PHYSIOLOGY OF THE KIDNEYS URINARY SYSTEM 2 PHYSIOLOGY OF THE KIDNEYS

Renal Plasma Clearance

Renal clearance is accomplished by Renal clearance – the kidney removes molecules from the blood plasma by excreting them in the urine. Renal clearance is accomplished by Filtration – moves most things out. Secretion – the opposite of reabsorption; moves molecules from the blood back to the filtrate.

Secretion is the reverse of reabsorption Secretion increases renal clearance Excretion rate = (filtration rate + secretion rate) – reabsorption rate.

Removal of Xenobiotics Xenobiotics – substances foreign to the body Organic anion transporter (OAT) family – Na+-independent transport that secretes some endogenous compounds as well as many xenobiotics Located in the basolateral membrane of the proximal tubule Larger xenobiotics are removed by OATs in the liver  bile Organic Cation transporters (OCTs)- secrete particular xenobiotics, e.g. metformin (for Diabetes type II)

INULIN CAN BE USED TO MEASURE GFR Inulin is filtered but not reabsorbed or secreted A great marker of GFR only Found in garlic, onion, dahlias, and artichokes.

Calculating GFR Using Inulin: If: V = rate of urine formation (ml/min) U = inulin concentration in urine (mg/ml) P = inulin concentration in plasma (mg/ml) V x U GFR = ---------- P

Example: If: V = rate of urine formation is 2 ml/min. U = inulin concentration in urine is 30 mg/ml P = inulin concentration in plasma is 0.5 mg/ml V x U 2 ml/min x 30 mg/ml GFR = ---------- = ---------------------------- = 120 ml/min P 0.5 mg/ml

Renal Plasma Clearance Calculation Renal Plasma Clearance = Volume of plasma from which a substance is completely removed by the kidneys in 1 minute (ml/min) Inulin is filtered only. Therefore, Clearance = GFR Anything that can be reabsorbed has a clearance < GFR. If a substance is filtered and secreted, it will have a clearance > GFR. Renal plasma clearance uses same formula as GFR. Clearance of urea is less than GFR – means some is reabsorbed (see next slide)

EXAMPLE: Clearance of Urea The urea concentration in urine (U) is about 7.5 mg/ml, and the amount of urea in the blood is 0.2 mg/ml (P). If the rate of urine formation is 2 ml/min, then… Urea clearance = (2ml/min)(7.5 mg/ml) = 75 ml/min 0.2 mg/ml This is LESS than 120ml/min (the clearance rate for INULIN), and therefore, some of the urea is reabsorbed.

USE OF PAH TO MEASURE TOTAL RENAL BLOOD FLOW PAH in glomerulus, some PAH is filtered, all PAH in peritubular capillaries is secreted. Therefore, PAH can be used to measure total renal blood flow. Normal PAH clearance = 625 ml/min Glomerular filtration is only 120 ml/min, or only 20% of plasma is filtered/80% is secreted.

Mechanism of Reabsorption in the proximal tubule Glucose and amino acids not found in urine. filtered out in the capsule Reabsorbed in PCT STEPS: 1) 2◦ active transport of glucose and Na+ into cyto 2) 1◦ active transport of Na+ by Na+/K+ pump. 3) Glucose  facilitated diffusion

Glucose Carriers Can Become Saturated Transport maximum (Tm) is when the glucose carriers are saturated. Occurs at 375 mg/min of glucose in the filtrate Normal glucose levels are about 125 mg/min Glycosuria – glucose appears in the urine.

What causes GLYCOSURIA? Glucose spills into the urine when plasma concentrations reach 180-200 mg/100 ml This is well below the Transport Maximum (Tm). Therefore, some nephrons may have lower Tm values than average Renal Plasma Threshold – a more convenient term Is the minimum plasma concentration of a substance that results in the excretion of that substance in the urine. Hyperglycemia – when glucose exceeds renal plasma threshold; (fasting hyperglycemia = diabetes mellitus)

Renal Control of Electrolyte and Acid-Base Balance

Electrolyte Excretion The kidneys match electrolyte (Na+, K+, Cl−, bicarbonate, phosphate) excretion to ingestion. Control of Na+ levels is important in blood pressure and blood volume. Control of K+ levels is important in healthy skeletal and cardiac muscle activity. Aldosterone plays a big role in Na+ and K+ balance.

Reabsorption and Secretion of Na+ and K+ In PCT: 90% of Na+ and K+ is reabsorbed at a constant rate early in the nephron. occurs at constant rate, not subject to hormonal regulation. In DCT and cortical region of collecting duct: Na+ (into blood) and K+ (out of blood) regulation occurs by aldosterone.

SODIUM REABSORPTION Without Aldosterone: 90% is reabsorbed (aldosterone-independent) in PCT Of the 10% remaining, 80% is reabsorbed in the DCT and 20% is excreted (about 30 g/day). Cl- is also passively reabsorbed, following Na+ With Aldosterone: No Na+ is excreted Aldosterone raises blood pressure

Aldosterone raises blood pressure Aldosterone stimulates Na+/K+ Pumps

Potassium Secretion Purpose: to maintain a set-point [K+] in the blood A rise in blood K+ leads to the following… Stimulates adrenal cortex to secrete aldosterone. Aldosterone causes K+ to be secreted into the filtrate Aldosterone-independent secretion of K+ Synthesis of K+ channels in the apical membrane of the cortical collecting duct. When blood K+ falls, these channels are removed.

Aldosterone-dependent Secretion of K+ Aldosterone raises blood pressure Aldosterone-dependent Secretion of K+

Relationship Between Na+ and K+ Increases in Na+ absorption drive extra K+ secretion. Due to: Potential difference created by Na+ reabsorption, which drives K+ secretion through K+ channels. Stimulation of Renin-angiotensin-aldosterone system by water and Na+ in filtrate. Increased flow rates in tubule bend cilia on the cells of the distal tubule, resulting in activation of K+ channels.

Student Activity Diuretics (drugs that increase urine volume) inhibit Na+ transport in the nephron loop and increase delivery of Na+ to the collecting duct, and increased Na+ reabsorption in the collecting duct. Why would a person who is taking diuretics might have to take K+ supplements?

Student Activity ANSWER Diuretics (drugs that increase urine volume) inhibit Na+ transport in the nephron loop and increase delivery of Na+ to the collecting duct. Why would a person who is taking diuretics might have to take K+ supplements? ANSWER: Increased delivery of Na+ to the collecting duct increases secretion of K+ and excretion of K+ into the urine.

Control of Aldosterone Secretion A rise in blood K+ directly stimulates (depolarizes) the adrenal cortex  produce aldosterone. A fall in blood Na+ indirectly stimulates production of aldosterone via the renin- angiotensin-aldosterone system. aldosterone

Location of Juxtaglomerular Apparatus Located where the afferent arteriole comes into contact with the distal tubule.

SECRETION OF RENIN When there is a fall in blood volume, due to a fall in plasma Na+, Renin is secreted by the granular cells. RENIN is an enzyme.

Renin converts angiotensinogen to angiotensin I Angiotensin I is converted to angiotensin II by ACE ACE = angiotensin converting enzyme Angiotensin II stimulates the adrenal cortex to secrete aldosterone. Aldosterone raises blood pressure by causing Na+ reabsorption in the DCT and cortical collecting duct, and increases secretion of K+ Angiotensin II also stimulates vasoconstriction of afferent and efferent arterioles, lowering Na+ excretion.

Regulation of Renin Secretion Low salt leads to lower blood volume Reduced blood volume is detected by granular cells that act as baroreceptors. They then secrete renin. 2) Granular cells are also stimulated by sympathetic innervation from the baroreceptor reflex POINT – If b.p. is low  renin is secreted  Na+ reabsorption  b.p. goes up

Homeostasis of Plasma Na+

Macula Densa Sensor for tubuloglomerular feedback needed for regulation of GFR: High Na+ and H2O in the filtrate, cause macula densa to release ATP, which constricts the afferent arteriole. 2) constriction lowers GFR, which lowers Na+ and H2O (negative feedback) b. ALSO – High Na+ and H2O in the filtrate causes the granular cells to lower their production of renin. This results in less reabsorption of Na+, allowing more to be excreted. This helps lower Na+ levels in the blood.

ANP DECREASES BLOOD PRESSURE Increases in blood volume also increase the release of ANP hormone from atria of the heart when atrial walls are stretched. Stimulates kidneys to excrete more salt and therefore more water Decreases blood volume and blood pressure ANP IS OPPOSITE TO RENIN

Reabsorption of Na+ stimulates the secretion of other positive ions, such as K+ and H+ Acidosis stimulates the secretion of H+ and inhibits the secretion of K+ ions; acidosis can lead to hyperkalemia. Alkalosis stimulates the secretion and excretion of more K+. Increases reabsorption of H+ Hyperkalemia stimulates the secretion of K+ and inhibits secretion of H+; can lead to acidosis

ACID BASE REGULATION Proximal tubule uses Na+/H+ pumps to exchange Na+ out and H+ in. Some of the H+ brought in is used for the reabsorption of bicarbonate. Antiport secondary active transport

ACID BASE REGULATION Kidneys maintain blood pH by reabsorbing bicarbonate and secreting H+; urine is thus acidic.

ACID BASE REGULATION Bicarbonate cannot cross the inner tubule membrane so must be converted to CO2 and H2O using carbonic anhydrase. Bicarbonate + H+  carbonic acid Carbonic acid (w/ carbonic anhydrase)  H2O + CO2 CO2 can cross into tubule cells, where the reaction reverses and bicarbonate is made again. This diffuses into the interstitial space.

ACID BASE REGULATION Aside from the Na+/H+ pumps in the proximal tubule, the distal tubule has H+ ATPase pumps to increase H+ secretion.

pH Disturbances Kidneys can help compensate for respiratory problems b. Alkalosis: Less H+ is available to transport bicarbonate into tubule cells, so less bicarbonate is reabsorbed; extra bicarbonate secretion compensates for alkalosis. Acidosis: Proximal tubule can make extra bicarbonate through the metabolism of the amino acid glutamine. Extra bicarbonate enters the blood to compensate for acidosis. Ammonia stays in urine to buffer H+.

Disturbances of Acid-Base Balance

Urinary Buffers Nephrons cannot produce urine with a pH below 4.5. To increase H+ secretion, urine must be buffered. Phosphates and ammonia buffer the urine. Phosphates enter via filtration. Ammonia comes from the deamination of amino acids.

Clinical Applications

Use of Diuretics Used clinically to control blood pressure and relieve edema (fluid accumulation) Diuretics increase urine volume, decreasing blood volume and interstitial fluid volume. Many types act on different portions of the nephron.

Types of Diuretics Loop diuretics: most powerful; inhibit salt transport out of ascending loop of Henle Example: Lasix Can inhibit up to 25% of water reabsorption

Types of Diuretics b. Thiazide diuretics: inhibit salt transport in distal tubule Can inhibit up to 8% of water reabsorption

Types of Diuretics Carbonic anhydrase inhibitors: much weaker; inhibit water reabsorption when bicarbonate is reabsorbed Also promote excretion of bicarbonate

Types of Diuretics d. Potassium-sparing diuretics: Aldosterone antagonists block reabsorption of Na+ and secretion of K+.

Types of Diuretics, cont. e. Osmotic diuretics: reduce reabsorption of water by adding extra solutes to the filtrate Example: Mannitol Can occur as a side effect of diabetes

Renal Function Tests PAH and inulin clearance Can diagnose nephritis or renal insufficiency Urinary albumin excretion rate: detects above-normal albumin excretion Called microalbuminuria Signifies renal damage due to hypertension or diabetes Proteinuria: overexcretion of proteins; signifies nephrotic syndrome

Kidney Diseases Acute Renal Failure Ability of kidneys to regulate blood volume, pH, and solute concentrations deteriorates in a matter of hours/days. Usually due to decreased blood flow through kidneys due to: Atherosclerosis of renal arteries Inflammation of renal tubules Use of certain drugs (NSAIDs)

Glomerulonephritis Inflammation of the glomerulus Autoimmune disease with antibodies produced in response to streptococcus infection Many glomeruli are destroyed, and others are more permeable to proteins. Loss of proteins from blood reduces blood osmotic pressure and leads to edema.

Renal Insufficiency Any reduction in renal activity Can be caused by glomerulonephritis, diabetes, atherosclerosis, or blockage by kidney stones Can lead to high blood pressure, high blood K+ and H+, and uremia = urea in the blood. Patients with uremia are placed on a dialysis machine to clear blood of these solutes.

Dialysis “Artificial” kidney Hemodialysis – blood cleansed of wastes as it passes through dialysis fluid CAPD – continuous ambulatory peritoneal dialysis – dialysis fluid introduced to the abdominal cavity where wastes can pass out of abdominal blood vessels; fluid is then pumped out of the abdominal cavity