransporter in the luminal
membrane of the proximal convoluted and straight tubule cells
o The relatively high level of phosphate excretion is physiologically important because
unreabsorbed phosphate serves as a urinary buffer for H+
-
Calcium regulation:
[loop diuretics give risk of hypocalcaemia BUT risk of hypercalcaemia with thiazides!!]
o Only Ca unbound to plasma proteins is ultrafiltrateable
o Ca2 reabsorption is tightly coupled to Na reabsorption in the proximal tubule and
loop of Henle;
 DHTK mech for this but think of as the Na pulling the Ca through with it:
 consequence is that if body / drugs are trying to expel Na at these locations
Ca will be excreted at high levels too
 eg loop diuretics give risk of hypocalcaemia
o Only in the distal tubule is the reabsorption of Na and Ca dissociated:
 ie drugs / physiology act independently on the two ions here: in fact the
reverse relationship exists!: thiazides which INHIBIT Na reuptake will
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
-
STIMULATE Ca reabsorbtion (ie risk of hypercalcaemia with thiazides):
By lowering the sodium concentration within the distal tubule epithelial
cells, thiazides increase the activity of the Na+/Ca2+ antiporter on the
basolateral membrane to transport more Ca2+ into the interstitium.
PTH gives inc Ca reabsorbtion at distal tubule but will not affect Na uptake
Magnesium regulation:
o Main site of reabsorption is the thick ascending limb
o Frusemide will inhibit Mg reabsorption at thick ascending limb
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ANTIDIURETIC HORMONE:
As described in the preceding section, ADH has three actions on the renal tubule [but note
that the hormone does have other effects; see endocrinology for full detail]:
o (1) It increases the water permeability of the principal cells of the late distal tubule
and collecting ducts.
o (2) It increases the activity of the Na-K-2Cl cotransporter of the thick ascending limb,
thereby enhancing countercurrent multiplication and the size of the osmotic
gradients to aid water retention.
o (3) It increases urea permeability in the inner medullary collecting ducts (principal
cells; UT-A1 transporters), enhancing urea recycling and therefore giving greater
urea concentration in urine and eventual excretion in a smaller volume of water
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[nb ADH is acting at V2 receptors]
Summary
- Total body water is distributed between ICF and ECF. As percentages of body weight, 60% is
total body water, 40% is ICF, and 20% is ECF. ECF consists of plasma and interstitial fluid.
Volumes of the body fluid compartments are measured by dilution of marker substances.
-
ECF and ICFosmolarity are always equal in the steady state. When there is a disturbance of
body fluid osmolarity, water shifts across cell membranes to re-establish the equality of ECF
and ICF osmolarity. These shifts produce changes in ECF and ICF volume. Renal clearance is
the volume of plasma cleared of a substance per unit time and is determined by its renal
handling. Substances with the highest clearances are both filtered and secreted. Substances
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with the lowest clearances either are not filtered or are filtered and subsequently
reabsorbed. Inulin is a glomerular marker whose clearance equals the GFR.
-
RBF is autoregulated over a wide range of arterial pressures by changes in the resistance of
the afferent arterioles. Effective RPF is measured by the clearance of PAH, and RBF is
calculated from the RPF.
-
GFR is determined by the permeability of the glomerular capillary barrier (Kf) and the net
ultrafiltration pressure. Net ultrafiltration pressure is the sum of three Starling pressures
across the glomerular capillary: PGC, pGC, and PBS. If any of the Starling pressures change,
net ultrafiltration pressure and GFR are altered.
-
Reabsorption and secretion modify the ultrafiltrate that is produced by glomerular filtration.
The net reabsorption or secretion rate of a substance is the difference between its filtered
load and its excretion rate. Glucose is reabsorbed by a Tm limited process: When the filtered
load of glucose exceeds the Tm, then glucose is excreted in the urine (glucosuria). PAH is
secreted by a Tm-limited process.
-
Na reabsorption is greater than 99% of the filtered load and occurs throughout the nephron.
In the proximal tubule, 67% of the filtered Na is reabsorbed isosmotically with water. In the
early proximal tubule, Na is reabsorbed by Na-glucose cotransport, Na –amino acid
cotransport, and Na-H exchange. In the late proximal tubule, NaCl is reabsorbed. ECF volume
expansion inhibits proximal tubule reabsorption, and ECF volume contraction stimulates it.
In the thick ascending limb of the loop of Henle, a water-impermeable segment, 25% of the
filtered Na is reabsorbed by Na-K-2Cl cotransport. Loop diuretics inhibit the Na-K-2Cl
cotransporter. In the distal tubule and collecting ducts,8%of the filtered Na is reabsorbed. In
the early distal tubule, the mechanism is Na-Cl cotransport, which is inhibited by thiazide
diuretics. In the late distal tubule and collecting ducts, the principal cells have aldosteronedependent Na channels, which are inhibited by K-sparing diuretics.
-
K balance is maintained by shifts of K across cell membranes and by renal regulation. The
renal mechanisms for K balance include filtration, reabsorption in the proximal tubule and
thick ascending limb, and secretion by the principal cells of the late distal tubule and
collecting ducts. Secretion by the principal cells is influenced by dietary K aldosterone, acidbase balance, and flow rate. Under the conditions of low K intake, K is reabsorbed by aintercalated cells of the distal tubule.
-
Body fluid osmolarity is maintained at a constant value by changes in water reabsorption in
the principal cells of the late distal tubule and collecting duct. During water deprivation, ADH
is secreted and acts on the principal cells to increase water reabsorption. During water
drinking, ADH secretion is suppressed, and the principal cells are impermeable to water.
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BONUS info:
-
To investigate diabetes mellitus biopsy: use electron microscopy to look for glomerular
basement membrane (GBM) thickening
o Diabetes causes Glomerulosclerosis: refers to a thickening and hardening (scarring)
of the glomerulus
-
Mesangial cells are specialized smooth muscle cells and are one contributor to control of
GFR
-
Extraglomerular mesangial cells: the fibroblasts that secrete EPO are in amongst these cells
-
the kidney consists of three main layers: the cortex, medulla (together called the
parenchyma) and pelvis
-
imaging is used to investigate pre-renal and post-renal problems but not renal problems
-
renal problems: Light microscopy, electron microscopy and immunohistochemistry are the
three major modalities for investigating renal problems ie post-biopsy
-
to investigate immune complexes: all three modalities can be used but only light microscopy
for larger deposits
-
despite Costanzo diagram K+ is regulated in the distal tubule
-
Total glomerular filtrate is 180 litres per day in a healthy individual
-
In cases of reduced blood pressure local nitric oxide and prostaglandins are released in the
renal arteries to allow maintenance of renal blood flow over a range of blood pressures
-
Gitelman syndrome: This mild disease is caused by inactivation of the sodium chloride cotransporter of the distal convoluted tubule
-
Cells on lumen side of nephrons can be called parietal cells: eg Aldosterone increases
numbers of sodium channels on parietal cells of the cortical collecting duct
-
Acute renal failure:
o
Pre-renal failure and acute tubular necrosis contributes towards >80% of cases of
ARF.
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
o
o
o
Common causes of pre-renal failure (40-70%) include renal hypoperfusion
(Reduction of renal blood flow).
 ATN (10-50%) is the damage to renal tubular cells by immune reactions or
nephrotoxins, for example antibiotics and radiological contrasting agents.
Heart problem is a common trigger via pre renal failure mech:
 Renal hypoperfusion is the leading cause of ARF. commonly caused by
congestive heart failure, cirrhosis and renal artery stenosis.
Pulmonary oedema is a common complication of ARF (prob via failure of excretion
of fluid), and both can be caused by congestive heart failure or sepsis.
Impaired potassium excretion is commonly observed in ARF patients, which leads to
elevated serum potassium level, i.e. hyperkalaemia.
-
Hyperkalaemia: intravenous calcium can be used to correct the condition [think of as giving
Ca to stop the K+ induced bradycardia]
-
Pseudohypoaldosteronism
o
o
is a condition that mimics hypoaldosteronism. However, the condition is due to a
failure of response to aldosterone, and levels of aldosterone are actually elevated,
due to a lack of feedback inhibition.
there are two independent forms of PHA with different inheritance patterns:
 T1: Renal form with autosomal dominant inheritance exhibiting salt loss
mainly from the kidneys  thiazide unresponsive
 T2: multi-system form with autosomal recessive form exhibiting salt loss
from kidney, lung, and sweat and salivary glands  thiazide responsive
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