Urinary Flashcards
LO 1.1 Describe the overall functions of the urinary system
The Kidney must:
- Control volume
- Control osmolarity
- Help to control pH
- 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).
Nephron Renal Corpuscle (Blood filtering component of the nephron) Glomerulus 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 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
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
Autoregulation
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)
4)Vasodilators
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 oExocytosis
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
Intestines
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.
Kidneys
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.
Symptoms
Gastrointestinal Anorexia Nausea/Vomiting Constipation Acute pancreatitis (rarely)
Cardiovascular
Hypertension
Shortened QT interval on ECG
Enhanced sensitivity to digoxin
Renal
Polyuria and polydipsia
Occasional nephrocalcinosis
Central Nervous System
Cognitive difficulties and apathy
Depression
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
Acidaemia
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
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
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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.
