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Flashcards in Urinary Deck (108):

LO 1.1 Describe the overall functions of the urinary system

The Kidney must:
1. Control volume
2. Control osmolarity
3. Help to control pH
4. Excrete some waste products

It achieves this by filtering a very large amount of ECF. Each litre of ECF is filtered over 10 times a day


LO 1.2 Describe the gross structure of the urinary system in both the male and female

LO 1.3 Describe the anatomical position of the kidneys, the bladder and the prostate

The Kidneys are retroperitoneal organs that sit either side of the spine in the abdominal cavity, roughly at the level of T12-L3. The right kidney usually sits slightly lower than the left due to the position of the liver. The Kidneys have a mobility of ~3cm when you breathe due to their proximity to the diaphragm, and the tops of the kidneys are protected by the 11th and 12th ribs.

The bladder sits right behind the pubic bone in an adult and above it in a child. It distends upwards when it fills with urine.

The prostate sits directly below the bladder. The urethra passes through it, and if the prostate undergoes hypertrophy it can prevent urination.


LO 1.4 Describe the course of the ureters and the relationships in the pelvis to the iliac vessels and uterine vessels, ovary/vas and the urethra in both males and females and the common locations of ureteric stones in patients

The ureters arise from the renal pelvis on the medial aspect of each kidney
Descend towards the bladder on the front of the psoas major muscle (moving laterally to medially).
Cross the pelvic brim near the bifurcation of the iliac arteries (cross anteriorly over the common iliac)
Under the uterine artery/ductus deferens and down the pelvic sidewall to insert in the posterior surface of the bladder.

There are three constricted segments of the ureters, where a kidney stone is likely to cause a blockage (very painful):

The junction of the renal pelvis and the ureter
The point at which the ureters cross the brim of the pelvis (Iliac bifurcation)
Where the ureters pass into the wall of the urinary bladder


LO 1.5 Describe and identify the medulla, cortex, renal pyramids and associated structures within a human kidney

The kidney is surrounded by a fibrous capsule.

Under this capsule is the renal cortex, the outer portion of the kidney. It forms a number of projections (cortical columns) that extend down between the pyramids. It contains the Glomerulus and Bowman’s capsules. Therefore, ultrafiltration takes place in the cortex. It also contains the renal tubules, except for parts of the loop of Henle, which descends into the medulla.

The renal medulla is split into sections, known as pyramids and is hypertonic compared to the filtrate in the nephron. It includes some areas the loop of Henle and the collecting tubule, which are invoked in salt and water balance in the body.

The pyramids empty urine into the minor calyxes. The points at which they do this are the papilla. The minor calyxes surround the apex of the renal pyramids and then join together to form the major calyxes. Urine passing through the calyxes then moves through the renal pelvis into the ureters.


LO 1.6 Describe the renal blood supply

The kidneys receive around 20% of cardiac output.

The renal arteries arise from the side of the abdominal aorta at the level of L1/L2, immediately below the superior mesenteric artery. Due to the position of the aorta and the IVC, the right renal artery is longer than the left.

Supernumerary renal arteries (two or more arteries to a single kidney) are the most common vascular anomaly, occurrence ranging from 25% to 40% of kidneys.

Renal Artery -> Segmental -> Interlobar -> Arcuate -> Interlobular -> Afferent Arteriole -> Glomerulus -> Efferent Arteriole


2.1 Describe and identify the Gross Anatomy of the Kidney

Gross Anatomy of the Kidney
The kidney is surrounded by a fibrous capsule and is organised into two layers, the cortex and the medulla. The cortex contains the renal corpuscles, and the medulla tubules.
Renal blood supply is from the renal artery, a branch off the abdominal aorta. This eventually becomes the glomeruli and the vasa recta, the ‘straight vessels’ that run up and down the medulla (see session 1 notes for detailed blood supply).

Renal Corpuscle (Blood filtering component of the nephron)
Bowman’s Capsule
Proximal Convoluted Tubule
Loop of Henle
Distal Convoluted Tubule


LO 2.2 Describe and identify the ultra-structure of the ureter and its muscle layers

The ureter is a tube running from the renal pelvis to the bladder. It has two layers of muscle, with a third appearing in the lower third

longitudinal - circular - longitudinal

It is lined by transitional epithelium (or urothelium).


LO 3.1 Describe glomerular filtration, tubular reabsorption, secretion; pumps leak systems and the mechanism of Na+ and fluid uptake by the peritubular region

Glomerular Filtration
Blood is supplied to the kidney via the renal artery. The millions of afferent arterioles each deliver blood to a single nephron, and the diameter of each afferent arteriole is slightly greater than the diameter of the associated efferent arteriole. This diameter difference increases the pressure of the blood inside the glomerulus. This increased hydrostatic pressure helps to force the below components out of the blood in the glomerular capillaries. However, only 20% of the delivered blood is actually filtered, 80% exits via the efferent arteriole.

Relatively small particles are filtered (including water, salt, glucose, urea). RBCs and plasma proteins are not filtered, as they are too large. The water and solutes that have been forced out of the glomerular capillaries pass into Bowman’s space and become the glomerular filtrate/ultrafiltrate.

The Filtration Barrier has a size limit for filtration of a molecular weight 5,200 or an effective molecular radius of 1.48nm. And it actively repels negatively charged proteins and so anions (Negative charge) repels and so are more difficult to get through, while cations (Positive charge) allow slightly bigger molecules through. There are three layers that make up the filtration barrier:

Capillary endothelium
Filtrate moves between cells
Filters Water, salts, glucose

Basement Membrane
Acellular gelatinous layer of collagen/glycoproteins
Permeable to small proteins
Glycoproteins (-‘ve charge) repel protein movement

Podocyte Layer
Pseudopodia interdigitate to form filtration slits

Plasma filtration is only due to three physical forces.
Hydrostatic pressure in the capillary (can be regulated)
Hydrostatic pressure in Bowman’s capsule
Osmotic pressure difference between the capillary and tubular lumen
Net filtration pressure = 10mmHg

Tubular Reabsorption
Only about 1% of glomerular filtrate actually leaves the body, the rest is reabsorbed into the blood as it passes through the renal tubules. This process is called tubular reabsorption and occurs via three mechanisms, osmosis, diffusion and active transport. It is called reabsorption and not absorption as these substances have already been absorbed once (particularly in the intestines). Reabsorption in the PCT is isosmotic, and driven by sodium uptake. Other ions accompany sodium to maintain electro-neutrality, e.g. Chloride and Bicarbonate. Solutes move from Tubular lumen -> Intersticium -> Capillaries, and reabsorption can either be transcellular or paracellular (around cells through tight junctions).

Tubular Reabsorption of Na+
Na+ is pumped out of tubular cells across the basolateral membrane by 3Na-2K-ATPase.
Na+ moves across the apical (luminal) membrane down its concentration gradient
This movement of Na+ utilises a membrane transported or channel on the apical membrane.
Water moves down the osmotic gradient created by the reabsorption of Na+

Secretion provides a second route, other than glomerular filtration, for solutes to enter the tubular fluid. This is useful as only 20% of plasma is filtered each time the blood passes through the kidney. It also helps to maintain blood pH (7.38 – 7.42). The substances secreted into the tubular fluid are:
o Protons (H+)
o Potassium (K+)
o Ammonium ions (NH¬4+)
o Creatinine
o Urea
o Some hormones
o Some drugs (e.g. penicillin)

Model for Organic Cation (OC+) Secretion in the PCT
Mediated diffusion across the basolateral membrane down favourable concentration and electrical gradients, created by the Na-2K-ATPase pump allows entry by passive carrier
H+/OC+ exchanger that is driven by the H+ gradient created by the Na+/H+ Anti-porter. Causes secretion into the lumen


LO 3.2 Describe the role of active transport and co-transport in tubular reabsorption and secretion and give the Na+ channels in each section of the tubule.

Different segments of the tubule have different types of Na+ transporters and channels in the apical membrane. This allows Na+ to be the driving force for reabsorption, using the concentration gradient set up by 3Na-2K-ATPase (active transport).

Proximal Tubule:
Na-H Antiporter
Na-Glucose Symporter (SGLUT)

Loop of Henle:
Na-K 2Cl Symporter

Early Distal Tubule:
Na-Cl Symporter

Late Distal Tubule and Collecting Duct:
ENaC (Epithelial Na-Cl)


LO 3.4 Describe how the kidney handles organic substances such as glucose, amino acids and soluble vitamins

Na+ travels down its concentration gradient set up by 3Na-2K-ATPase from the tubule lumen into the Intersticium. In many cases this occurs with the help of Symporter. This is the mechanism through which the body reabsorbs glucose, amino acids, water-soluble vitamins (B,C) lactate acetate, ketones and other Krebs cycle intermediates. These then move on through cells via diffusion and/or other transport processes.

Glucose Reabsorption
Glucose is reabsorbed in the PCT using the Na-Glucose Symporter SGLUT. This moves glucose against its concentration gradient into the tubule cells. Glucose then moves out of the tubule cell on the basolateral side by facilitated diffusion. 100% of glucose is normally reabsorbed, but the system has a maximum capacity, or Transport Maximum (Tm). If the plasma concentration exceeds Tm, the rest spills over into the urine. If this happens, water follows into the urine, causing frequent urination (polyuria). The renal threshold for glucose is 200mg/100ml.


LO 3.5 Describe the concept of and be able to calculate clearance

The volume of plasma from which a substance (X) can be completely cleared to the urine per unit time. The renal artery is the input to the kidney and the kidney has two possible outputs, the renal vein and the ureter. Therefore, if a substance is not metabolised or synthesised, an equal amount must leave in the urine and the renal venous blood.

Clearance can be calculated with the equation:
Clearance=(Amount in urine × Urine flow rate)/(Arterial Plasma Concentration)

E.g. Substance X is present in the urine at a concentration of 100mg/ml. The urine flow rate is 1ml/min. The excretion rate of substance X is therefore:
Excretion rate = 100mg/ml x 1ml/min = 100mg/min
If Substance X was present in the plasma at a concentration of 1mg/ml then its clearance would be:
Clearance=100/1=100 ml per min
100ml of plasma would be completely cleared of substance X per minute.


LO 3.6 Describe basic renal processes including renal blood flow and GFR

GFR is a measure of the kidney’s ability to filter a substance, thus overall function. It is an indication of how well the kidney works and is therefore useful in clinical practise, as a fall in GFR generally means kidney disease is progressing and vice versa.

GFR=(Amount of X in urine × Urine flow rate)/(Arterial Plasma Concentration of X)
X must be a non secreted and non reabsorbed substance (e.g. inulin), however creatinine is the common and close to this requirement but not exact.

Normal GFR for Men = 120 ml/min
Normal GFR for Women = 100 ml/min

Renal blood flow = 1100ml/min
Renal plasma flow = 605ml/min (only 55% of blood is plasma, the rest is RBC)
Filtration fraction = 125ml/min (Only 20% of all plasma is filtered)


LO 3.7 Describe the regulation of renal blood flow and GFR

Auto-regulatory mechanisms keep the GFR within normal limits when arterial BP is within physiological limit because smooth muscle will try to mainatin its lumen size.

Myogenic Response
Arterial BP rises -> Afferent Arteriole Constriction
Arterial BP falls -> Afferent Arteriole Dilation

Tubular Glomerular Feedback
Changes in tubular flow rate as a result of changes in GFR change the amount of NaCl that reaches the distal tubule. Macula densa cells respond to these changes.
If NaCl increases then Adenosine released, causes vasoconstriction of afferent arteriole causing GFR to decrease
If NaCl decreases then Prostaglandins released causing vasodilation of afferent arteriole causing GFR to increase


LO 3.8 Discuss aminoaciduria

There are two types of Aminoaciduria

General Overflow Aminoaciduria
All AA’s present in the urine. This is normally due to inadequate deamination in the liver, or an increased GFR. It is often seen in early pregnancy.

Specific Overflow Aminoaciduria
Only a specific AA is present in the urine. This is usually due to a genetic inability to break down one AA, e.g. phenylalanine in PKU (lack of phenylalanine hydroxylase).

Stone Formation
Renal aminoaciduria is mainly confined to the dibasic acids, and it due to a genetically determined lack of the specific transport protein(s). For some reason cysteine is an abnormally insoluble amino acid, especially in acidic urine, and cystinuria may be associated with stone formation.


LO 4.1 Describe fluid compartments and their electrolyte compositions

The water in the body is located in two compartments, the Intracellular Fluid (ICF) and the Extracellular Fluid (ECF). They are separated by the cell membrane.

The volumes of the compartments are tightly regulated by their ionic compositions and osmosis. For example the ECF volume, which includes the vascular system, is determined largely by the concentration of NaCl. By regulating the excretion of NaCl the kidney can maintain the ECF’s volume within a very narrow margin.


LO 4.2 Describe how the kidney handles sodium in order to change ECF volume

The kidneys must balance the amount of Na+ excretion with ingestion. This matching process is known as sodium balance.

ECF Expansion
If Na+ excretion is less than intake (patient is in positive balance), it is retained in the bodily – primarily in the ECF. Water is drawn out of the nephron causing a corresponding increase in volume. Blood volume and arterial pressure increases, and oedema may follow.

ECF Contraction
If Na+ excretion is greater than intake (patient is in negative balance), the Na+ content of the ECF decreases. Less water is drawn out of the nephron, so ECF volume decreases, as does blood volume and arterial pressure.

ECF Osmolarity does not change in this process as water is always following the Na+


LO 4.3 Describe the handling of sodium in the PCT

100% of Na+ is filtered in the glomerulus, and 67% is reabsorbed in the PCT.

This is a proportion of Na+ that is always reabsorbed, regardless of the actual amount that is filtered (Glomerular Tubular Balance). Autoregulation prevents the GFR from changing too much, but if any changes occurs despite this Glomerular Tubular Balance blunts the Na+ excretion response. Na+ reabsorption is mainly active, driven by 3Na-2K-ATPase pumps on the basolateral membrane. Different segments of the tubule have different types of Na+ transporters and channels in the apical membrane.

Section 1 – Na+ Reabsorption
o Co-Transported with glucose
o Na-H exchange
o Co-transport with AA/Carboxylic Acids
o Co-transport with phosphate ([PTH])
o Aquaporin
o  [Urea/Cl-] down S1
o Increased Conc. Gradient for Cl- reabsorption in S2/3

Section 2/3 – Na+ and Water Reabsorption
o Na-H exchanger

S2/3 also has:
o Paracelluar Cl- reabsorption
o Transcellular Cl- reabsorption
o Aquaporin

This sets up an ~4mOsmol gradient favouring water uptake from the lumen.


LO 4.4 Describe isosmotic reabsorption as a hallmark of the PCT

The PCT is highly water permeable and so this allows reabsorption to be isosmotic with plasma.

The reabsorption of water is driven by:
o Osmotic gradient established by solute reabsorption
o Hydrostatic force in Interstitium
o Oncotic force in the peritubular capillary due to the loss of 20% filtrate at the glomerulus, but cells and proteins remained in the blood.


LO 4.5 Describe Glomerulotubular (GT) balance and the effect of ECF volume

Glomerulotubular balance is the balance between Glomerular Filtration Rate and the rate of reabsorption of a certain solute. It must be kept as constant as possible, so if GFR increases, the rate of reabsorption must also increase. For example 67% of Na+ is always reabsorbed in the PCT regardless of GFR

If ECF volume increases, cardiac output will increase causing an increase in arterial blood pressure. This in turn will increase GFR thus balancing the change.


LO 4.6 Describe sodium reabsorption in the loop of Henle

In the loop of Henle, the reabsorption of solute and water is separated and so it is known as the diluting segment (Dilutes the NaCl in the filtrate). Descending limb reabsorbs water but not NaCl while the Ascending limb reabsorbs NaCl but not water. Tubule fluid leaving the loop is therefore hypo-osmotic (more dilute) compared to plasma

Thin Descending Limb
The increase in intracellular concentrations of Na+ set up by the PCT allows for paracellular reuptake of water from the descending limb (No tight junctions). This concentrates the Na+ and Cl- in the lumen of the descending limb, ready for active transport in the ascending limb.

The thin Ascending Limb
Impermeable to water (tight junctions, not loose junctions)

Thick Ascending Limb (TAL)
NaCl is transported from the lumen into cells by NaKCC2 channel.
Na+ then moves into the Intersticium due to the action of 3Na-2K-ATPase.
K+ ions diffuse back into the lumen via ROMK
Cl- ions move into the Intersticium

This region uses more energy than any other region of the nephron, and is particularly sensitive to hypoxia.. It is also the target of loop diuretics (NaKCC2). which can lead to Increased loss of K+ in the urine and thus hypokalaemia.


LO 4.7 Describe sodium uptake by the early and late distal tubule

Distal Convoluted Tubule
Water permeability in the early DCT is fairly low, and the active reabsorption of Na+ results in dilution of the filtrate. This further dilution means the fluid that leaves is more hypo-osmotic than when it enters. Hypo-osmotic fluid enters from the loop and ~5-8% of Na+ is actively transported by the NaCC transporter, driven by 3Na-2K-ATPase.
The DCT is also a major site of calcium reabsorption via PTH. The NCC transporter is sensitive to Thiazide Diuretics.

The late DCT and Collecting Duct
This is the region responsible for fine-tuning the filtrate. It is able to respond to a variety of stimulants, and has two distinct cell types:

Principal Cells make up 70% of CD cells and reabsorb Na+ by Epithelial Na+ Channel (ENaC) that are driven by 3Na-2K-ATPase. They produce a luminal charge which is used for for paracellular Cl- reabsorption and K+ secretion into the lumen. They have a variable water uptake through Aquaporin which is dependent on ADH and have a more distinct membrane than Intercalated cells

Intercalated Cells actively reabsorb Chloride and secrete H+ ions or HCO3-


LO 4.8 Describe how hormones, sympathetic nerves, dopamine and Starling forces regulate NaCl reabsorption and thus blood pressure

There are five neurohormonal factors controlling blood pressure. These factors all work in part by controlling sodium balance and ECF volume ( increased Na+ reabsorption, inreasing BP).

1)Renin-angiotensin-aldosterone system

2)Sympathetic nervous system
Vasoconstriction by α1-adrenoceptors
Inc. force/rate of heart contraction β1-adrenoceptors

3)Decreased Renal Blood flow
Decreased GFR and Na+ excretion
Activates Na/H exchanger in PCT
Stimulates renin release from juxtaglomerular cells
Increased Angiotensin II/Aldosterone levels

4)Antidiuretic hormone (ADH)

5)Arial Natriuretic Peptide (ANP)
Acts in the opposite direction to the others
Synthesised and stored in atrial myocytes
Promotes Na+ excretion
Vasodilation of afferent arteriole
High BP leads to Stretch Atrial Cells
Increased release of ANP leads to Na+ excretion, volume decreases, BP decreases
Low BP leads to Atrial Cells being less stretched
Reducing ANP release and thus Na+ excretion, volume increases, BP increases
Also Inhibits Na+ reabsorption along the nephron


LO 4.9 Describe how the renin-angiotensin system regulates sodium uptake in response to changes in blood pressure

Reduced perfusion pressure in the kidney detected by baroreceptors in the afferent arteriole, causes the release of renin from the granular cells of the juxtaglomerular apparatus. Decreased NaCl Concentration at the Macula Densa cells (Due to low perfusion and therefore low GFR) causes Sympathetic stimulation to the JGA. This also increases the release of renin. (Also causes Macula Densa cells to release Prostaglandins -> Afferent Vasodilation)

Renin cleaves Angiotensinogen -> Angiotensin I, which is in turn cleaved by Angiotensin Converting Enzyme (ACE) to form the active hormone Angiotensin II. Renin aslo breaks down Bradykinin which is a vasodilator

Angiotensin II
There are two types of Angiotensin II receptors, AT1 and AT2. They are both G-protein coupled receptors. Angiotensin II’s main actions are via the AT1 receptor
Actions of Angiotensin II

1) Works on vascular smooth muscle cells, increases TPR thus BP specfically in the afferent and efferent arteriole

2)Stimulates the adrenal cortex to synthesise and release Aldosterone which stimulates Na+ and therefore water reabsorption. It Acts on principal cells of CD activating ENaC and apical K+ channels leading to an increased basolateral Na+ extrusion via 3Na-2K-ATPase

3)Increased Sympathetic Activity leads to Vasoconstriction by α1-adrenoceptors and Inc. force/rate of heart contraction β1-adrenoceptors, and leads to an increase Na+ reabsorption by Stimulating the Na-H exchanger in the apical membrane of PCT

4)Stimulates ADH release at hypothalamus causing thirst


LO 4.10 Describe the sympathetic control of ADH (Anti-Diuretic Hormone) secretion and the role of the baroreceptor

The baroreceptor reflex works well to control acute changed in BP. It produces a rapid response, but does not control sustained increases as the threshold for baroreceptor firing resets.

A 5-10% drop in blood pressure causes low-pressure baroreceptors in the atria and pulmonary vasculature to send signals to the brainstem via the vagus nerve. This activity modulates both sympathetic nerve outflow, secretion of the hormone ADH and reduction of ANP release.

A 5-150% change in blood pressure causes high-pressure baroreceptors (carotid sinus/aortic arch) to send impulses via the vagus and glossopharyngeal nerves. A decrease in blood pressure will increase sympathetic nerve activity and the secretion of ADH.

Actions of ADH

Addition of Aquaporin to Collecting Duct which will increase reabsorption of water, forming concentrated urine and release stimulated by increases in plasma osmolarity or severe hypovolemia

Stimulates apical Na/K/Cl co-transporter in the
Thick Ascending Limb, causing less Na+ to move out into the medulla, reducing osmotic gradient for water to exit the lumen into the peritubular capillaries from the thin descending limb


LO 4.11 Discuss prostaglandins and NSAIDs

Prostaglandins are vasodilators. Locally acting prostaglandins (mainly PGE2) enhance glomerular filtration and reduce Na+ reabsorption. They therefore may have an important protective function by acting as a buffer to excessive vasoconstriction by the sympathetic nervous system and the RAAS.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) inhibit the cyclo-oxygenase (COX) pathway that is involved in the formation of prostaglandins. As prostaglandins help to maintain renal blood flow and GFR in the presence of vasoconstrictors, if NSAIDs are administered when renal perfusion is compromised (e.g. in renal disease) GFR can be further decreased, leading to acute renal failure. In heart failure or hypertensive patients, NSAIDs can exacerbate the condition by increasing NaCl and water retention.


LO 4.12 Describe essential and secondary hypertension including causes and treatments

Hypertension is a sustained increase in blood pressure.
In around 95% of cases, the cause is unknown. This is known as Essential Hypertension. Genetic and environmental factors may both be involved and the pathogenesis is unclear. Where a cause can be defined, hypertension is referred to as secondary hypertension. Here it is important to treat the primary cause. Examples include:
o Renovascular disease
o Chronic Renal Disease
o Aldosteronism
o Cushing’s syndrome

Renovascular Disease
Renovascular Disease is caused by an occlusion of the renal artery, causing a fall in perfusion pressure in that kidney. Decreased perfusion leads to that kidney releasing renin and activating RAAS. Vasoconstriction and Na+ retention will then take place at the other kidney.

Adrenal Causes
Conn’s Syndrome, an Aldosterone secreting adenoma causing hypertension and hypokalaemia
Cushing’s Syndrome where there is excess cortisol, which at high concentrations acts on aldosterone receptors causing Na+ and water retention
Pheochromocytoma is a tumour of the adrenal medulla that secretes noradrenaline and adrenaline

Treatment of Hypertension
1)ACE Inhibitors - Prevent the production of Angiotensin II from Angiotensin I

2)Angiotensin II receptor antagonists

3)Thiazide Diuretics - Inhibit NaCC co-transporter on apical membrane of DCT, may cause hypokalaemia (more K+ lost in urine)

Including Ca2+ channel blockers, reduce Ca2+ entry into smooth muscle cells or α1 receptor blockers that reduce sympathetic tone

5)Beta Blockers that block β1-receptors in the heart, reducing heart rate and contractility

Non-pharmacological approaches to the treatment of hypertension include diet, exercise, reduced Na+ intake, reduced alcohol intake.


LO 5.1 Describe the regulation of body fluid osmolarity in terms of responses to water deprivation and drinking

Water Intake < Excretion -> Plasma osmolarity increases
Water Intake > Excretion -> Plasma osmolarity decreases

The more urine is produced, the less concentrated it is.

Body fluid osmolarity is maintained by osmoregulation at about 275-295 mOsm/kg

Disorders of water balance manifest as changes in body fluid osmolarity. In contrast, problems with Na+ balance causes changes in volume


LO 5.2 Describe and distinguish the factors that regulate thirst and cause secretion of ADH

Changes in plasma osmolarity are detected by the Hypothalamic Osmoreceptors. The osmoreceptors are located in the Organum Vasculoum of the Laminae Terminalis (OVLT). The OVLT is anterior and ventral to the third ventricle and has a fenestrated leaky epithelium to expose it directly to the systemic circulation.

When a change in plasma osmolarity is sensed, it coordinates responses via two different efferent pathways, which work to concentrate urine and increase thirst respectively. You only feel thirsty at ~10% dehydration.


LO 5.3 Describe the role of ADH and the production of Hypo and Hyperosmotic Urine

If plasma osmolarity increases (1% change) due to a predominant loss of water, osmoreceptors in the hypothalamus (OVLT) initiate the release of ADH from the POSTERIOR Pituitary. Similarly, decreased osmolarity inhibits ADH secretion.

ADH is a small peptide, 99 AA’s long. It acts on the kidney to regulate the volume and osmolarity of the urine. It achieves this by increasing the permeability of the kidneys to water and urea.

ADH causes the addition of the water channel Aquaporin-2 to the apical membrane of the nephron’s collecting duct. This allows for the reabsorption of water to decrease plasma osmolarity.
Aquaporin 2

In the absence of ADH, apical membranes do not contain Aquaporin 2. When ADH is released it is inserted into the membrane and when ADH is removed the channel is retrieved from the apical membrane via endocytosis.

The basolateral membrane always contains Aquaporin 3 and 4, so is constantly permeable to water. This means any water that enters across the apical membrane is able to pass into the peritubular blood.

Urea Recycling

ADH also increases the permeability of the medullary part of the collecting duct to urea, causing its reabsorption. This in turn causes water to follow. The rise in urea concentration in the tissues causes it to passively move down its concentration gradient into the ascending limb, which is permeable to Urea but impermeable to H2O. Urea then passes back into the collecting duct, where it is reabsorbed in the medullary portion and more water follows. Urea is therefore recycled.


LO 5.4 Describe the syndrome of secretion of inappropriate ADH (SIADH) and its inappropriate consequences/symptoms

In SIADH the secretion of ADH is not inhibited by the lowering of blood osmolarity (negative feedback is removed). This means that excessive amounts of water is retained, causing blood osmolarity to drop and cause hyponatremia (Low blood Na+ concentration).

Symptoms of hyponatremia include nausea and vomiting, headache, confusion, lethargy, fatigue, appetite loss, restlessness and irritability, muscle weakness, spasms, cramps, seizures and decreased consciousness or coma. If hypernatremia comes about because of SIADH the condition may be treated with ADH Receptor Antagonists.


LO 5.5 Describe the corticopapillary osmotic gradient

At the cortico-medullary border, there is no osmotic gradient. However the medullary Intersticium is hyperosmotic up to 100 mOsmol/Kg at the papilla. There is a gradient of increasing osmolarity as you descend.

The active transport of NaCl out of the TAL and the recycling of urea sets up the osmotic gradient. The action of the TAL is crucial, removing solute without water, diluting the filtrate and increasing Intersticium osmolarity. If you block the NaK2Cl transporters in the TAL with a loop diuretic (E.g. Furosemide) the medullary Intersticium becomes isosmotic and large amounts of dilute urine is produced.

Counter-Current Multiplication
The Loop of Henle acts as a counter current multiplier, to set up the osmotic gradient: Tubule filled initially with isotonic fluid
Na+ ions are pumped out of the ascending loop (Na/K/2Cl co-transporter), raising the osmotic pressure outside the tubule and lowering it inside.
(Max concentration difference inside to out is 200 mOsmol/L) Fresh fluid enters from the glomerulus, and enters the descending limb. As the descending limb is permeable to water, it leaves via osmosis to raise the osmotic pressure inside the descending tubule to 400mOsmol/L. More fluid enters from the glomerulus, pushing the concentrated (400mOsmol/L) fluid into the ascending limb. The Na+ pump then produces another 200 mOsmol/L gradient across the membrane. But it started with a more concentrated solution (400mOsmol/L). So external osmolarity rises to 500mOsmol/L. Fresh fluid again enters; water leaves via osmosis until the osmotic pressure in the descending tubule is 500mOsmol/L. This is then pushed into the ascending limb, where the Na+ pump produces yet another 200 mOsmol/L gradient, raising the interstitial osmolarity to 700mOsmol/L. The final gradient will be limited by the diffusional process.

Counter Current Exchange
The concentration gradient that the loop of Henle sets up would not last long though without the Vasa Recta.
These are blood vessels that run alongside the loops, but with opposite flow direction. This counter-current flow allows for the maintenance of the concentration gradient.
Isosmotic blood in the descending limb of the vasa recta enters the hyperosmotic milieu of the medulla, where there is a high concentration of ions (Na+, Cl-, Urea). These ions therefore diffuse into the vasa recta and water diffuses out. The osmolarity of the blood in the vasa recta increases as it reaches the tip of the hairpin loop, where it is isosmotic with the medullary Intersticium. Blood ascending towards the cortex will have a higher solute content than the surrounding Intersticium, so solutes move back out. Water will also move back in from the descending limb of the loop of Henle. Therefore, although there is a large amount of fluid and solute exchange across the vasa recta, there is little net dilution of the concentration of the interstitial fluid because of the U shape of the vasa recta allowing it to act as a counter current exchanger.
The vasa recta therefore do not create the medullary hyperosmolarity, but do prevent it from being dissipated.


LO 5.6 Explain the significance of maintaining serum calcium levels within set limits and the forms Ca2+ is transported in.

Calcium plays a critical role in many cellular processes:
oHormone secretion
oNerve conduction
oInactivation/activation of enzymes
oMuscle contraction

Therefore, the body very carefully regulates the plasma concentration of free ionised calcium, its physiologically active form, and maintains free plasma [Ca2+] within a narrow range (1.0 - 1.3mmol/L).

In plasma, calcium exists as:
oFree ionised species – 45% (Active Form)
oProtein Bound – 45% (80% to Albumin)
oComplexed – 10% (Citrates, phosphate etc)


LO 5.7 Discuss the handling of Ca2+ by the intestine and kidneys

The absorption of Calcium is under the control of Vitamin D. About 20-40% of dietary calcium (25mmol) is absorbed and some is excreted back into the gut (2-5mmol). Absorption increases in growing children, pregnancy, lactation and decreases with advanced age. Complexing calcium (e.g. with oxalates) reduces its absorption.

The kidneys filter 250mmol of Calcium per day, 95-98% of which is reabsorbed, giving a urinary calcium excretion of < 10mmol/day. 65% is reabsorbed in PCT (being associated with Na+ and water uptake), while 20-25% is reabsorbed in loop of Henle and 10% in the DCT, this is under the control of PTH


LO 5.8 Discuss the role of Vitamin D and Parathyroid Hormone in Calcium absorption

Vitamin D2 (Absorbed by Gut) and Vitamin D3 (absorbed by the skin as UV light) are hydroxlylated by the liver to form Calciferol, as Vitamin D has a short half-life, Calciferol is then hydroxylated a second time in the Kidney to form Calcitriol, this increases Ca2+ absorption by binding to Ca2+ in the Gut. Parathyroid Hormone is produced by the parathyroid Gland and acts to convert Calciferol to Calcitriol. It also increases Ca2+ release from bone and Ca2+ reabsorption in kidney. It also decreases the reabsorption of phosphate and bicarbonate, as if they are present in the blood with Calcium, stones will form. Calcium levels regulate PTH via negative feedback.


LO 5.9 Discuss the causes, symptoms and management of Hypercalcaemia

Hypercalcaemia Causes
oPrimary hyperparathyroidism (1/1000 people)
oHaematological malignancies (production of PTHrP. which has AA homology with PTH and works to increase plasma Ca2+ concentration via PTH mechanisms
oNon-Haematological malignancies

Hypercalcaemia of malignancy comes about due to the production of Parathyroidhormone-Related Peptide (PTHrP). This peptide has AA homology with the active portion of PTH and works to increase plasma Ca2+ concentration via the mechanisms shown above.


Acute pancreatitis (rarely)

Shortened QT interval on ECG
Enhanced sensitivity to digoxin

Polyuria and polydipsia
Occasional nephrocalcinosis

Central Nervous System
Cognitive difficulties and apathy
Drowsiness, coma

Hypercalcaemia Management
oGeneral measures
Hydration – Increase Ca2+ excretion
Loop diuretics – Increase Ca2+ excretion

In general you can hydrate the patient and give loop diuretics, which increase Ca2+ excretion. However you should also give Bisphosphonates (which inhibit the breakdown of bone) and calcitonin (which opposes the action of PTH), obviously you should aim to treat the underlying cause.


LO 5.10 Discuss Calcium renal stones and their formation

Approximately 20% of men and 5-10% of women will develop renal stones in their lifetime, and 70-80% of all renal tract stones are made of Calcium. Factors involved in their formation include low urine volume, hypercalcuria and low urine pH (< 5.47). The mechanism of stone formation is complex, and involves the super-saturation of urine with calcium oxalate.
Conservative management of renal stones includes increasing fluid intake, restricting dietary oxalate and sodium, and considering the dietary restriction of calcium and animal protein.


LO 6.1 Describe and be able to state the normal range of plasma pH

The normal range of plasma pH is 7.38 – 7.42


LO 6.2 Describe the clinical effects of acidaemia and alkalaemia

The effects of Acidaemia are severe below pH 7.1, and life threatening below pH 7.0. They include:
o Reduced enzyme function
o Reduced cardiac and skeletal muscle contractility
o Reduced glycolysis
o Reduced hepatic function
o Increased plasma potassium

Alkalaemia reduces the solubility of calcium salts, which means that free Ca2+ leaves the ECF, binding to bone and proteins, resulting in hypocalcaemia. This increases the excitability of nerves. 45% Mortality when pH > 7.55 or 80% Mortality when pH > 7.65. Symptoms include:
o Paraesthesia
o Tetany (uncontrolled muscle contractions)


LO 6.3 Describe the carbon dioxide/hydrogen carbonate buffer system and the factors influencing pCO2 and [HCO3]. What are the 6 main types of alkalaemia or acidameia

The H+ ion concentration in the ECF is very low, so the addition of small amounts of acid changes the concentration and therefore pH dramatically. To prevent this, H+ ions are buffered by binding to various sites. The most important buffer is the Carbon Dioxide/Hydrogen Carbonate system. The extent the reversible reaction proceeds is determined by the ratio of pCO2 of plasma (controlled by the lungs) to [HCO3-] (largely created by RBCs, but concentration is controlled in the kidneys). The normal ratio of HCO3- to pCO2 is 20 : 1. Anything that alters this ratio will also alter pH.

Respiratory Alkalaemia
As hyperventilation leads to hypocapnia (fall in pCO2), the ratio is altered and pH will rise. There is more CO2 compared to HCO3- than nomral and so relatively more H+ ions are buffered, causing the pH increase. This is known as Respiratory Alkalaemia (pH > 7.45).

Respiratory Acidaemia
Conversely, hypoventilation leads to hypercapnia (rise in pCO2). The ratio is altered and pH will fall. There is less CO2 compared to HCO3- than nomral and so relatively less H+ ions are buffered, causing the pH decrease. This is known as Respiratory Acidaemia (pH < 7.35).

Compensation by the Kidneys
Because the pH is controlled by this ratio and not absolute values, respiratory acidaemia or alkalaemia can be compensated for by changes in [HCO3-] controlled by the kidney. The kidney controls [HCO3-] via variable renal excretion/production. If pCO2 rises, [HCO3-] rises proportionately to restore pH. Alternatively if pCO2 falls, [HCO3-] falls proportionately to restore pH.

Metabolic Acidosis
Metabolically produced H+ ions (e.g. from the metabolism of amino acids or the production of ketones) react with HCO3- to produce CO2 in venous blood. This CO2 is then breathed out through the lungs, giving a directly proportional (1 mmol acid: 1 mmol HCO3-) reduction in arterial HCO3-. This alters the [HCO3-] : pCO2 ratio, meaning that there is less HCO3- compared to CO2 than normal. Relatively less H+ ions are buffered, causing a pH decrease. This is known as Metabolic Acidosis (pH < 7.35).

Metabolic Alkalosis
If plasma [HCO3-] rises, for example after persistent vomiting, the [HCO3-] : pCO2 ratio will be altered. More HCO3- compared to CO2 will be present, so relatively more H+ ions are buffered, causing a pH increase. This is known as Metabolic Alkalosis (pH > 7.45).

Compensation by the Lungs
Again, as pH depends on the ratio of [HCO3-] : pCO2, these changes may be compensated for by altering pCO2. pCO2 is normally kept within tight limits by the Central Chemoreceptors. Changes in plasma pH drive changes in pCO2 via the Peripheral Chemoreceptors. If [HCO3-] falls, pCO2 is lowered proportionately by increasing ventilation and if [HCO3-] rises, pCO2 may be slightly raised by reducing ventilation, meaning that you can only partially compensate for Metabolic Alkalosis


LO 6.4 Describe and be able to identify from values, respiratory acidaemia (acidosis) and alkalaemia (alkalosis), and metabolic acidosis and alkalosis

Respiratory Acidaemia (acidosis)
pH pCO2 [HCO3-] pO2
\/ /\ - \/

Compensated (Partially or fully) Respiratory Acidaemia (acidosis)
pH pCO2 [HCO3-] pO2
\/ or - /\ /\ \/

Respiratory Alkalaemia (alkalosis)
pH pCO2 [HCO3-] pO2
/\ \/ - - / /\

Compensated (Partially or fully) Respiratory Alkalaemia (alkalosis)
pH pCO2 [HCO3-] pO2
/\ or - \/ \/ /\

Metabolic Acidosis
pH pCO2 [HCO3-] pO2 Anion Gap
\/ - \/ - /\

Compensated (Partially or fully) Metabolic Acidosis
pH pCO2 [HCO3-] pO2 Anion Gap
\/ or - \/ \/ /\ or - /\

Metabolic Alkalosis
pH pCO2 [HCO3-] pO2
/\ - /\ -

Compensated (Partially or fully) Metabolic Alkalosis
pH pCO2 [HCO3-] pO2
/\ or - /\ /\ \/ or -


LO 6.5 Describe cellular mechanisms of reabsorption of HCO3- in the PCT

Like most ions, a large fraction of HCO3- is reabsorbed in the PCT. 3Na-2K-ATPase sets up a Na+ concentration gradient in PCT cells. H+ ions are pumped out of the apical membrane up their concentration gradient in exchange for the inward movement of Na+ down its concentration gradient. This H+ reacts with filtered HCO3-, producing CO2, which enters the cell and reacts with water to produce H+ ions. The H+ is quickly exported, recreating HCO3-, which crosses the basolateral membrane to enter the plasma.

80-90% of filtered HCO3- is reabsorbed in the PCT, and up to 15% is also reabsorbed in the TAL of the loop of Henle by a similar method.


LO 6.6 Describe cellular mechanisms of H+ excretion in the DCT

By the DCT most/all of the filtered HCO3- has been recovered. The Na+ gradient is also insufficient to drive H+ secretion, so H+ is pumped across the apical membrane by a H+-ATPase. These proton pumps are similar to those found in the stomach.

When cells export H+, K+ is absorbed into the blood. So if you export a lot of H+, you will also absorb a lot (perhaps too much) K+. This relationship means that blood pH is linked to [K+].


LO 6.7 Describe the mechanism of buffering H+ in the urine, and explain the concept of titratable acid, and the role of NH4+

The minimum pH of urine is 4.5 ([H+] of 0.04mmol/L).

There is no HCO3- however, so H+ is buffered by phosphate. Phosphate is a Titratable acid, meaning that it can freely gain H+ ions in an acid/base reaction.

The rest of the H+ in the urine is attached to ammonia as ammonium.


LO 6.8 Describe the interactions between acid base status and plasma [K+]

Metabolic acidosis is associated with hyperkalaemia. As [K+] rises, the kidney’s ability to reabsorb and create HCO3- is reduced. Hyperkalaemia makes intracellular pH alkaline, favouring HCO3- excretion.

Metabolic alkalosis is associated with hypokalaemia. Hypokalaemia makes intracellular pH acidic, favouring H+ excretion and HCO3- recovery.


LO 6.9 Describe the interaction between renal control of acid base balance and control of plasma volume

[HCO3-] increases after persistent vomiting, alongside dehydration. When this occurs the kidneys cannot excrete HCO3- as they are trying to compensate for the dehydration. HCO3- and Na+ recovery is favoured to increase the osmolarity of the plasma and cause the osmotic movement of water.

In this case you cannot rely on the kidneys to correct the [HCO3-], however if you correct the dehydration by giving fluids, HCO3- will be excreted very rapidly.


LO 6.10 Describe the common causes of metabolic alkalosis, in particular the effects of persistent vomiting

[HCO3-] increases after persistent vomiting (metabolic alkalosis), so the body stops actively secreting H+, as it would make metabolic alkalosis worse.

As H+ secretion has stopped, so has K+ reabsorption (Antiporter, Intercalated cells). This means that a dangerous side effect of persistent vomiting is hypokalaemia, which causes paraesthesia, tetany and CVS problems.


LO 6.11 Describe the main classes of metabolic acidosis, and the role of the anion-gap measurement in distinguishing between them

Metabolic acidosis will occur if there is excess metabolic production of acids, (lactic acidosis, ketoacidosis) acids are ingested, HCO3- is lost or there is a problem with the renal excretion of acid. If excess acid is produced, the associated anion (e.g. lactate in lactic acid) will replace HCO3- in the plasma. This will influence the anion gap.

The Anion Gap
The anion gap is the difference between the sum of the measured concentrations of Na+ and K+ and the sum of the measured concentrations of Cl- and HCO3-. If HCO3- is replaced in the plasma by another anion (see above), which is not included in the calculation, the gap will increase. If the problem causing metabolic acidosis lies with the renal excretion of H+, this will change the [HCO3-] directly without replacement by an unmeasured ion, so the anion gap is less likely to change.


LO 6.12 Describe why the internal balance of potassium is so important

K+ ions are the most abundant intra-cellular Cation. And so small changes in external levels can have big effects on concentration. The body tightly maintains plasma [K+] to a range of 3.5-5.3 mmol/L

High [K+] inside cells and inside mitochondria is essential for:
oMaintaining cell volume
oRegulating intra-cellular pH
oControlling cell-enzyme function
oDNA / Protein synthesis
oCell Growth

Low [K+] outside cells is necessary for maintaining the steep K+ ion gradient across cell membranes that is largely responsible for the membrane potential of excitable and non-excitable cells.
oIncreased ECF [K+] depolarises the cell membrane
oDecreased ECF [K+] hyperpolarises the cell membrane

Therefore, changes in extracellular [K+] can cause severe disturbances in excitation and contraction. The potentially life threatening disturbances of cardiac rhythm that are a result of hyperkalaemia are particularly important.

Extremely low extracellular [K+] leads to several metabolic disturbances:
oInability of the kidney to form concentrated urine
oA tendency to develop metabolic alkalosis
oLarge enhancement of renal ammonium excretion


LO 6.13 Describe how potassium handling occurs in the various segments of the nephron and factors affecting K+ secretion.

K+ is freely filtered in the glomerulus

K+ secretion in the DCT and Cortical CD, in the Principal cells and by passive processes driven by electro-chemical gradient for K+ between the principal cell and the lumen Na+ is reabsorbed via ENaC and this favours K+ secretion through the SEPARATE K+ channel, by creating a negative charge in the lumen. This process is driven by Na-K-ATPase in the basolateral membrane which creates the gradient for Na+ absorption

Factors affecting K+ secretion by principal cells

Tubular factors include:
1)Levels of aldosterone (a steroid hormone, that increases the transcription of Na-K-ATPase in the basolateral membrane and ENaC / K+ channels in the apical membrane, increasing the amount of channels gives increase K+ excretion).
2)Hyperkalaemia – Stimulates aldosterone secretion (Inc. K+ secretion)
3)Acid base status, Changes in the ECF pH cause reciprocal shifts in H+ and K+ between ECF and ICF. Acidaemia decreases [K+] in principal cells, thus decreasing secretion while alkalaemia increases [K+] in principal cells, thus increasing secretion.

Luminal Factors inlcude:
Increased Distal tubular flow rate = Increased K+ loss
Increased Na+ delivery to distal tubule = Increased K+ loss

K+ absorption in the DCT and Cortical CD
o Intercalated cells
o Active process
o Mediated by H+-K+-ATPase in the apical membrane


LO 6. 14 Describe potassium balance and the regulation of ECF and ICF potassium concentrations. This should include an understanding of the hormonal control (e.g. adrenaline, insulin and aldosterone)

Potassium Balance
Two homeostatic mechanisms keep the ECF [K+] tightly controlled, External and Internal balance.

External Balance
o Regulates the total body K+ content, which depends on dietary intake, and excretion (renal/GI).
o Responsible for the long-term control of K+
o Controlled by renal excretion

Internal Balance
o Regulates K+ movement between ECF and ICF
o Responsible for moment to moment control - quick, within minutes, acts as a K+ buffer

If ECF/Plasma [K+] increases, K+ moves into cells via the If ECF/Plasma [K+] decreases, K+ moves out of cells by the action of K+ channels

Factors Causing K+ shift from ECF to ICF

If ECF/Plasma [K+] increases

K+ in splanchnic blood stimulates insulin secretion from the pancreas. Insulin increases the amount of Na-K-ATPase, as it provides the drive for the Na-Glucose transporter. The increase in Na-K-ATPase results in uptake of K+.
2)Catecholamines (B2 Agonists)
B2 adrenoceptors stimulate Na-K-ATPase. Exercise and trauma increases K+ exit from cells, but also increases catecholamines to help offset the ECF [K+] rise.
3) Aldosterone is a steroid hormone, that increases the transcription of Na-K-ATPase in the basolateral membrane and ENaC / K+ channels in the apical membrane. This increased amount of these channels gives increase K+ excretion.
4)Alkalosis (Increased ECF/Plasma [H+])

Factors causing K+ shift from ICF to ECF

If ECF/Plasma [K+] falls

Skeletal muscle contraction gives a net release of K+ (during recovery phase of action potential K+ exits the cell). Increase in plasma [K+] is directly proportional to the intensity of the exercise. Uptake of this K+ from the blood by non-contracting tissues is important in preventing hyperkalaemia (release of Catecholamines).
2)Cell lysis (Trauma)
With cell lysis K+ is released from the ICF into the ECF. Possible causes include trauma to skeletal muscle, intravascular haemolysis and cancer chemotherapy.

3)Plasma Hyperosmolarity
Increase in plasma osmolarity causes water to move from the ICF to ECF via osmosis. This increases the [K+] of the ICF, and K+ leaves down its concentration gradient.

4)Acidosis (reduced ECF/Plasma [H+])

Acid Base Balance
Changes in the ECF pH cause reciprocal shifts in K+ between the ECF and ICF, and changes in the ECF [K+] can cause changes to the ECF pH.


LO 6.16 Describe the causes, effects, ECG changes and treatment of hypokalaemia

Hypokalaemia hyperpolarises cardiac cells, leading to more fast Na+ channels available in active form and thus making the heart more excitable

Hypokalaemia ([K+] < 3.5 nmol/L)

External Balance Problems
Inadequate intake
Excessive loss
oGI – Diarrhoea / Vomiting
oRenal – Diuretic drugs / osmotic diuresis (Diabetes)
oHigh aldosterone levels
Internal Balance Problems
oShift of potassium ECF to ICF, possibly due to Alkalosis

Clinical Features
oHeart excitablitiy changes - More excitable
oGI - Neuromuscular dysfunction leading to paralytic ileus
oSkeletal Muscle - Neuromuscular dysfunction leading to muscle weakness
oRenal -Dysfunction of CD cells as they are Unresponsive to ADH leading to Nephrogenic diabetes

ECG Changes
Shallow T wave (no pot no tea)
Prominent U wave
ST depression

Treat cause
K+ replacement – IV/Oral
If due to high aldosterone:
1)K+ sparing diuretics that block action of aldosterone on principal cells
2)K+ sparing – Amiloride
3)Aldosterone Antagonist - Spironolactone


LO 7.1 Describe normal urinary tract defence mechanisms

The urinary tract is protected form infection by a variety of defence mechanisms. Most important is the regular flushing during voiding, which removes organisms from the distal urethra. Between voiding such organisms may ascend the urethra, therefore infection in commoner in females because the urethra is comparatively short. Other defence factors include antibacterial secretions into the urine and urethra.


LO 7.2 Describe the pathogenesis of infection – Host and bacterial factors

Host Factors
Shorter urethra - More infections in female
Obstruction - Enlarged prostate, pregnancy, stones, tumours
Neurological - Incomplete emptying, residual urine
Ureteric reflux - Ascending infection from bladder, especially in children

Bacterial Factors
Faecal flora - Potential urinary pathogens colonise periurethral area
Adhesion - Fimbriae and adhesins allow attachment to urethral and bladder epithelium
K Antigens - Allow some E. coli to resist host defences by producing polysaccharide capsule
Haemolysins - Damage membranes and cause renal damage
Urease - Produced by some bacteria e.g. proteus. Breaks down Urea for energy.


LO 7.3 Describe how to recognise clinical syndromes, including Lower UTI Bacterial cystitis, upper UTI acute pyelonephritis, or covert asymptomatic bacteriuria.

Many UTI’s are mild, but renal infections may lead to long term renal damage, and the urinary tract is a common source of life threatening Gram –‘ve bacteraemia. The commonest UTI is one of the lower tract, cystitis. Upper UTI (pyelonephritis) may result from haematogenous or ascending routes of infection.

Lower UTI Bacterial cystitis
Frequency and dysuria, often with pyuria and haematuria

Abacterial cystitis
As above but without ‘significant bacteriuria’
Prostatitis Fever, dysuria, frequency with perineal and low back pain

Upper UTI Acute pyelonephritis
Symptoms of cystitis plus fever and loin pain

Chronic interstitial nephritis
Renal impairment following chronic inflammation – infection one of many causes

Asymptomatic Covert bacteriuria
Detected only be culture. Important in children and pregnancy


LO 7.4 Describe the organisms responsible for UTIs

The commonest pathogens in the community (80%) are Gram –‘ve rods, particularly Enterobacteriaceae (‘Coliforms’, especially E. coli).

Young women and hospitalised patients may also develop a UTI due to coagulase-negative staphylococci, e.g. Staph. Saprophyticus. This is due to increased risk factors, such as catheterisation (biofilms).


LO 7.5 Describe the principles of microbiological investigation

Uncomplicated UTI – Healthy women
Complicated UTI – e.g. pregnancy, treatment failure, suspected pyelonephritis, complications, males, paediatric

Uncomplicated UTIs
There is no need to culture urine in Uncomplicated UTIs, infection is indicated by Nitrite/Leukocyte esterase dipstick testing.

Complicated UTIs
Sample Collection
o A mid-stream specimen is collected, as we do not want to culture the urethra’s normal flora, so allow for a small amount of urine to be passed to ‘clear’ it before collecting the sample.
o It can be difficult to collect samples from small children, so an adhesive bag can be placed over their genitals. This gives a false positive rate of 20%.
o Catheter samples can be taken, not from the bag but by using a needle up a special tube in the catheter.
o Supra-Pubic aspiration can be used to get a sample of bladder urine, by using a needle through the abdominal wall, but this is rare.
Collected samples are transported at 40C, with a small amount of boric acid in the collection tube. This stops bacterial division to keep the sample representative of the collection time.

o Turbidity - Look to see if the sample is cloudy. Cloudy urine is indicative of UTI.
o Dipstick Testing
Leukocyte esterase (Indicates presence of WBCs)
Nitrite – Indicates presence of Nitrate reducing bacteria
Haematuria – Many reasons, can’t diagnose UTI
Proteinuria – Many reasons, can’t diagnose UTI

o Kidney disease
o Loin pain, nephritis, hypertension, toxaemia, renal colic, haematuria, renal TB, casts
o Suspected endocarditis
o Children under 6
o Schistosomiasis
o Suprapubic aspirates
o Urine Culture when requested

o A single urine specimen is 80% predictive.
o Used to investigate complicated UTI’s
o Increased sensitivity (down to 102 cfu/ml)
o Epidemiology of isolates
o Sensitivity testing
o Control of specimen quality
o Can differentiate between properly collected and contaminated samples (poorly collected samples may contain epithelial cells).

Interpretation of Culture Report
o Clinical details
Previous antibiotics
o Quality of specimen
o Delays in culture
o Microscopy (if available)
o Organism(s) located

Sterile Pyuria (Pus in urine)
A UTI is present, but unable to be cultured. Reasons for this include the patient having already been treated with antibiotics, or infected with bacteria that are difficult to isolate or culture (e.g. chlamydia). Can also be due to tuberculosis, or appendicitis (appendix stuck on the bladder)

Symptomatic Adult Women
Not 100% of adult women who present with classic UTI symptoms have a UTI. All are treated as though they have one though until proved otherwise.
o 50% Significant bacteriuria
o 50% Urethral syndrome
Low-count bacteriuria
Fastidious organisms
Vaginal infection/inflammation
Sexually transmitted pathogens – urethritis
Mechanical, physical and chemical causes


LO 7.6 Describe the principles of UTI treatment

General – Increase fluid intake, address underlying disorders. Bacteria may be present asymptomatically - only treat once symptoms appear.

o 3 Day course of antibiotics
o 3 day course reduces the selection pressure for resistance

o 7 Day course of antibiotics.
o Amoxicillin not appropriate as 50% of isolates are resistant

o 14 day course of antibiotics
o Use more potent agent with systemic activity

o Three or more episodes in one year
o No treatable underlying condition
o Single, low, nightly dose of antibiotics to prevent bacteria build up in static urine
o All breakthrough infections documented


LO 7.7 Describe and summarise the main classes of diuretics and their mechanisms of action

Diuretics block the reabsorption of Na+ and therefore water by the kidney.

Loop Diuretics
Loop diuretics are the most powerful, capable of causing the excretion of 10-25% of filtered Na+ ions. They work by blocking the Na-2Cl Symporter in the apical membrane. E.g. Furosemide, Bumetanide

Thiazide Diuretics
Thiazide Diuretics act on the early DCT. They are less potent than loop diuretics, inhibiting only 5% of Na+ reabsorption. They are ineffective in the treatment of renal failure. They work by blocking the Na-Cl Symporter. E.g. Bendroflumethiazide

K+ Sparing Diuretics and Aldosterone Antagonists
Both types act on the late DCT to reduce Na+ channel activity. They are both mild diuretics, inhibiting only 2% on Na+ reabsorption. Both reduce the loss of K+ and are called K+ sparing diuretics, and can both produce life threatening hyperkalaemia, e.g. in renal failure. K+ Sparing Example - Amiloride. Aldosterone Antagonist Example – Spironolactone


LO 7.8 Describe the adverse affects of diuretics use and abuse

Diuretics and Potassium
Loop and Thiazide diuretics increase the loss of Potassium in urine. This may cause Hypokalaemia. As diuretics reduce ECF volume, they will also cause the activation of RAAS. This increase aldosterone secretion, increasing Na+ absorption and K+ secretion, helping to contribute to hypokalaemia.

o Decreased ECF volume due to excessive loss of Na+ and water
o Monitor weight, signs of dehydration and BP (Look for postural hypotension)

Increase Uric acid levels in blood
o Can precipitate attack of Gout

K+ sparing diuretics and Aldosterone antagonists reduce the loss of Potassium in urine. This may cause Hyperkalaemia.

Metabolic effects
o Glucose intolerance
o Increased LDL levels


LO 7.9 Describe treatment with diuretics

Diuretics are used to treat:

o Conditions with ECF expansion and Oedema
Congestive Heart failure
Nephrotic syndrome
Kidney failure (loop diuretic)
Ascites and oedema due to cirrhosis of the liver (spironolactone)

o Acute Pulmonary Oedema
IV Furosemide
Due to left heart failure

o Hypertension
Thiazide diuretics
Spironolactone in primary hyperaldosteronism (Conn’s syndrome)

o Hypercalcaemia
Loop Diuretics promote calcium excretion by the Loop of Henle

o Osmotic diuretics
E.g. Mannitol
Used in cerebral oedema

o Carbonic anhydrase inhibitors
Acetazolamide useful in Glaucoma

Other Substances with Diuretic Action:

o Alcohol
 Inhibits ADH release
o Coffee
  GFR and  Tubular Na+ reabsorption
o Other drugs – Lithium, demeclocyline
 Inhibit ADH action on Collecting ducts

Some Diseases causing Diuresis:

Symptom – Polyuria (More than 2.5L urine/day)

Some Causes:
o Diabetes Mellitus
 Glucose in filtrate  Osmotic Diuresis
o Diabetes Insipidus (Cranial)
  ADH release from posterior pituitary  Diuresis
o Diabetes Insipidus (Nephrogenic)
 Poor response of Collecting ducts to ADH  Diuresis
o Psychogenic polydipsia
 Increase intake of fluid


LO 8.1 Describe the anatomy of the urinary bladder

Detrusor Urinae muscle
Made from a mesh-work of muscle fibres in roughly 3 layers Longitudinal - Circular- Longitudinal . This arrangement of muscle fibres gives the bladder strength, irrespective of which direction it is being stretched in. Supplied by the autonomic nervous system, not under voluntary control with a bilateral spinal nerve supply

Internal Urethral Sphincter
Continuation of the Detrusor muscle and made of smooth muscle. It is a physiological sphincter at the bladder neck (no muscle thickening, action due to structure). It is the primary muscle of continence

External Urethral Sphincter
It is an anatomical sphincter (Localised circular muscle thickening to facilitate action) that is derived from pelvic floor muscles. It is made up of skeletal muscle, under somatic, voluntary control and contracts to constrict urethra and “hold in” urine


LO 8.2 Describe in general the innervation of the bladder

o Parasympathetic
Pelvic Nerve (S2-S4)
Ach -> M3 Receptors
o Sympathetic
Hypogastric Nerve (T10-L2)
NA -> B3 Receptors

Internal Urethral Sphincter
Hypogastric Nerve (T10-L2)
NA -> A1 Receptors

External Urethral Sphincter
Pudendal Nerve (S2-S4)
Spinal motor outflow from Onof’s Nucleus of the ventral horn of the cord
Ach -> Nicotinic Receptor


LO 8.3 Describe the normal voiding reflex

Release of urine
The threshold for feelings suggestive of a full bladder is ~400ml. When the bladder is full, an urge to urinate arises. Brain micturition centres signal spinal micturition centres which send signals by parasympathetic Neurones. The increase in parasympathetic stimulation to the bladder via the Pelvic nerve causes the Detrusor to contract and increase intravesicular pressure. The Cerebral Cortex then makes a conscious, executive decision to urinate, reducing somatic stimulation to the External Urethral Sphincter. The contraction of the Detrusor coupled with the relaxation of the External Urethral Sphincter results in the bladder emptying through the urethra.

Storage of Urine in the Bladder
The ureters, urinary bladder, internal and external urethral sphincters work together to pass urine into the urinary bladder and store it over many hours (e.g. at night). The walls of the bladder have many folds, which distend when filling with urine. Because of this, as the bladder fills intravesicular pressure hardly changes.
At around 400ml of filling, afferent nerves from the bladder wall (possible stretch receptors) start to signal the need to void the bladder (Pain/temperature sensation).
Brain Continence Centres signal Spinal Continence Centres which send signals via Sympathetic Neurones. The increase in sympathetic stimulation to the bladder via the hypogastric nerve causes the Detrusor to relax and the Internal Urethral Sphincter to contract. The Cerebral Cortex then makes a conscious, executive decision not to urinate, increasing somatic stimulation to the External Urethral Sphincter. This causes it to contract, constricting the urethra. The relaxation of the Detrusor, coupled with the contraction of the Internal and External Urethral sphincters reduces intravesicular pressure and constricts the urethra, preventing micturition.


LO 8.4 Describe the incidence of urinary incontinence

Types of Incontinence

Stress Urinary Incontinence (SUI)
Involuntary leakage on effort or exertion, or on sneezing or coughing

Urge Urinary Incontinence (UUI)
Involuntary leakage, accompanied by or immediately proceeded by urgency

Mixed Urinary Incontinence (MUI)
Involuntary leakage, associated with urgency and exertion, effort, sneezing or coughing

Overflow Incontinence
Retention of urine causing the bladder to swell. Can be low pressure and pain free. E.g. the man who went up 4 trouser sizes due to bladder swelling

Stress Urinary Incontinence is by far the most common


LO 8.6 Describe the risk factors associated with urinary incontinence

Risk factors include anything that can weaken the pelvic floor muscles, e.g. childbirth.

The support of the urethra by the muscles and ligaments of the pelvic floor are important for the efficiency of the sphincter mechanisms of the urethra that enable continence.


LO 8.7 Describe the initial investigation of patients with urinary incontinence

Asking the patient to record the amount of fluid they pass for two or three days can assess frequency of micturition.
Incontinence can be judged by the number of pads that the patient has to use per day to cope with the urine leakage. It should be possible to determine whether the leakage is continuous or intermittent and what precipitating factors there are, such as coughing and sneezing. This will allow to you begin to categorise the type of UI.

Urgency and frequency of micturition will often be made worse if there is an intravesicular inflammatory condition. Typically this could be a urinary tract infection, but other causes such as a stone in the bladder or even a tumour should be borne in mind with patients with persistent problems.

Previous surgery of the pelvic floor can be important as this may lead to denervation of parts of the bladder. Childbirth may also be an important factor in the development of SUI in women due to sphincter damage.

o Height/Weight
o Abdominal exam to exclude palpable bladder
o Digital rectal examination (DRE)
Prostate (male)
Limited neurological examination
o Females
External genitalia (stress test)
Vaginal exam

o Urine dipstick – UTI, haematuria, proteinuria, glucosuria

Basic non-invasive urodynamics
o Frequency-volume chart
o Bladder diary (~3 Days)
o Post micturition residual volume (Patients with voiding dysfunction)

o Invasive urodynamics (pressure-flow studies +/- video)
o Pad tests
o Cystoscopy


LO 8.8 Describe the initial management of patients with urinary incontinence

Management of urinary incontinence depends on which symptoms the patients has, the degree of bother they cause, previous or current treatments and the effects of treatments on any other symptoms they may have.

Conservative Management
General lifestyle interventions
o Modify fluid intake
o Weight loss
o Stop smoking
o Decrease caffeine intake (UUI)
o Avoid constipation
o Timed voiding – fixed schedule

Contained Incontinence
For patients unsuitable for surgery who have failed conservative or medical management:
o Indwelling Catheter - Urethral or Suprapubic
o Sheath device - Analogous to an adhesive condom attached to a catheter tubing and bag
o Incontinence pads

Specific Management of SUI
o Pelvic floor muscle training - 8 contractions, 3x a day for at least 3 months. And stopping stream during voiding

Specific Management of UUI
o Bladder training
o Schedule of voiding
Void every hour during the day and nothing in between, slowly increase gaps for at least 6 weeks


LO 8.9 Describe pharmacological management of patients with urinary incontinence

Duloxetine is a combined noradrenaline and serotonin uptake inhibitor. It increases the activity of the External Urethral Sphincter during the filling phase.
Duloxetine is not recommended by NICE as a first line or routine second line treatment, but may be offered as an alternative to surgery.

Act on muscarinic receptors, including the M3 receptors that cause the Detrusor to contract. There are many side effects though due to affects on M receptors at other sites. E.g. Oxybutynin

Botulinum toxin
A potent biological neurotoxin that inhibits Ach release. Prevents Detrusor muscle contraction, as the pelvic nerve cannot release Ach to act on the M3 receptors.


LO 8.10 Describe the surgical management of patients with urinary incontinence


Permanent Intention
o Low-tension vaginal tapes are the commonest surgical intervention. It is a minimally invasive technique with a success rate of > 90%. They work by supporting the mid urethra with a polypropylene mesh.
o Open retropubic suspension procedures correct the anatomical position of the proximal urethra and improve urethral support.
o Classic fascial sling procedures support the urethra and increases bladder outflow resistance. It involves autologous transplantation of the fascia lata or rectus fascia.

Temporary Intention
o Intramural bulking agents improve the ability of the urethra to resist abdominal pressure by improving urethral coaptation. This is achieved by injections of autologous fat, silicone, collagen or hyaluron-dextran polymers.


o Artificial urinary sphincter is the gold standard treatment in urethral sphincter deficiency. The cuff is a mechanical (hydraulic) device that simulates the action of a normal sphincter to circumferentially close the urethra. Problems include infection, erosion and device failure.
o Male sling procedure corrects SUI in men, the cause of which is usually iatrogenic (radical prostatectomy, colorectal surgery, radical pelvic radiotherapy). It is an experimental/emerging treatment, using a bone-anchored tape. The long-term results are unknown.


LO 9.1 Describe the basic structural patterns of glomerular injury and their underlying mechanism and define proteinuria

The site of glomerular injury determines a patient’s clinical presentation. The injury may be primary (just affecting the glomerulus) or secondary (systemic disease that has in turn damaged the glomerulus).

There are four sites of glomerular injury:
o Subepithelial - Anything that effects podocytes/podocyte side of glomerular basement membrane
o Within Glomerular Basement Membrane
o Subendothelial - Inside the Basement membrane
o Mesangial/paramesangial - Supporting capillary loop

Pathology of the Glomerulus
Filter can block
o Renal failure - Hypertensive with Haematuria
Filter can leak
o One or both of Proteinuria (Albumin) and/or Haematuria depending on damage

Proteinuria is the presence of excess serum proteins (<3.5g filtered every 24hours) in urine. The presence of protein in urine is due to podocyte damage, the widening fenestration slits causing protein to be ‘leaked’ when it would normally not be filtered. Proteinuria is a ‘less severe’ Nephrotic Syndrome.


LO 9.2 Describe the basic mechanisms/factors responsible for the different expression of immune complex mediated disease

Subepithelial Deposits
Antigen abnormally recognised on podocytes, circulating IgG binds to it, forming immune complexes in the glomerulus (Not circulating immune complexes causing damage). E.g. Membranous Glomerulonephritis

Mesangial Deposits
Immune complexes can be deposited directly in the mesangium, as there is no podocytes or basement membrane to act as a barrier. E.g. IgA Nephropathy


LO 9.3 Describe the epidemiology of prostate cancer

Prostate cancer is the most common cancer in men in the UK. It is also the second most common cause of death from cancer in men. However, most men who are diagnosed with prostate cancer are more likely to die with it than of it.


LO 9.4 Describe the risk factors of Prostate Cancer

There is a correlation with increasing age and is very uncommon in men younger than 50.

Family History
4x increased risk if one 1st degree relative is diagnosed with Prostate Cancer before age 60 however after age 60 any diagnosis was probably age related

Incidence in Asian < Caucasian < Afro-Caribbean


LO 9.5 Describe the clinical presentation of Prostate Cancer

Vast majority asymptomatic

Urinary symptoms
Benign enlargement of prostate
Bladder over activity
+/- CaP

Bone pain if advanced metastatic

Haematuria is unusual but can be see in advanced prostate cancer


LO 9.6 Describe the diagnostic pathway of Prostate Cancer

A Digital Rectal Examination (DRE) and Serum PSA (Prostate specific antigen) are used to assess whether or not a biopsy of the prostate is necessary. If it is, it is carried out via a TRUS (TransRectal UltraSound) guided biopsy of prostate.

Lower urinary tract symptoms (LUTS) are treated with a TransUrethral Resection of Prostate.


LO 9.7 Describe the principles of prostate cancer treatment

Factors influencing treatment decisions include:
DRE (what stage?) - Localised (T1/2), Locally advanced (T3), Advanced (T4)
PSA Level
Biopsies - Gleason Grade
MRI scan and Bone scan (Are there nodal/visceral metastases)

Treatment of Localised Prostate Cancer
Established Prostate Cancers
Surveillance – if the cancer is low risk, i.e. the Gleason score is quite low sometimes it is appropriate just to watch the cancer, as treatment may do more damage than good.
Radical Prostatectomy – Open, laparoscopic or robotic
Radiotherapy – External beam or low dose brachytherapy (implanted beads)

Developmental Prostate Cancers
High Intensity Focused Ultrasound (HIFU)
Primary Cryotherapy – Freeze the prostate
Brachytherapy – High dose

Treatment of Metastatic Prostate Cancer
Hormones – Surgical castration, medical castration (LHRH agonists)
Palliation – Single-dose radiotherapy, bisphosphonates, chemotherapy

Treatment of Locally Advanced Prostate Cancer
Hormones & Radiotherapy


LO 9.8 Discuss the classification of haematuria

Haematuria is classified as Visible or Non-Visible.

If Haematuria is visible, on investigation there is a 20% chance a malignancy is present (e.g. kidney, ureter).

Non-Visible haematuria can be symptomatic or asymptomatic. It is detected via microscopy or urine dipstick (peroxidation of haem).


LO 9.9 Discuss the differential Urological diagnosis of haematuria

Renal cell carcinoma (RCC)
Upper tract transition cell carcinoma (TCC)
Bladder cancer
Advanced prostate cancer

Benign prostatic hyperplasia (large)

Nephrological (Glomerular)


LO 9.10 Describe the investigation of haematuria

Smoking, Occupation, painful or painless, other lower urinary tract symptoms and family history need to be asked about.

Abdominal mass
Varicocele – collection of veins in the scrotum (‘bag of worms’)
Leg swelling
Assess prostate by DRE (male) – Size, texture

Urine culture and cytology (abnormal cells)
full blood count
flexible cystoscopy (look at bladder)


LO 9.11 Describe the epidemiology of Bladder Cancer

Bladder Cancer is the 7th most common cancer in the UK, but its incidence is decreasing. The male to female ratio is 2.5:1, and 90% are Transitional Cell Carcinomas (TCC)


LO 9.12 Describe the risk factors of Bladder Cancer

Smoking - 4x Increased Risk

Occupational exposure (Rubber or plastics manufacture or handling of carbon, crude oil, combustion. Painters, mechanics, printers, hairdressers

Schistosomiasis (e.g. Egypt)


LO 9.13 Discuss the principles of the staging and treatment of Bladder Cancer

o 75% of Cancers are superficial (Ta/T1)
o 5% are Tis (In situ)
o 20% are muscle invasive

1)High risk non-muscle invasive TCC - Check cystoscopies along with intravesical chemotherapy/immunotherapy
2)Low risk non-muscle invasive TCC - Check cystoscopies
3)Muscle Invasive TCC - Potentially curative - Radical cystectomy or radiotherapy (+/- chemotherapy)
4)Not curative - Palliative chemotherapy/radiotherapy
5)Radical Cystectomy -The removal of the urinary bladder. A piece of Ileum may be used to make a conduit from the ureters to the abdomen, where urine can be collected in a bag. May also attempt to reconstruct the bladder from a piece of small intestine.

Renal Cell Carcinoma (RCC)
1)Epidemiology - Renal Cell Carcinoma is the 8th most common cancer in the UK, making up 95% of all upper urinary tract tumours. The incidence and mortality are increasing. There is a Male to Female ratio of 3:2, and 30% of RCC have metastases on presentation.
2)Risk Factors - Smoking doubles risk, Obesity, Dialysis
3)Metastases - Metastases of RCC can spread to lymph nodes, up the renal vein and vena cava into the right atrium and into the subcapsular fat (Perinephric spread).
Established - Surveillance, Radical nephrectomy - Removal of kidney, adrenal, surrounding fat, upper ureter or Partial nephrectomy
Developmental - Ablation (removal of tumour from the surface of kidney via an erosive process)
Palliative - Molecular therapies targeting angiogenesis

Upper Tract Transitional Cell Carcinoma (TCC)
1) Epidemiology - Only 5% of all malignancies of upper urinary tract (Rest are RCC) 5% are due to the spread of cancer from the bladder up the ureter. 40% of cancers of the upper urinary tract spread to the bladder.
2) Investigation
Hydronephrosis – Swelling of kidney due to backup of urine
CT Urogram - looking for Filling defect or Ureteric structure
Retrograde pyelogram – Inject contrast into the ureter
Ureteroscopy - Biopsy or Washings for cytology
Nephro-ureterectomy – Removal of the kidney, fat, ureter and cuff of bladder.


LO 10.1 Describe an overview of the causes of oliguria and AKI
LO 10.4 Describe the causes of oliguria and AKI

“Little urine" - Less than 500ml of urine/day or less than 20ml/hour

“No urine” - Less than 100ml of urine/day. This Indicates blockage of urine flow

Acute Kidney Injury (AKI)
Pre-Renal Disease - Decreased perfusion
Post-Renal Failure - Obstruction
Intrinsic Renal Failure - Damage to kidney


LO 10.2 Describe the methods used to investigate patients with AKI

o Are the kidneys Underperfused?
o Shock
o Hypovolaemic
o Sepsis
o Pyrexia and rigors
o Vasodilation, warm peripheries
o Bounding pulse
o Rapid capillary refill
o Hypotension
o Cardiac Failure (Overloading kidneys)
o Gallop rhythm
o Raised BP
o Raised JVP
o Pulmonary oedema – Basal crackles and dyspnoea
o Peripheral oedema (Sacral/ankle)
o Severe Vascular Disease
o Emboli

o Are nephrotoxins implicated?
o Drugs
o Sepsis
o Myoglobin
o Parenchymal Disease
o Multisystem disease

o Is there a renal tract obstruction?
o Anuria
o Prostatism
o Urinary Tract Obstruction
o Anuria
o Single functioning kidney
o History of renal stones, prostatism or previous pelvic/abdominal surgery
o Palpable bladder
o Pelvic/abdominal masses
o Enlarged prostate (DRE)

Serum Biochemistry
o Increased Urea & Creatinine in all causes of AKI.
o Hyperkalaemia, Hyponatraemia, Hypocalcaemia and Hyperphosphataemia.

ECG - Changes in hyperkalaemia
o Tall T waves
o Small/Absent P waves
o Increase P-R interval
o Wide QRS complex
o ‘sine wave’ pattern
o Asystole

Urine Testing
o Dipstick testing
o Blood
o Protein
o Leucocytes

Proteinuria Haematuria Microscopy
Pre-Renal - - Normal
ATN - - Muddy Brown Casts
Glmerlonphritis + + RBC Casts

o Pre-Renal - Hyaline cast (Normal Aggregations of protein seen in concentrated urine)
o Acute Tubular Necrosis - Muddy Brown Cast
o Rapidly Progressive Glomerulonephritis - Red Blood Cell Cast

Soluble Immunological Tests
Circulating Antibodies
Anti-Nuclear Antibody (ANA) - SLE
Anti-Neutrophil Cytoplasmic Antibody - Systemic Vasculitis
Anti-glomerular Basement Membrane Antibodies - Goodpasture’s Disease

Ultrasound - Renal Size, Hydronephrosis, Presence of obstruction
CXR - Pulmonary oedema

A biopsy is obtained and looked at when pre-renal and post-renal AKI have been ruled out, a confident diagnosis of ATN cannot be made or Systemic inflammatory symptoms or signs are present.


LO 10.3 Describe the principles of treatment of AKI
LO 10.7 Describe the theraoeutic strategies employed in AKI, including dialysis

Treatment of AKI is dictated by its cause:

Pre-Renal Failure
Volume Correction
Hypovolaemia -> Fluid administration
Heart Failure -> Diuretic

Post-Renal Failure
Urological intervention to re-establish urine flow

Acute Tubular Necrosis
Treatment is supportive, maintaining good kidney perfusion and avoiding nephrotoxins

Dialysis is initiated if the kidneys can no longer adequately excrete salt, water and potassium.


LO 10.8 Describe Asymptomatic glomerular disease

Asymptomatic glomerular disease is detected incidentally by dipstick urinalysis, e.g. at a health check or life insurance medical. It may be detected as microscopy haematuria, proteinuria or both. Sometimes hypertension is detected at the same time. The first investigation carried out is a cystoscopy, with a renal biopsy not being mandatory.

Microscopic Haematuria
o Renal Stones / Tumours
o Arteriovenous malformations
o Glomerular Disease

Microscopic Proteinuria
o Non-nephrotic proteinuria < 3.5g/24hrs protein in urine
o May be associated with other conditions other than glomerulonephritis


LO 10.9 Describe Macroscopic Haematuria

Episodic macroscopic haematuria associated with glomerular disease is often brown or smoky in colour rather than red. Clots are very unusual. It needs to be distinguished from other causes of red or brown urine, including haemoglobinuria, myoglobinuria and consumption of food dyes (e.g. beetroot).

Macroscopic Haematuria is usually painless.

Commonest glomerular cause is IgA nephropathy.

Requires urological work up.


LO 10.10 Describe Nephrotic Syndrome

A non-specific disorder, where the kidneys are damaged, leaking a large amount of protein into the urine

Classic Triad of Findings:
o Proteinuria (>3.5g/24hrs)
o Hypoalbuminaemia
o Oedema
o +/- Hyperlipidaemia)
o +/- Muehrcke’s Bands)

Requires renal biopsy for diagnosis, using an ultrasound-guided needle. The biopsy is aimed at the bottom of the kidney, to try to make sure a piece of cortex is biopsied. As there are no glomeruli in the medulla, it would not be useful for diagnosis.


LO 10.11 Describe Nephritic Syndrome

A collection of signs (syndrome) associated with disorders affecting the kidneys (specifically glomerular disorders), characterised by having small pores in the podocytes of the glomerulus large enough to permit proteins and red blood cells.

Nephritic Syndrome:
o Rapid onset
o Oliguria
o Hypertension
o Generalised oedema
o Haematuria with smoky brown urine
o Normal serum albumin
o Variable renal impairment
o Urine contains blood protein and red blood cell casts


LO 10.12 Differentiate between nephrotic and nephritic syndromes table

Typical Features Nephrotic Nephritic
Onset Insidious Abrupt
Oedema ++ +
Blood Pressure - Raised
JVP Norm Raised
Proteinuria ++ +
Haematuria + or - +++
Red Cell Casts Absent Present
Serum Albumin - - or slightly reduced


LO 10.13 Describe Rapidly Progressive Glomerulonephritis

Rapidly Progressive Glomerulonephritis describes a clinical situation in which glomerular injury is so severe that renal function deteriorates over days.
The patient may present as a uraemic emergency with evidence of extrarenal disease. It is associated with crescentic glomerulonephritis. A renal biopsy is required for diagnosis.


LO 10.14 Describe Chronic Renal Failure and its symptoms

The natural course of many forms of glomerulonephritis is slowly progressive renal impairment, including hypertension, dipstick abnormalities and uraemic syndrome. It is often associated with small, smooth, shrunken kidneys. Biopsies are hazardous and unlikely to provide diagnostic material.

Symptoms of Chronic Renal Failure
o Tiredness and lethargy
o Breathlessness
o Nausea and vomiting
o Aches and pains
o Sleep reversal
o Nocturia
o Restless legs
o Itching
o Chest pains
o Seizures and coma


LO 11.1 Describe the main causes of Chronic Kidney Failure

Chronic Kidney Failure is defined as the progressive and irreversible loss of renal function over a period of months to years.

Functioning renal tissue is replaced by extra-cellular matrix; histologically this gives rise to glomerulosclerosis and tubular interstitial fibrosis. As a result, there is a progressive loss of both the excretory and hormone functions of the kidney. Most Glomerular disease that leads to Chronic Renal Failure is characterised by the development of proteinuria and systemic hypertension.

Causes of Chronic Kidney Disease
Immunologic - Glomerulonephritis
Infection - Pyelonephritis
Genetic - Polycystic Kidney Disease (PCK) orAlport’s Syndrome
Obstruction and reflux nephropathy
Systemic Disease - Diabetes or Myeloma
Cause unknown

Classification of CKD according to GFR

% Population

Stage 1
GFR = >90
Kidney damage with normal or increased GFR
Need other evidence of kidney damage (U/A or USS) 3.3%

Stage 2
GFR = 60-89
Kidney damage with mild GFR fall
Need other evidence of kidney damage (U/A or USS) 3%

Stage 3
GFR = 30-59
Moderate fall in GFR
Symptoms +/-

Stage 4
GFR = 15-29 Severe fall in GFR
Symptoms ++ 0.2

Stage 5
GFR = <15 or RRT
Established Renal Failure Symptoms present
Dialysis is started at <10ml/min GFR

85% of patients with CKD will be identified by looking in registries for diabetes, hypertension and ischaemic heart disease. It is more common in the Elder, Ethnic minorities and the socially disadvantaged.


LO 11.2 Describe the ways in which Chronic Kidney Failure affects the cardiovascular, haematopoietic, musculoskeletal and nervous systems

o Atherosclerosis
o Cardiomyopathy
o Pericarditis

o Anaemia - Decreased or resistance to Erythropoietin

o Renal Bone Disease
o Decreased GFR means that less Phosphate is excreted, increasing its serum concentration. It then forms complexes with free Calcium, reducing its effective serum concentration. This stimulates the Parathyroid to produce PTH, causing over activity of Osteoclasts, leading to Osteitis Fibrosa Cystica.
o Damage to the kidneys means less Vitamin D undergoes its 2nd Hydroxylation to its active form. This also causes hyperparathyroidism, but additionally causes Osteomalacia.
o Non-Bone (e.g. extra articular) Calcification

o Neuropathy
o Seizures
o Coma

General Symptoms
o Tiredness
o Breathlessness
o Restless legs
o Sleep reversal
o Seizure
o Aches and pains
o Nausea and vomiting
o Itching
o Chest Pain

Patients with CKD are more likely to die from a CVS event than require dialysis.


LO 11.3 Describe the principles of conservative management of Chronic Kidney Failure and understand the principles of dialysis and transplantation

Investigating CKD
Measuring Renal Function
A normal GFR range is 80-120ml/min, and renal function can be expressed by a percentage of this. GFR can be measured via Inulin clearance or 24hr Creatinine clearance. If Creatinine is used to measure GFR, it needs to be modified to Estimated GFR (eGFR) by an equation to take into account age, sex, gender and ethnicity. Creatinine is not a perfect marker for renal function, as someone with a GFR of 40% of normal can still have a normal Creatinine level. Further to this it is only accurate in adults and only defines Chronic kidney disease (Not useful in acute renal failure).

Assessment of Cause of CKD
o Auto-Antibody screen
o Complement
o Immunoglobulin
o Imagining of kidneys including Ultrasound for size and Hydronephrosis, CT and possible MRI

Conservative Management of CKD
To prevent delay of progression, there are several potentially modifiable risks:
o Lifestyle
o Smoking
o Obesity
o Exercise
o Treat Diabetes (If present)
o Treat Blood Pressure (If high)
o ACE Inhibitors / Angiotensin Receptor Blockers
o Lipid Lowers (Diet / Statins)

Further to this the patient should be monitored by checking their eGFR and indications for initiation of dialysis

Renal Replacement Therapy (RRT)
When native renal function declines to a level when it is no longer adequate to support health, usually when GFR is < 10ml/min. RRT is either dialysis or renal transplantation.

Indications for Dialysis include uraemic symtoms, acidosis, pericarditis, fluid overload and hyperkalaemia. There are two types of dialysis, Haemodialysis and Peritoneal Dialysis.

Haemodialysis requires the creation of a Ateriovenous (AV) Fistula, a connection between an artery and vein. The difference in pressure means that blood moves from the artery -> vein, causing it to dilate and develop a muscular wall. This provides vascular access.
Using this vascular access, the patient is connected up to a dialysis machine, which contains highly purified water across a semi-permeable membrane. This allows for ‘filtering’ of the patient’s blood.
Anti-coagulation is also needed to prevent the patient’s blood from clotting in the machine.

Effective (Survivors > 25 years)
4/7 days free from treatment
Dialysis dose easily prescribed

Fluid/Diet restrictions
High capital cost
CVS instability
Limits holidays
Access problems

Peritoneal Dialysis
Peritoneal dialysis requires the peritoneal membrane, blood flow and peritoneal dialysis fluid. In peritoneal Dialysis Fluid is put into the peritoneal cavity, and the dialysis occurs across the peritoneal membrane (semi-permeable membrane). The fluid is then drained away and disposed of.

Low Technology
Home technique
Easily learned
Allows mobility
CVS stability
Better for elderly and diabetics?

Frequent exchanges (~4/day)
No long term survivors yet
High revenue costs
Limited dialysis dose range
Frequent treatment failures

Renal Transplantation
All patients with progressive CKD or end-stage renal failure should be considered from transplantation. When a kidney is transplanted, it is not to the normal anatomical location, but to the iliac fossa. This is because it can easily be connected both to the iliac vessels and the bladder.

Restores near normal renal function
Allows mobility and “rehabilitation”
Improved survival
Good long term results
Cheaper than dialysis

Not all are suitable
Limited donor supply
Operative morbidity and mortality
Life long immunosuppression
Still left with progressive CKD


LO 2.1 Describe and identify the Renal Corpuscle

Renal Corpuscle

Vascular Pole – Afferent/Efferent Arterioles, Glomerulus
Urinary Pole – Bowman’s capsule

In development, the renal tubule is derived from the ureteric bud. It envelops the growing glomerulus, resulting in a double-layered cover. This is Bowman’s capsule.

The filtration barrier in the kidney is made up of the capillary endothelium and the visceral layer of Bowman’s capsule, podocytes. Podocytes are ‘cells with feet’, and look like lots of tentacles wrapped around the capillaries.

The capillary endothelium is fenestrated (it is the leakiest capillary in the body), and podocytes invest in it, making filtration slits.

Podocytes and the fenestrated capillary endothelium share a basement membrane.

The parietal layer of Bowman’s capsule makes a ‘funnel’ to collect the ultrafiltrate to drain into the PCT at the urinary pole.


LO 2.1 Describe and identify the Proximal Convoluted Tubule

Proximal Convoluted Tubule

The PCT is the longest, most convoluted section of the tubule. It is where reabsorption begins (see session 1) and is lined with a simple cuboidal epithelium with a pronounced brush border membrane.


LO 2.1 Describe and identify the Loop of Henle

Consists of four parts: (see diagram above)
o Pars recta
o Thin descending limb
o Thin ascending limb
o Thick ascending limb
The four parts are described on the basis of appearance/epithelial lining. Each part has a specialised function.
Thin Limb (Descending/Ascending)

The thin limb dips down into the medulla and is lined with simple squamous epithelium. There is no active transport, and no brush border.

It looks a lot like a small capillary, but there are no RBCs.

Thick Ascending Limb

The tick ascending limb is best seen in the medulla, interspersed with thin limbs, vasa recta and collecting duct. It is lined with simple cuboidal epithelium, but has no brush border. This differentiates it from the PCT. Active transport takes place here.


LO 2.1 Describe and identify the Distal Convoluted Tubule and The Juxtaglomerular Apparatus

The DCT is Cortical (in the cortex), and makes contact with its ‘parent’ glomerulus. It contains numerous mitochondria. When compared to the PCT, it has no brush border and a larger lumen.

The Juxtaglomerular Apparatus
Structures named for their close proximity to the glomerulus of each nephron. It consists of:
o Macula Densa
o Dense staining region of the DCT
o Juxtaglomerular Cells
o Cells of afferent arteriole of the glomerulus
o (Blood vessels bringing blood to Bowman’s communicate with DCT)
o Extraglomerular Mesangial Cells (aka lacis cells)


LO 2.1 Describe and identify the Collecting duct and Renal Pyramid

Collecting Duct

The collecting duct is a continuation of the DCT via the collecting tubule. It is similar in appearance to the thick limbs of Henle’s loop, but the lumen is larger, and tends to be more irregular rather than circular.

Renal Pyramid

Progressively larger ducts merge together and empty at the renal papilla. This forms a pyramid shape.


LO 2.3 Describe and identify the musculature of the bladder

The urinary bladder, like the lower third of the ureter, has three layers of muscle. Its internal epithelium is transitional, and it is surrounded by an outer adventitia.

“Urothelium” is a stratified epithelium, the “umbrella cells” on the surface layer making it impermeable.


What are the Sources of kidneys for transplantation

Cadaver donors
Non-heart beating donors
Living related donors/friends
Autristic donors


LO 6.16 Describe the causes, effects, ECG changes and treatment of hyperkalaemia

Hyperkalaemia depolarises cardiac cells, meaning more fast Na+ channels remain in inactive form and the heart less excitable

Hyperkalaemia ([K+] > 5 nmol/L)

oExternal Balance Problems
Inadequate renal excretion (Increased intake only causes hyperkalaemia in the presence of renal dysfunction). So AKI, CKD, or Reduced mineralocorticoid effect lead to this.
Drugs which reduce/block aldosterone action
K sparing diuretics
ACE Inhibitors
Adrenal insufficiency
oInternal Balance Problems
Shifts of K+ from ICF to ECF like in Acidaemia (Ketoacidosis / Metabolic Acidosis) or Cell Lysis

Clinical Features
oHeart - reduced excitablility
oGI - Neuromuscular Dysfunction leading to Paralytic ileus

ECG changes
Tall, peaked T waves
Prolonged P-R Interval
Tall T waves
ST Segment depression
Widened QRS Interval
Ventricular fibrillation

oReduce K+ effect on heart - IV Calcium Gluconate
oShift K+ into ICF via glucose and insulin IV to Remove excess K+

Longer Term
oRemove excess K+ by Dialysis or Oral K+ binding resins to bind K+ in the gut
oReduce Intake
oTreat cause


What is Nephritic syndrome and its main causes

Nephritic Syndrome
Renal failure due to the blocking of filter.

IgA Nephropathy
The commonest Glomerular Nephropathy, which can occur at any age, characterised by the deposition of IgA antibody in the Glomerulus. It is classically present with visible/invisible haematuria and has been shown to have a relationship with mucosal infections (IgA protects mucosal surfaces). It has variable histological features and course. Some, but not all, patients have proteinuria, and a significant proportion of patients, but not all, progress to renal failure. It is unknown why this variation occurs. Mesangial proliferation and scarring may occur. There is no effective treatment.

Hereditary Nephropathies
There are two hereditary nephropathies, Thin GBM Nephropathy and Alport Syndrome.
The two are not completely distinct however, with a grey area between them.

Thin GBM Nephropathy
Benign Familial Nephropathy
Isolated Haematuria
Thin GBM
Benign Course

Alport Syndrome
X linked
Abnormal collagen IV
Associated with deafness
Abnormal appearing GBM
Progresses to renal failure

Diabetes Mellitus
Progressive proteinuria
Progressive renal failure
Microvascular (Damages glomerulus directly)
Mesangial sclerosis -> nodules
Basement membrane thickening to 4-5x normal

Goodpasture Syndrome
Relatively uncommon, but clinically important as it is very rapidly progressing Glomerular Nephritis. The disease is brought about by an autoantibody to collagen IV in basement membranes, but only seems to affect the kidney for an unknown reason. It is treatable by immunosuppression and plasmaphoresis if caught early. Characterised by IgG deposition but no Extracellular Matrix deposit.

An inflammation of blood vessels that will therefore affect the highly vascularised kidney. Blood vessels are attacked directly in the glomerulus by Anti Neutrophil Cytoplasmic Antibody (ANCA), and is treatable if caught early.


What is nephrotic syndrome and what are its main causes

Nephrotic Syndrome
Over 3.5g of Protein is filtered in 24hrs is known as Nephrotic Syndrome. As a lot of protein is being filtered, oncotic pressure is reduced giving generalised oedema. Podocyte/Subepithelial damage is the likely site of injury.


Minimal Change Glomerulonephritis
Presents in childhood/adolescence with incidence reducing with increasing age. It causes heavy proteinuria or Nephrotic syndrome.
The disease responds well to steroids, but may reoccur once weaned off treatment. There is usually no progression to renal failure and is normally purely protein loss from the kidney. Minimal Change Glomerulonephritis is named as such because when looking at the glomeruli under a light microscope they appear to be completely normal. However, under an electron microscope, the damage to podocytes is evident, widening fenestration slits and allowing protein to ‘leak’ through. Pathogenesis is unknown.

Minimal Change Focal Semgental Glomerulosclerosis (FSGS)
o Focal – Involving less than 50% of glomeruli on light microscopy.
o Segmental – Involving part of the glomerular tuft.
o Glomerular Sclerosis – Scarring
Presents in adulthood and is less responsive to steroids than minimal change glomerulonephritis. Podocytes undergo damage and subsequent scarring, so protein is present in the urine. A circulating factor is responsible for the damage, evidenced by the fact that transplanted kidneys undergo the same damage. Minimal change FSGS can progress to renal failure, but the pathogenesis is unknown.

Membranous Glomerulonephritis
The commonest cause of Nephrotic syndrome in adults. Results from immune complex deposits in the sub-epithelial space and probably has an autoimmune basis (autoantibody to podocytes). However there is also evidence that it may be secondary, as it is associated with other conditions, particularly malignancies e.g. lymphoma. Follows the rule of thirds:
o 1/3 just get better
o 1/3 ‘Grumble along’, proteinuria but are fine
o 1/3 Progress to renal failure

Diabetes Mellitus (microvascular complications affect kidneys)



Describe Pre-Renal AKI and its causes

Pre-Renal AKI
Pre-renal AKI is caused by a reduction in renal perfusion. Unless the cause is recognised and treated promptly, Acute Tubular Necrosis (ATN) will develop. Causes of reduced renal perfusion include:

Reduced effective ECF volume
o Hypovolaemia
Blood Loss
Fluid Loss
o Systemic Vasodilation
o Cardiac Failure
LV dysfunction
Valve disease

Impaired Renal Autoregulation
Renal Autoregulation maintains a normal perfusion over a range of systemic BP.
o Preglomerular vasoconstriction
Hepatorenal syndrome
Drugs – NSAIDS
o Postglomerular vasodilation
ACE Inhibitors
Angiotensin II Antagonists


Describe Post-Renal AKI and its causes

Post-Renal AKI
Post-renal disease indicates an obstruction to urine flow after the urine has left the tubules. It accounts for approximately 10% of AKIs. The obstruction can occur at three anatomical sites:
1. Ureters (bilateral)
2. Bladder
3. Urethra

The obstructions can be further classified:

Within the Lumen
o Calculi (stones)
Both renal pelves/urters (Unless only one functioning kidney)

Neck of the bladder
Stones > 10mm will not usually pass, pain and haematuria is common
o Blood clot
o Papillary necrosis
o Tumour of renal pelvis, ureter, bladder

Within the wall
o Congenital
Pelviureteric neuromuscular dysfunction
Neurogenic bladder
o Ureteric stricture
o Usually cause Chronic not Acute Kidney Injury

Pressure from Outside
o Prostatic hypertrophy
o Malignancy
o Aortic aneurysm
o Diverticulitis
o Accidental ligation of ureter (during surgery)


Describe Intrinsic AKI and its causes

Intrinsic AKI accounts for 30% of all AKIs. It is direct injury to the kidney.
o Acute Tubular Necrosis (ATN)
o Severe Acute Ischaemia
o Toxic Acute Tubular Necrosis
o Glomerular and arteriolar disease
o Immune disease affecting the glomerulus
o Acute tubule-interstitial nephritis
o Inflammation of kidney Intersticium

Acute Tubular Necrosis
oSevere Acute Ischaemia
Pre-Renal Causes - If the fall in renal perfusion is not treated promptly, tubular necrosis results

Toxic Acute Tubular Necrosis
Nephrotoxins damage the epithelial cells lining the tubules, and cause cell death and shedding into the lumen. These nephrotoxins can be Endogenous or Exogenous (drugs). ATN is much more likely if there is reduced perfusion and a nephrotoxin. There will be muddy Brown casts and a Fractional Excretion of Na+ of ≥ 3%

Nephrotoxic Drugs
o Gentamicin
o ACE Inhibitors
o Angiotensin Receptor Blockers
o NSAIDs - Prostaglandins normally cause vasodilation of afferent arterioles in Renal Autoregulation. However NSAIDs inhibit Prostaglandin production (Inhibit COX enzyme). This unopposed vasoconstriction of afferent arteriole leads to reduced glomerular perfusion pressure and thus AKI

Glomerular and Arteriolar Disease
Acute Glomerulonephritis

Immune disease affecting the glomerulus
Primary - Disease only affects the kidneys
Secondary - Kidneys are involved as part of a systemic process e.g. SLE, Vasculitis

Acute Tubulo-Interstitial Nephritis
Inflammation of the Kidney interstitium
Infection - Acute pyelonephritis (Ascending bacterial infection)
Toxin induced - Drugs