Genitourinary Physiology

Role of the kidney filtration system

• Water and salt balance in body: we consume about 20-25% more salt and water than required each day
- Intake: ingested in the form of liquid and food; formed from oxidation of carbohydrate
- Loss: sweat, breathing, faeces and urination
• Passive movement of water and urea:
- There are no active pumps for water in the body. Water moves by osmosis to area of low water concentration (hyperosmole) depending on ion concentration (which is actively pumped)
- Urea passively follows the movement of water but at a slower rate
• Aquaporin: passive channel for water entrance and exit across the cell membrane.
• Overall mechanism of the kidney: as water and urea does not have pumps, direct excretion of the excess substance is not possible. Instead a large volume of fluid and ions is filtered and then around 99% is reabsorbed back into the plasma leaving behind the water, salt and urea.
• Role of the kidney: to regulate water and ion balance in the body
• Filtration: large amount of protein-free plasma is made in the bowmen’s capsule through the filtration of blood (through the pedicles, endothelium, and basement membrane that is not large enough to permit protein to pass through). Around 6L is filtered per hour.
- The renal filtration tubule is impermeable to urea except aquaporins. Thus its necessary to reabsorb the 99% filtered fluid as fast as possible before the urea passes through the aquaporin with water.
- Urine: The resultant 60mL per hour of water that is left within the tubule (not reabsorbed) containing all the trapped urea
• Role of the proximal tubule: to remove water from the proximal tubule into the interstitial space against the concentration gradient created by the tubular urea. This is achieved through ion pumps.
- Salts such as Na+, K+, Cl- and bicarbonate in addition to glucose and amino acids are actively pumped form the tubule back into plasma using ATP as fuel
- As along as the plasma osmolality is greater than the tubular urea’s, water will exit following the movement of the solute. Water content drops from 6L to 1.5L.
- The resultant concentration of both tubule and plasma is at equilibrium (water will always diffuse to balance the concentrations)
• The remaining fluid in the proximal tubule:
- Contains almost zero amino acid and glucose
- Urea concentration increased by 4 folds than the original filtrate
- Salt concentration is significant lower than original
• Role of loop of henle: create a hyperosmotic environment to remove as much as the final 1.5 L of water.
- The ascending loop of henle is impermeable to water with no aquaporin. As a result, the continual pumping of the salt (Na+ and Cl-) from the fluid into the extracellular space will reduce the osmolality in the tubule fluid
- The salt pumped out from the ascending limb can return to the descending limb through the Na+ and Cl- ion channels hence increasing the osmolality of the fluid passing down the descending limb.
- Now the hyperosmolar fluid at the tip of the loop will therefore absorb water from its surrounding creating an extremely dry hyperosmotic environment in its vicinity.
- Countercurrent mechanism: allows the diluted fluid to be brought back to the renal cortex and then re-enter the medulla through the descending collecting duct down an increasing concentrated environment to remove the remaining water.
• Role of the collecting duct: epithelium of the collecting duct has the ability to insert aquaporin-2 into the luminal side when ADH binds to vasopressin 2. This allows the hyperosmotic environment of the medulla to drain the final bit of water out from the collecting duct reducing 1.5L/h of fluid to only 15mL/h.
- The concentration of the urine will be the same as that of the inner medulla.
• ADH: anti-diuretic hormone functions by binding to V2 which will cause endosomes with AQP-2 to fuse with the cell membrane and hence inserting water channels.
- APQ are removed from the luminal membrane by clathrin coated vesicles
- In the absence of ADH, the water is not absorbed causing diuresis
• Removal of water from the medulla: two methods
- Removed by vasa recta that follows the loop
- Limitations: vasa recta is passive system and to remove water, energy would have to be expended which is unlikely. Also osmolality of the return flow from ascending limb is higher than when it entered showing that vasa recta is actually losing water in the medulla.
- Removal by the hairpin loop of henle. This is based on the fact that when water is absorbed into the loop, the osmolality of the fluid decreases further and at the distal tubule, it is even lower than that of the surrounding plasma allowing water to move out by osmosis.
• Vasa recta: capillary system of the kidney that follows closely with the loop of henle but blood travels in the opposite direction.
- Function: contains vasopressin that exits the vessel to bind to vasopressin receptors and tranduce a signal to insert aquaporins. Osmolality of the vasa recta as it passes into the inner medulla is just above that of the inner medulla, hence able to absorb water at each level (as it gets diluted) to maintain hyperosmolality.
• Secretion of waste product: most waste products are simply not absorbed back. Only substances secreted in the proximal tubular fluid are drugs such as toxic products of food produced by plants and fungi, e.g. bread, coffee. Also concentrates of plants, fungal and bacterial substances provided by pharmacist.
• Osmotic diuresis: occurs through the countercurrent multiplier effect
- When amino acids or glucose is not properly absorbed in the proximal tubule, it can osmotically retain water thus increasing the flow rate of water down the proximal tubule.
- In addition, ions pumped out of the ascending loop of henle are added to each litre of tubular fluid in the hairpin bend of the loop of henle. But due to the faster flow rate, the effect of osmolality increase is not high.
- The result an ineffective hyperosmotic environment

Glomerular filtration

• Glomerular filtration rate: renal blood flow is approximately 20% of total cardiac output and given a red cell mass of about 40% in blood, renal plasma flow rate is 0.5 – 0.6L/min. This yield a final filtration rate of around 125-150mL/min
- Proportional to size
- Depends on net filtration pressure and plasma flow rate
- Autoregulated by tubuloglomerular feedback and neurohormally controlled
• Filter:
- Pores in endothelium
- Basal lamina
- Filtration slit between the pedicels
• Net filtration pressure: determined by starling’s force equation

- Capillary pressure (Pc): hydrostatic pressure of the blood in the capillary to push blood out
- Interstitial pressure: (Pi): hydrostatic pressure of the blood in the capsule to push blood back into the capillaries (physical pressure by wall contraction)
- Capillary oncotic pressure (πc): osmotic pressure created by the unfiltered protein that remain in the capillaries to draw the water back
- Interstitial oncotic pressure (πi): glomerulus osmotic pressure created by the filtered ions, glucose, amino acids etc in the capsule to draw water out of the capillary
- Filtration coefficient: Kf reflects the surface area ad hydraulic conductivity (rate of water flux for a fixed pressure gradient). In the glomerulus, the conductivity is 40-50 times more than normal capillaries
• Pattern of glomerular NFP: the hydrostatic pressure difference between the capillary and capsule remain relatively constant through the length of the glomerulus. However the capillary oncotic pressure becomes increasing greater as components of the blood is being filtered out. Consequently NFP decreases from afferent end to the efferent end.
• Bowen’s capsule: the glomerulus is surrounded by afferent and efferent arteriole with no vein. Hence there is no reabsorption
• Pathological effect on GFR: The GFR is usually able to autoregulate to maintain steady rate and is not dependent on arterial pressure. Major changes are due to:
- diabetes thickens basement membrane thicken the filtration and decrease filtration
- Severe hypotension
- Tubular dysfunction and injury
- Back pressure from blockages in collection systems
• Constriction of blood vessel:
- Afferent constriction: vasoconstriction of the afferent arteriole increase resistance hence reducing renal blood flow and GFR.
- Vasocosntriction stimulated by sympathetic nerve and adenosine with endothelin and thromboxane as vasoconstrictors. Vasodilators are NO, PG-E2 and ANP
- Efferent constriction: vasoconstriction of the efferent arteriole causes pressure to build up in the glomerulus hence increasing GFR
- Vasoconstriction stimulated by angiotensin II mainly
• Mechanism of autoregulation:
- Intrinsic: local myogenic vascular response mediated by PG and NO and tubuloglomerular feedback response
- Extrinsic: Renin-angiotensin pathway (maintain GFR at low MAP) and sympathetic pathway. Also ANP/BNP
• Macula densa: group of specialize sensor cells located in the wall of the section of distal convoluted tubule that is juxtaposed with the glomerulus (between efferent and afferent arterioles)
- Increase GFR cause increased delivery of solute to the macula densa
- Paracrine signaling from macula densa to the JG cells of afferent arterioles causing them to constrict
- GFR decreases in response
- Adenosine is found to mediate this feedback response
• Renin feedback system: can be stimulated by
- macula densa in response to increase GFR
- baroreceptors in the afferent arteriole
- direct innervation of the renal sympathetic nerve activity
• ANP: hormone produced in the atrial myocytes and released in response to atrial distention (stretch) due to high blood pressure, sympathetic stimulation and angiotensin II. It act on the kidney to increase GFR and reduced body fluid volume.
- Dilate the afferent arteriole, constrict efferent arteriole and relax mesangial cells.
- Causes around 60% of flow rate through loop of henle (1.5L/h to 2.5 L/h) and diminishing its effectiveness to generate a hyperosmolar environment, i.e. as the ion in the tubule is diluted
- Water reabsorption will be overall compromised in the collecting duct and hence causing increase urination.

Tubular function

• Reabsorption at proximal tubule: active transcellular and passive paracellular transport of solute from the tubule into interstitial space.
- Primary active transport: movement of substance up an electrochemical gradient
- Secondary active transport: using the gradient of a substance to move another one through symporter or antiporter.
• Apical surface: large surface due to the villi and micro-villi with specific transporters. Tight junctions also used for reabsorption.
• Basolateral surface:
- Na+/K+ ATPase establish the sodium gradient for solute by pumping out into the interstitial fluid 3Na+ in exchange for 2 K+
• Glucose transport: glucose absorption is coupled with Na+ through the glucose symporter through the apical surface (which pulls glucose into the cell against its concentration gradient) and glucose exits by facilitated diffusion out the basement surface.
• Na+ transport:
- In the proximal tubule with glucose and amino acids and accompanied by H+ secretion (antiport)
- In the ascending limb of loop with Cl- through symporter
• HCO3- transport: Carbonic anhydrase on the brush border of tubular cells accelerate the production of carbon dioxide and water from the bicarbonate ions. Carbon dioxide diffuse into the cells and combine with water again to form H2CO3 which dissociates into bicarbonate and H+ (pumped into tubule)
• Chloride reabsorption: Chloride concentration is increased down the proximal tubule with reabsorption of Na+ along with water. At the end of the proximal tubule, the gradient becomes so large, passive movement of chloride occurs into paracellularly into the interstitial fluid, pulling more sodium ions along with it
• Amino acid transport: symport with Na+ (around 3 mmol/L in plasma). There are 5 carrier systems each with their independent TM
- Acidic
- Basic
- Neutral
- Imino
- glycine
• Phosphate transport: symport with sodium on the luminal side. Exist mainly due to the result of protein metabolism with 1 mmol/L in plasma.
• Calcium transport: reabsorped in proximal tubule parallel with Na+ and water so its concentration remains relatively stable. It enters passively down the electrochemical gradient but leaves the cell via a Ca2+/Na+ antiporter or Ca2+ ATPase.
- Around 40% of Ca is bound to plasma proteins so not easily filtered by the glomerulus
• Potassium transport: 90% K+ is absorbed passively in the proximal tubule paracellularly as a result of increasing concentration from the movement of sodium and water. The remaining 10% occurs in the thick ascending limb of loop of henle.
• Organic ions: actively secreted in the proximal tubule. These are the end products of metabolism such as bile acid, creatinine, adrenaline and exogenous organic compound, e.g. penicillin, aspirin and morphine.
- Bounded to plasma proteins so not free filtered in the glomerulus. Secretion is key method of eliminating these toxic substances
• Saturation kinetics: an increase in substrate concentration will yield an increase in transportation rate until a certain point at which the transporter reaches its full capacity (TM).
- Glucose transporter: saturates at 300mg/100mL reaching a maximum rate of 375mg/min
- The length of the proximal tubule can vary so transport maximum varies also. This produce a non-linear relationship of concentration of substrate lost in the urine with the plasma concentration at the start.
- Bicarbonate: also there is no active transporter for bicarbonate, the reabsorption process behaves as if there is a transport maximum of around 25mmol/L.
- Phosphate: close to normal filtered amount so increase plasma concentration will lead to excess excreted. Rate of reabsorption is regulated by parathyroid hormone (decrease) and calcitriol (increase)
• Acidification of urine: H+ is released from
- Carbonic acid dissociation in the cells
- Ammonium excreted by the cells from H+ and amino acids
- Phosphoric acid filtered in the tubule
• Potassium balance: The kidney is much faster at excretion than conservation of potassium hence hyperkaelemia is very unlikely even with large potassium intake. But if intake is restricted, hypokaelemia is likely to develop.
- Feature of K+: 98% of potassium in the body is stored within cells. Renal response to K+ changes is very slow usually involving immediate local adjustment, such as uptake of K+ into cells with a K+ load.
- Potassium deficiency: since potassium adjustment is very slow, deficiency of serum K+ usually does not indicate a huge total body deficiency (however if it was proportional, 4 to 3 mmol/L loss would mean a total 1 mol/L loss of K+)
- Potassium secretion: appearance of K+ in urine indicates distal secretion. The K+ secretion cells are the principle cells. Potassium is brought into the cell by Na+/K+ ATPase at the basolateral membrane. While some K+ returns back, most passively escapes through the apical membrane into the tubule as it is more permeable
• Role of aldosterone: aldosterone stimulates K+ secretion by increasing uptake via the Na+/K+ ATPase and increasing K+ permeability of apical cell membrane to potassium. Furthermore, aldosterone increase Na+ reabsorption to further stimulate counter-ion release of K+
• Luminal flow rate: increase in tubular fluid flow rate will increase K+ secretion due to the tubule attempting to maintain a consistent favourable K+ gradient.
• Effect of diuretics: diuretics act on K+ secretory sites will increase urinary K+ loss. These include osmotic diuretics, loop diuretics (frusemide and thiazides).
- Loop diuretics inhibit symporters hence inhibiting reabsorption of K+ on the ascending thick limb
- Diuretics prevent water reabsorption so increase in luminal flow rate will also increase K+ loss
- K-sparing diuretics prevent K+ loss in the urine through inhibition of its secretion, e.g. spironolactone and amiloride (inhibit Na+ entry)

Renal Function Tests

• Renal function tests:
- Glomerular function: assessing GFR from plasma creatinine, urea and also assess glomerular permeability to large molecules such as urine proteins or albumins.
- Tubular function: urine volume and content such as Na+, pH and protein
• GFR testing: the best method for accessing overall renal function. Requires:
- Insulin clearance
- 51Cr-EDTA clearance
- Not practical for normal clinical use as it requires injection of substance and measuring rate of disappearance (labour-intensive)
- Estimated GFR: in clinical practice, GFR is estimated using plasma creatinine clearance.
• Adjustment for GFR: as bigger size individual have bigger kidney, GFR is adjusted to body surface 1.73m2 (arbitrarily set standard).
- Reference range for normal is 80-120 mL/min/1.73m2. Can be used to assess stages of renal disease.
- Unadjusted GFR however is still important in calculation of drug dosage as the absolute GFR is required to take into account.
• Plasma urea: main excretory product for waste nitrogen, formed in liver from amino acids and urea cycle. Amount depends on:
- Dietary protein intake
- Protein breakdown, increased by infections, trauma, immobilization (sickness)
- Bleeding into GIT
- Renal processing: urea is filtered and variable amount is absorbed from diffusion. Fraction increases when flow rate is slow and excretion is dependent on GFR.
• Plasma urea indication: in renal failure, plasma urea increases. In adults normal range is 3.2-7.7 mmol/L. This is a rough index of glomerular function and but not as good as plasma creatinine (increases more than creatinine in dehydration)
• Creatinine: derived from creatine but an unstable form with no biological functions. 1% of creatine spontaneously converts irreversibly to creatinine hence creatinine is proportional to muscle mass.
- Creatine: present in large quantities in muscles as the ATP stores.
- As creatinine is freely filtered and there is no tubular reabsorption/secretion, it is proportional to GFR, i.e. plasma creatinine increases when GFR decreases.
- Plasma creatinine however is an insensitive index of renal function as it doesn’t detect early onsets (i.e. GFR drops by a large amount before changes is seen in plasma creatinine). However over time, serial measurement can be used to monitor progress.
- Standard ranges: male 50-120 micromol/L, female 40-100 micromol/L
• Effect of meat intake on creatinine: plasma creatinine rises by 10 to 30 micromol/L after a meat meal. This is because creatinine formation occurs in the meat, especially during cooking.
- A test taken at this point will falsely underestimate GFR. Hence blood sample should be taken after a meat-free period of 12 hours.
• Estimated GFR: derived using plasma creatinine. Equations used are usually MDRD and Cockcroft-Gault equation. eGFR of above 80 is normal while lower than 80 mL/min/1.73m2 is renal disease. Disadvantages:
- Creatinine is affected by muscle mass so in severe muscle wastage, renal failure may not be indicated and vice versa.
- eGFR is only valid for patient in steady state of stable creatinine level. It is not valid if creatinine is rising in acute renal failure or falling during recovery.
• Equations of eGFR:
- MRDR: requires plasma creatinine, age and sex
- Cockcroft-Gault: requires plasma creatinine, age, sex, weight and height
• Decline of GFR: with age, GFR decreases. Hence for older people, the normal range of plasma creatinine is much higher which may mask effect of renal failure at times.
• Creatinine clearance: a measurement of GFR independent of muscle mass. Urine creatinine is divided by plasma creatinine as a method to adjust for muscle mass. Normal range is 90-140 mL/min The equation is:

where UC is urine creatinine, PC is plasma creatinine, UV is urine volume and TC is time of collection
- Error: over-collection and incomplete collection
• Urine creatinine output: a test for the “completeness” of urine collection.
• Primary renal disease:
- Clinical presentation: increasing tiredness and frequent headaches
- Examination: hypertensive and excessive protein with urine dipsticks test. Serum creatinine and urea are both elevated while eGFR is extremely low. Creatinine clearance was low.
- Explanation: damage to the renal vessels and tissue causes glomerulus dysfunction and hence protein excretion in urine and loss of GFR making creatinine levels high.
• High muscle mass:
- Clinical presentation: hypertension
- Examination: no protein in dipstick test but elevated serum creatinine and urea with lowered eGFR. Creatinine clearance is also higher than normal.
- Explanation: due to high muscle mass, creatinine level is higher causing all the creatinine related markers to be elevated. The renal function is normal. The high urea content is possibly due to his high protein diet
• Chronic renal failure:
- Clinical presentation: dizzy spells, hypertensive and anemic.
- Examinations: serum creatinine is at high range while serum urea is elevated. eGFR and creatinine clearance is both low.
- Explanation: serum creatinine was within the normal range due to her low muscle mass even though she has renal dysfunction.
• Assessment of glomerular permeability: albumin is the maximum size protein filtered so protein above 66kDa of weight are retained
• Renal handling of plasma protein: proteins below 60kDa that are filtered are
- Cystatin C: plasma concentration can be used as a measure of GFR (similar to creatinine)
- Immunoglobulin: appear in urine in myeloma
- Amylase: appears in urine in pancreatitis
- Filtered small proteins are taken up endocytosis and catabolised to amino acids by proximal tubule cells (these have highest rate of protein catabolism in the body)
- Due to this reason, chronic renal failure suffers greater damage from ischemia as proximal tubule is very ATP dependent.
• Proteinuria: protein in urine
- Normal: <23mg/mmol ratio of protein to creatinine, <2.5mg/mmol ratio albumin to creatinine
- Abnormal: albumin in the range only 2.5 to 25 mg/mmol creatinine is microalbuminuria while nephritic syndrome causes it to be increased to 400mg/mmol creatinine.
- Albumin is a much more sensitive index of early renal disease than total protein, i.e. albumin is the first substance to get through with renal disease
• Clinical significance of proteinuria:
- Albumin/creatinine ratio is the most sensitive test
- Allows for early detection for renal disease from hypertension nephropathy, diabetic nephropathy, pre-eclampsia, silent renal disease (pick up early for prevention)
- Assessment and monitoring of known renal disease
- Dipstick test: detects moderate-severe proteinuria but may miss mild proteinuria and does not detected immunoglobulin light chains.
• Orthostatic proteinuria: benign conditions of proteinuria that occurs when standing upright with around 500mg per day lost. There is no hypertension and other renal function tests are normal.
• Nephrotic syndrome: massive proteinuria and the urine may appear frothy. Loss of protein cause low serum albumin and oedema.
• Electrophoresis patterns of proteinuria:
- Selective proteinuria: only transferrin albumin present
- Non-selective proteinuria: all serum proteins present
- Tubular proteinuria: low MW protein
• Microscopy of urine sediment: red and white cells can be from anywhere in urinary tract.
- Hyaline: normal cast
- Granular: cellular debris (abnormal)
- RBC: glomerulonephritis
- WBC: pyelonephritis
- Last 3 types of cast indicate renal disease is present

Regulation of water balance

• Plasma osmolality: osmolality of solute and ion in the plasma is tightly regulated due to their important functions:
- Setting the membrane potential
- Generate electrical activity in nerves and muscle
- Initiation of muscle contraction
- Providing energy for uptake of nutrients and the expulsion of waste products
- Generation of intracellular signaling cascade
- Most importantly: cell volume determined by the osmotically active particles within and outside the cell
• Role of water: the amount of salt present in ECF is usually constant or changes very slowly. Hence the chief determinant of osmolality is water
• Molarity: molecular weight of substance in grams
• Osmolality: number of osmoles dissolved per kilogram of solvent
• Osmolarity: number of osmoles in the total solution
• Dissociation of solutes:
- Glucose is one molecule hence 1 mole of glucose dissolved produces 1 osmole
- NaCl on the other hand dissociates into Na+ and Cl- in solution so 1 mole dissolved produces 2 osmole
• Tonicity: effective osmolality of the solutes which have the capacity to exert an osmotic formcee across the cell membrane.
- Hypertonic solution: ECF has greater osmolality so water will move out of the cell causing it to shrink
- Hypotonic solution: ECF has lower osmolality so water will move into the cell causing it to swell
- Isotonic solution: equal osmolality so cell volume stays the same
• Behaviour of solutes: 300 mosmole/L is a normal value for plasma osmolality. However if a substance can cross a plasma membrane, it cannot exert an osmotic pressure as the solute itself will diffuse to equilibrate.
- Salt: 150 mmol/L NaCl does not cross the cell membrane so is iso-osmotic and isotonic
- Urea: 300 mmol/L urea can cross the cell membrane (carrying water with it) so its iso-osmotic but hypotonic
- Glucose: 600mmol/L of glucose is hyperosmotic but hypotonic as it is absorbed into the cells and digested while carrying water with it.
• Hypothalamus: cell body of the supraoptic nerve of the hypothalamus extends down to the posterior pituitary. Increase in ECF osmolarity causes osmoreceptors cell in the capillary system to shrink and thereby increase firing rate of signalling to the hypothalamus. Signal is transduced along the supraoptic nerve and causes an increase in ADH secretion from the posterior pituitary to maintain water.
- Anteroventral region of 3rd ventricle also provide important input (lesion of this area cause multiple deficits in ADH, BP, thirst control)
- Thirst is usually experienced after increase in ADH
- Volume receptors in the cells are sensitive to 5-10% change in cell volume which will inhibit ADH release.
• Volume modulation by ADH: the priority of stabilizing body pressure/volume is below that of regulation of plasma concentration. However when great loss of blood volume occurs, the body will sacrifice a bit of control of osmolarity to compensate and release ADH.
• Stimulation of thirst:
- Decrease in blood volume detected via baroreceptors
- Increase in osmolarity detected via osmoreceptors
- Dryness and throat
- Metering of water intake in GI tract will decrease thirst stimulation
- Hence oral solution will reduce thirst while IV solution provision won’t
• Conn’s Syndrome: excessive aldosterone produces hypertension from Na+ retention and weakness with polykaelemia.
• Percussion: may cause syndrome of inappropriate ADH release (excess diuresis from inadequate ADH).

Regulation of salt and volume

• Regulation of salt: unlike water which is diuresed rapidly, salt contents are usually retained and their plasma concentration corrected slowly
• Aldosterone: steroid hormone released from the adrenal cortex that promote reabsorption of Na+ and secretion of K+ in the distal tubule and collecting duct.
- Produced in the zona glomerulosa from corticosterone.
- Synthesis: ACTH is the main transient stimuli of aldosterone production. In the absence of ACTH, sodium depletion can still activate renin-angiotensin system to stimulate aldosterone synthesis
• Function of aldosterone: to sustain extracellular fluid by conserving body sodium and maintaining arterial pressure.
- Depletion of body sodium causes a fall in extracellular fluid and plasma volume and hence loss of renal blood flow and pressure. This is sensed by the kidney and aldosterone is secreted in response
- Excess aldosterone can be a primary indirect cause of hypertension
- Cellular effects: aldosterone in the blood bind to receptors of the distal tubular cells and transducer a signal to increase cell expression of ATPase pumps, Na+ and K+ channels in the apical surface. This promotes K+ entrance into the cell through the pump and exit via the channels.
- Other intracellular mediators: induction of serum and glucocorticoid inducible kinase, corticosteroid hormone-induced factor and Kirsten Ras that increase early Na+/K+ channel activity
• Cortisol: the protein is capable of also binding to mineralocorticoid receptor and produces an effect that’s the same as aldosterone.
- However this is prevented in the cell by the enzyme 11beta-HSD2 (hydroxysteroid dehydrogenase) that converts cortisol into cortisone which is a biologically inactive metabolite.
- The enzyme does not act on aldosterone
• Hypokaelemia: result of excess aldosterone function which produce weakness in muscle contraction
• Retainment of Na+: active reabsoprtion of Na+ is followed passively with water which maintains the sodium concentration. Hence extracellular fluid volume expand isotonically
• Clearance of K+: potassium in ECF stimulates aldosterone synthesis (by depolarizing the zona glomerulosa cell membrane) hence providing a feedback mechanism as lowered K+ level inhibit aldosterone secretion.
- Potassium excreted daily is the result of aldosterone mediated tubular secretion. This is an important system to dispose of excess K+
• Time course of aldosterone:
- Latent: lack of response of Na+ transport levels
- Early stage: rapid increase in relative Na+ transport
- Late stage: elevated level of Na+ transport that remains stable and high
• Time course of salt excretion:
- Stable balance in salt absorption and excretion (1 day)
- Sudden increase in sodium absorption causes a net increase in Na+ levels. Excretion eventually increases to match intake rate reaching a new balance (3 days)
- Stable balance at a higher absorption and excretion rate (7 days)
- Sudden drop in sodium absorption to normal cause a net decrease in Na+ levels. Excretion follows in a gradual manner and reaches balance again
• Role of angiotensin II
- Systemic arterioles: vasoconstriction to increase TPR and increase mean arterial pressure
- Adrenal cortex: promote aldosterone secretion (acts on zona glomerulosa and increase cAMP level to stimulate aldosterone)
- Posterior pituitary: stimulate increase in ADH
- Hypothalamic neurons: thirst stimulation
• Renin-angiotensin pathway:
- Juxtaglomerular cells secrete renin in response to decreased blood pressure and increase sympathetic activity along with decrease Na+ concentration in the tubular fluid.
- Renin act on angiotensin secreted by the liver to form angiotensin I
- Angiotensin II is formed using ACE by cleaving angiotensin I.
• Sodium excretion: atrial natriuretic peptide is secreted by cells in the atria and ventricle due to increased stretch of the atrial wall (increased plasma volume). Function of NP is to excrete Na+ and reduce plasma volume as water follows.
- Increase plasma volume will increase GFR
- High GFR means decrease Na+ and H2O reabsorption (inhibit ADH also) to limit plasma volume.
• Function of Atrial natriuretic peptide:
- Hypothalamus: inhibits vasopressin
- Kidney: increase GFR and decrease renin
- Adrenal cortex: inhibits aldosterone
- Medulla oblongata: decreases blood pressure
• Natriuretic family: ANP is made in cardiac atria while BNP is made in cardiac ventricles but stored in the brain.
- Both are secreted in response to cardiac wall tension and other stimuli such as angtiotensin II
- While ANP is secreted in short bursts to counter acute changes (half life 3 mins), BNP is upregulated at the gene expression level hence responds to chronic rises in pressure (half life 20 mins).
- Activation: ANP and BNP are activated with their prohormones cleaved by serine protease to yield a large inactive N-terminal fragment and a smaller active polypeptide (ANP/BNP)
- Clearance: three mechanisms: NPR-C-mediated endocytosis, enzymatic degradation by NEP, and minorly glomerular filtration.
• Cardiac failure: high levels of ANP and BNP releases so body pumps less water and fluid volume

Complex System of Interaction:

• Replacement fluid: 0.9% saline solutions. This is calculated to be 154 mmol/L of NaCl. As NaCl dissociated into two particles, the final osmolality is 308 mosm/L
- However serum osmolarity is only around 290 mosmol/L so 0.9% saline solution is hypertonic.
- Usually electrolyte is diluted in about 6 – 8% of plasma proteins which gives 285 mosmol/L
• Acute hyponatremic encephalopathy
- History: marathon run, drinking sport solution with salt supplements
- Presentation: nauseated, vomiting, semi conscious
- Test results: O2 saturation only 67%, hyponatremic and hyperkaelemic. Radiology examinations shows pulmonary edema and cerebral edema with effacement of sulci
- Treatment: hypertonic 3% saline solution to suck fluid from brain
• Hyponatremia: major problem related to marathon running. Excessive dehydration is actually not dangerous
- Sweating causes dehydration and loss of salt and volume (hyponatremia and weight loss)
- Over drinking causes overhydration and dilutional hyponatremia (weight gain)
- Heat stroke from impaired sweating
- The most common cause is overhydration which can lead to severe hyponatremia.
• Weight gain during racing: overconsumption of fluid as a result of exaggerated thirst drive. However even in slow marathon, atheletes should be able safely ingest fluid at rate. Possible explanations include:
- retention of water in gut during race and sudden absorption at the end cause water overload
- sympathetic stimulation and renin release cause vasoconstriction of afferent arteriole and decrease GFR
- SIADH as an result of AII
- Release of water bound with glycogen as it is used up
• Disadvantage of measuring water balance with weight: participant loses weight variably due to oxidation of triglyceride and glycogen.
• Encephalopathy: when serum sodium levels drops below 135 mmol/L, individual suffers hyponatremia and is at risk of encephalopathy with brain swelling.
• Addison’s disease: adrenal insufficiency with inadequate production of cortisol and aldosterone caused through adrenal cortex destruction (autoimmune, tumour, haemorrhage etc).
- Clinical presentation: weak, fainting, vomiting, muscle cramps, extremely low blood pressure
- Results: hyponatremia and hyperkaelemia with insufficient level of serum cortisol.

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