Urinary Flashcards

Question

LO 4.11 Discuss prostaglandins and NSAIDs

Answer 1

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.

Answer 2

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.

Answer 3

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

Answer 4

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.

Answer 5

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.

Answer 6

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.

Answer 7

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.

Answer 8

``` 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)

Answer 9

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

Answer 10

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.

Answer 11

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.

Answer 12

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.

Answer 13

The normal range of plasma pH is 7.38 – 7.42

Answer 14

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)

Answer 15

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

Answer 16

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 -

Answer 17

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.

Answer 18

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+].

Answer 19

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.

Answer 20

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.

Answer 21

[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.

Answer 22

[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.

Answer 23

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.

Answer 24

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

Answer 25

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

Answer 26

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 1)Insulin 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 1)Exercise 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.

Answer 27

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) ``` Causes 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 Treatment 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

Answer 28

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.

Answer 29

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.

Answer 30

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

Answer 31

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).

Answer 32

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. Investigations 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 ``` Microscopy 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 Symptoms 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 ```

Answer 33

General – Increase fluid intake, address underlying disorders. Bacteria may be present asymptomatically - only treat once symptoms appear. Uncomplicated o 3 Day course of antibiotics o 3 day course reduces the selection pressure for resistance Complicated o 7 Day course of antibiotics. o Amoxicillin not appropriate as 50% of isolates are resistant Pyelonephritis/Septicaemia o 14 day course of antibiotics o Use more potent agent with systemic activity ``` Prophylaxis 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 ```

Answer 34

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

Answer 35

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

Answer 36

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 ```

Answer 37

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

Answer 38

``` Detrusor o Parasympathetic Pelvic Nerve (S2-S4) Ach -> M3 Receptors Contraction o Sympathetic Hypogastric Nerve (T10-L2) NA -> B3 Receptors Relaxation ``` ``` Internal Urethral Sphincter Sympathetic Hypogastric Nerve (T10-L2) NA -> A1 Receptors Contraction ``` ``` External Urethral Sphincter Somatic Pudendal Nerve (S2-S4) Spinal motor outflow from Onof’s Nucleus of the ventral horn of the cord Ach -> Nicotinic Receptor Contraction ```

Answer 39

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.

Answer 40

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 Incidence Stress Urinary Incontinence is by far the most common

Answer 41

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.

Answer 42

History 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. ``` Examination 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 ``` Investigation Mandatory 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) Optional o Invasive urodynamics (pressure-flow studies +/- video) o Pad tests o Cystoscopy

Answer 43

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

Answer 44

Duloxetine 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. Anticholinergics 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.

Answer 45

Females 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. Males 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.

Answer 46

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 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.

Answer 47

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

Answer 48

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.

Answer 49

Age 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 Race Incidence in Asian < Caucasian < Afro-Caribbean

Answer 50

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

Answer 51

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.

Answer 52

Factors influencing treatment decisions include: Age 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 Surveillance Hormones Hormones & Radiotherapy

Answer 53

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).

Answer 54

``` Cancer Renal cell carcinoma (RCC) Upper tract transition cell carcinoma (TCC) Bladder cancer Advanced prostate cancer ``` ``` Other Stones Infection Inflammation Benign prostatic hyperplasia (large) ``` Nephrological (Glomerular)

Answer 55

History Smoking, Occupation, painful or painless, other lower urinary tract symptoms and family history need to be asked about. Examination BP Abdominal mass Varicocele – collection of veins in the scrotum (‘bag of worms’) Leg swelling Assess prostate by DRE (male) – Size, texture ``` Investigations Urine culture and cytology (abnormal cells) full blood count ultrasound flexible cystoscopy (look at bladder) ```

Answer 56

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)

Answer 57

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)

Answer 58

Staging o 75% of Cancers are superficial (Ta/T1) o 5% are Tis (In situ) o 20% are muscle invasive Treatment 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). 4)Treatment 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 Immunotherapy 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 Ultrasound 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 3)Treatment Nephro-ureterectomy – Removal of the kidney, fat, ureter and cuff of bladder.

Answer 59

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

Answer 60

``` Pre-Renal 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 ``` ``` Renal o Are nephrotoxins implicated? o Drugs o Sepsis o Myoglobin o Parenchymal Disease o Multisystem disease o UTI ``` ``` Post-Renal 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 Microscopy 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 Imaging Ultrasound - Renal Size, Hydronephrosis, Presence of obstruction CXR - Pulmonary oedema Histology 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.

Answer 61

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

Answer 62

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

Answer 63

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.

Answer 64

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.

Answer 65

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 ```

Answer 66

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

Answer 67

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.

Answer 68

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 ```

Answer 69

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 Hypertension Vascular Systemic Disease - Diabetes or Myeloma Cause unknown ``` Classification of CKD according to GFR Stage GFR Description % 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 +/- 6% ``` 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 0.1% ``` Incidence 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.

Answer 70

Cardiovascular o Atherosclerosis o Cardiomyopathy o Pericarditis Haematology o Anaemia - Decreased or resistance to Erythropoietin Bone 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 CNS 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.

Answer 71

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 ANCA o CRP o SPEP/UPEP 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. Dialysis Indications for Dialysis include uraemic symtoms, acidosis, pericarditis, fluid overload and hyperkalaemia. There are two types of dialysis, Haemodialysis and Peritoneal Dialysis. Haemodialysis 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. Advantages Effective (Survivors > 25 years) 4/7 days free from treatment Dialysis dose easily prescribed ``` Disadvantages 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. ``` Advantages Low Technology Home technique Easily learned Allows mobility CVS stability Better for elderly and diabetics? ``` ``` Disadvantages Frequent exchanges (~4/day) No long term survivors yet Peritonitis 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. ``` Advantages Restores near normal renal function Allows mobility and “rehabilitation” Improved survival Good long term results Cheaper than dialysis ``` ``` Disadvantages Not all are suitable Limited donor supply Operative morbidity and mortality Life long immunosuppression Still left with progressive CKD ```

Answer 72

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.

Answer 73

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.

Answer 74

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.

Answer 75

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)

Answer 76

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.

Answer 77

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.

Answer 78

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

Answer 79

Hyperkalaemia depolarises cardiac cells, meaning more fast Na+ channels remain in inactive form and the heart less excitable Hyperkalaemia ([K+] > 5 nmol/L) Causes 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 oAcidosis ``` ECG changes Tall, peaked T waves Prolonged P-R Interval Tall T waves ST Segment depression Widened QRS Interval Ventricular fibrillation ``` Treatment Emergency oReduce K+ effect on heart - IV Calcium Gluconate oShift K+ into ICF via glucose and insulin IV to Remove excess K+ oDialysis Longer Term oRemove excess K+ by Dialysis or Oral K+ binding resins to bind K+ in the gut oReduce Intake oTreat cause

Answer 80

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 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. Vasculitis 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.

Answer 81

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. Causes: 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) Amyloidosis

Answer 82

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 Sepsis Cirrhosis Anaphylaxis o Cardiac Failure LV dysfunction Valve disease Tamponade ``` ``` Impaired Renal Autoregulation Renal Autoregulation maintains a normal perfusion over a range of systemic BP. o Preglomerular vasoconstriction Sepsis Hypercalcaemia Hepatorenal syndrome Drugs – NSAIDS o Postglomerular vasodilation ACE Inhibitors Angiotensin II Antagonists ```

Answer 83

``` 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 Urethra 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 Megaureter 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) ```

Answer 84

``` 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