Urinary system (CVS) - Dr Carolyn Voisey PDF

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Lecture slides by Dr Carolyn Voisey for the beginning of cycle 2 of the MPharm course. (CVS module). ...

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Dr Carolyn Voisey

URINARY SYSTEM Why? 

The kidneys are crucial for fluid balance  Blood volume & pressure are controlled by the balance of water and ion levels. The kidneys work together with the CVS to maintain these

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Heart and kidney diseases tend to go together  Damage to one usually leads to damage to the other. For example, if the kidneys become impaired, blood pressure is increased to compensate, which means the heart suffers from working against a higher blood pressure

Kidney structure The kidneys are positioned in the back abdominal wall. Urine flows via ureters into the bladder, before being expelled via the urethra. This happens due to contraction of the detrusor muscle & relaxation of the urethral sphincters (i.e. micturition).

Bowman’s capsule + glomerulus) - A tubule extending from the corpuscle to the collecting ducts - Tubules beginning in the cortex, flowing through the medulla & retuning to the cortex *KIDNEY BLOOD SUPPLY* Blood enters the kidney via the renal artery, which then flows via afferent arterioles into compact clusters of capillaries – glomeruli. ~20% of plasma flowing through each glomerulus leaks into the Bowman’s capsule; the remaining blood exits via efferent arterioles into the renal vein.

Dr Carolyn Voisey

Kidney functions     

Regulation of ion & water balance Removal of metabolic waste products from the blood Removal of foreign chemicals from the blood Gluconeogenesis Production of hormones & enzymes (e.g. erythropoietin, renin & 1,25-dihydroxy vitamin D)

The kidney achieves these functions via excretion, which involves: - Filtration of plasma - Secretion of substances into tubules - Reabsorption of certain substances (e.g. water & glucose) - Elimination of substances in urine These processes are regulated by homeostatic mechanisms.

Homeostasis This is a state of reasonably stable balance of physiological variables, such as temperature, oxygen, blood pressure & ion concentration. This stability is achieved by balancing inputs with outputs; a change in a variable triggers a negative feedback system that moves it back towards equilibrium. Constant values can’t be achieved; instead, variables are kept within a narrow range. There is a hierarchy of variables, meaning some may be shifted out of balance to maintain more important ones.

Glomerular filtration Blood in the glomerulus is separated from the Bowman’s space by 3 layers: - Glomerular capillary endothelium - Basal lamina (aka basement membrane) - Bowman’s capsule epithelium The glomerular capillaries are highly permeable; glomerular filtrate contains the majority of soluble nonprotein contents in plasma at the same concentrations. The only exceptions are substances bound to plasma proteins (such as Ca2+ -> will have a lower conc.) and fatty acids. The hydrostatic pressure of glomerular blood (55 mmHg) is significantly higher than in the capsule (15 mmHg), as well as the blood colloid osmotic pressure (BCOP -> 30 mmHg). This allows for a filtration rate of ~180 I/day (125ml/min) for a 70kg adult. This allows the kidneys to regulate plasma composition rapidly and excrete large quantities of waste.

Dr Carolyn Voisey Glomerular capillaries are fed by and drain into arterioles. Therefore, the glomerular filtration rate (GFR) is controlled by the constriction/dilation of arterioles (both afferent and efferent). - Constriction of AFFERENT arterioles decreases blood flow, which decreases GFR - Constriction of EFFERENT arterioles increases capillary pressure, which increases GFR

Renal excretion The extent to which a substance is excreted via the kidneys depends on: - Filtration in the renal corpuscle - Secretion in the tubule - Reabsorption in the tubule

Regulation in the tubule For secretion: - Usually requires active transport from the interstitium into the epithelial cell/from the cell into the lumen - Usually coupled to reabsorption of Na+ - Some are secreted into the tubule as well as/instead of being filtered into the renal corpuscle (e.g. H+, K+, choline, creatinine & uric acid) - Many foreign chemicals are actively secreted (e.g. penicillin & morphine) For reabsorption: - Some substances are reabsorbed to prevent excessive loss (e.g. water, Na+ & glucose) - Can occur via passive diffusion along osmotic/electrochemical gradients (e.g. urea) - Can occur via active transport (e.g. glucose & vitamins)

Reabsorption Water and Na+ are filtered freely in the renal corpuscle – neither is actively secreted into the tubule. Almost all of both (> 99%) are reabsorbed. Na+ reabsorption is an active process that occurs in all sections of the tubule apart from the descending limb of the loop of Henle, while water reabsorption is a passive process entirely dependent on Na+ reabsorption. The primary mechanism of Na+ reabsorption is via Na+/K+ ATPase pumps, which pump Na+ out of the tubular epithelium and into the interstitium. This leads to low [Na+] within epithelial cells, which provides an electrochemical gradient that favours movement of Na+ from the lumen to the cells. Secondary mechanisms of Na+ movement from the lumen into cells include Na+ channels, co-transporters, and Na+/H+ exchangers.

Dr Carolyn Voisey

PCT

Na+ is reabsorbed in exchange for H+. HCO3- is reabsorbed by a mechanism involving carbonic anhydrase. Clthen follows Na+ via paracellular transport, and water follows NaCl via passive diffusion. The fluid in the tubule remains isosmotic with the plasma (same concentration).

Loop of Henle  The descending limb is permeable to water, but doesn’t reabsorb Na+ 

Na+ is reabsorbed in the ascending limb by a Na+/K+/2Cl- co-transporter

 Passive diffusion of water out of the descending limb produces hyperosmotic tubule fluid 

Active transport of Na+ out of the ascending limb produces hyperosmotic interstitium

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The ascending limb is impermeable to water, allowing the fluid inside to become hyperosmotic

As water diffuses out of the descending limb, NaCl remains in the tubule. This causes fluid in the tubule to become increasingly concentrated down the tubule. Therefore, once Na+ is reabsorbed out of the ascending limb, the fluid becomes more diluted again. *COUNTER-CURRENT SYSTEM* Active transport of Na+ produces a hyperosmotic medullary interstitium. Because the ascending limb is impermeable to water, an osmotic gradient is formed which allows water to passively diffuse out of the descending limb, which can’t reabsorb Na+.

Dr Carolyn Voisey

DCT Na+ and Cl- are reabsorbed by the Na+/Cl- co-transporter, while H+ and K+ are secreted. Because the late DCT is permeable to water, fluid in the tubule becomes isosmotic with the cortical interstitium. Ca2+ is also reabsorbed under the control of the parathyroid hormone, which controls Ca2+ homeostasis.

Collecting ducts DCT epithelial cells (macula densa) and juxtaglomerular cells (found in afferent arteriole walls) form the juxtaglomerular apparatus. This is a specialised structure that regulates blood pressure and the filtration rate of the glomerulus. In the cortical collecting ducts, low [Na+] is detected by the macula densa cells. This stimulates renin secretion from juxtaglomerular cells, which causes the cleaving of angiotensinogen to form angiotensin – which in turn causes the release of aldosterone from the adrenal cortex. This promotes Na + reabsorption in exchange for K+, as well as an increase in blood pressure. In the medullary collecting ducts, the permeability of water is regulated by antidiuretic hormones (ADH & vasopressin). In the presence of ADH, water is reabsorbed due to the hyperosmolarity of the medullary interstitium, meaning urine is hyperosmotic. As water is reabsorbed, urea in the tubule exceeds that in the interstitium, which leads to some reabsorption of urea via passive diffusion. Therefore, 100% excretion of urea can’t be achieved without excessive loss of water.

Chronic renal disease This is common and can be diagnosed using estimated GFR, which measures kidney function (specifically, protein in urine). Risk factors include age, high blood pressure, diabetes, and a family history of chronic renal failure. This can potentially lead to total kidney failure. Symptoms include: - Swollen ankles/feet/hands (due to water retention) - Anaemia (due to blood loss in urine) - Tiredness - Nausea - Shortness of breath Treatment for chronic kidney failure depends on the stage of the disease: - Early stages -> lifestyle changes and medication that controls blood pressure & blood cholesterol - Late stages/kidney failure -> dialysis and kidney transplant

Other kidney diseases 

GLOMERULONEPHRITIS The most common cause of chronic renal failure; this can result from the deposition of immune complexes in the glomerulus. Can cause impaired filtration, leading to fluid retention and hypertension. Inflammation of the glomerulus can also lead to loss of protein and blood in the urine.

Dr Carolyn Voisey 

ACUTE RENAL FAILURE Causes reduced glomerular filtration, which leads to total reabsorption of NaCl in the PCT. This means the remainder of the tubule receives no fluid, so urine flow ceases. Treated with osmotic diuretics (e.g. mannitol), which holds water inside the tubule.

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DIABETES INSIPIDUS Causes a deficiency of ADH, which leads to excessive water loss in urine. Treated with desmopressin – an ADH analogue....