Endocrine and Synthetic functions

Endocrine and Synthetic functions
Urinary System Introduction • The urinary system Filters the body of waste materials ,Homeostaticaly regulates bodys fluid status,electrolyte balance and acid base balance. Endocrine and Synthetic functions EPO Controls RBC production from stem cells in marrow Stimulated by reduced PO2 in kidney (not systemic PO2) Vitamin D Active form (calcitrol) produced by a hydroxlation in kidney & liver Important for calcium absortion from GI and also neuronal development in-utero Renin An enzyme. Synthesized in juxtaglomerular (granular) cells in afferent arteriole Stimulated by a fall in circulating volume Leads to the production of Ang II and Aldosterone

Basic Anatomy of the Kidney
Renal Hilus: Renal artery, vein, nerves, lymphatics & renal pelvis Cortex Medulla: Renal Pyramids Medullary rays Papilla

Internal Structure of the Kidney
85% Internal Structure of the Kidney • Internally, the human kidney is composed of three distinct regions: 1. Renal Cortex • The outermost layer is called the renal cortex. It contains about one million nephrons, the filtering units that form urine. • Types of Nephrons: • Cortical nephrons - lie largely within the cortex • Juxtamedullary nephrons - lie in both the cortex and medulla 2. Renal Medulla • The middle layer is called the renal medulla, in which you can see the triangular renal pyramids. These pyramids look striated because of parallel bundles of ducts carrying urine from the nephrons. • The areas between pyramids are the renal columns. They are extensions of the cortex that provide a route for the passage of blood vessels and nerves to and from the outer cortex. 3. Renal Pelvis • The funnel-shaped renal pelvis is within the renal sinus. The renal pelvis collects urine from the pyramids and conveys it into the ureter for passage to the urinary bladder. 15%

Nephron Structure: Associated Blood Vessels
Renal → segmental → interlobar → arcuate → cortical radial (interlobular) → afferent → glomerulus → efferent Nephron Structure: Associated Blood Vessels • Blood entering the kidney through the renal artery flows first into the segmental arteries. • From there, it enters the interlobar arteries, the arcuate arteries, the small cortical radiate arteries, and the still smaller afferent arterioles, which empty into a capillary bed called the glomerulus. • Leading away from the glomerulus is the efferent arteriole. Notice that the afferent arteriole is larger in diameter than the efferent arteriole. • Blood passes from the efferent arteriole into the peritubular capillaries and vasa recta. • From there, blood drains into the cortical radiate vein, flows into the arcuate vein and enters the interlobar vein, eventually reaching the renal vein. Two arterioles and two capillary beds in series The Kidney Has The Highest Blood Flow Per Unit Mass Among Major Organs. 1250 ml/min = 25% of cardiac output

Nephron Structure

Cellular Features of the Renal Corpuscle
• The glomerulus, with its larger incoming afferent arteriole and smaller outgoing efferent arteriole, is nested within the glomerular capsule something like a fist thrust into a balloon. Together, these structures are called the renal corpuscle. • The visceral layer of the glomerular capsule is made up of specialized cells called podocytes, which surround the permeable capillaries. • Between the visceral and parietal layers of the capsule lies the capsular space, which collects the fluid and solutes being filtered from the blood.

filtration membrane. In longitudinal section, the endothelial lining shows small openings called fenestrations, which allow for the passage of water and solutes such as ions and small molecules. • There are fenestrations between endothelial cells in the capillary. • The porous basement membrane encloses the capillary endothelium. • Surrounding the basement membrane is a layer of podocytes. These cells have large ‘leg-like’ extensions, which in turn have small ‘fringe-like’ extensions called pedicels. • Pedicels from adjacent areas interdigitate loosely to form spaces called filtration slits. • Substances being filtered must pass first through the fenestrations, then through the basement membrane, and finally through the filtration slits and into the capsular space. • Together, the capillary endothelium, basement membrane, and podocytes make up the filtration membrane. Structure of the Filtration Membrane in Cross Section • A cross section of the filtration membrane reveals a large podocyte with its nucleus and pedicels. The white areas are portions of the capsular space. Gaps between the pedicels are the filtration slits. • The basement membrane of the capillary endothelium separates the podocyte from the capillary with its fenestrations.

The Filtration Membrane and Glomerular Filtration
• Just as a filter keeps grounds out of your coffee, the glomerular filtration membrane keeps blood cells and proteins out of the urine passageways. • The filtration membrane is composed of three layers: 1. Fenestrated glomerular endothelium 2. Basement membrane 3. Filtration slits formed by pedicels of the podocytes • Passage through the filtration membrane is limited not only on the basis of size but also by charge. • Glomerular filtration is a process of bulk flow driven by the hydrostatic pressure of the blood. • Small molecules pass rapidly through the filtration membrane, while large proteins and blood cells are kept out of the capsular space. • If the filtration membrane is damaged, proteins will leak through and end up in the urine. • If the filtration membrane is very badly damaged, then blood cells will leak through. • Consequences of loss of protein in the urine: • Loss of albumin causes a decrease in osmotic pressure. Fluid will leak into the interstitial spaces and edema results. Eventually there will be a low circulatory volume and possibly shock. • Loss of blood clotting proteins can cause uncontrolled bleeding. • Loss of globulins and complement proteins make the individual prone to infection. • Passage through the filtration membrane is limited not only on the basis of size but also by charge. • Glomerular filtration is a process of bulk flow driven by the hydrostatic pressure of the blood. • Small molecules pass rapidly through the filtration membrane, while large proteins and blood cells are kept out of the capsular space.

Filtration barrier nephrotic syndrome Neutral molecule Anion Anion
Shape Filtration barrier Neutral molecule Anion Anion nephrotic syndrome proteinuria Glomerulonephritis: loss of negative charge on glomerular membranes

The Juxtaglomerular Apparatus
• As the thick ascending loop of Henle transitions into the early distal convoluted tubule, the tubule runs adjacent to the afferent and efferent arterioles. • Where the cells of the arterioles and of the thick ascending loop of Henle are in contact with each other, they form the monitoring structure called the juxtaglomerular apparatus. • The modified smooth muscle cells of the arterioles (mainly the afferent arteriole) in this area are called granular cells. These enlarged cells serve as baroreceptors sensitive to blood pressure within the arterioles. • Cells of the thick ascending segment in contact with the arterioles form the macula densa. These cells monitor and respond to changes in the sodium chloride concentration of the filtrate in the tubule. baroreceptors

Cells of the Proximal Convoluted Tubule (PCT)
The simple cuboidal cells of the proximal convoluted tubule are called brush border cells because of their numerous microvilli, which project into the lumen of the tubule. • These microvilli greatly expand the surface area of the luminal membrane, adapting it well for the process of reabsorption. • Tight junctions between adjacent cells permit passage of water but limit the escape of large molecules from the tubular lumen into the interstitial space. • The highly folded basolateral membrane of the cells contains numerous integral proteins involved in passive or active transport of substances between the intracellular and interstitial spaces. Numerous mitochondria provide the ATP necessary for these active transport processes.

Cells of the Thin Loop of Henle
The key feature of these cells is that they are highly permeable to water but not to solutes. Cells of the Thick Ascending Loop of Henle and DCT • The key feature of the cells of the ascending limb is that they are highly permeable to solutes, particularly sodium chloride, but not to water. The cells of the DCT are more permeable to water than those of the ascending limb. Cells of the Thin Loop of Henle • The cells of the thin segment of the descending loop of Henle are simple squamous epithelial cells. • These cells lack brush borders, which reduces their surface area for reabsorption. • These cells continue to be permeable to water, they possess relatively few integral proteins that function as active transport molecules for reabsorbing solutes from the filtrate. • The key feature of these cells is that they are highly permeable to water but not to solutes. Cells of the Thick Ascending Loop of Henle and DCT • The epithelia of the thick ascending loop of Henle and the distal convoluted tubule are similar. They are composed of cuboidal cells, but they have several structural differences compared to the cells of the proximal convoluted tubule. For example, these cells have fewer and smaller microvilli projecting into the lumen. • In addition, the cells of the ascending limb are covered by a glycoprotein layer, which, along with ‘tighter’ tight junctions, greatly restricts the diffusion of water. • The basolateral membrane is similar to that of the PCT, containing many integral proteins and closely associated mitochondria for passive and active membrane transport processes. • The key feature of the cells of the ascending limb is that they are highly permeable to solutes, particularly sodium chloride, but not to water. The cells of the DCT are more permeable to water than those of the ascending limb.

Cells of the Cortical Collecting Duct:- 1. Principal Cells
2. Intercalated Cells The key feature of principal cells is that their permeability to water and solutes is physiologically regulated by hormones. Cells of the Cortical Collecting Duct • The cuboidal cells of the cortical collecting duct fall into two distinct structural and functional types: principal cells and intercalated cells. 1. Principal Cells The more numerous principal cells have few microvilli and basolateral folds. These specialized cells respond to certain hormones that regulate the cell’s permeability to water and solutes, specifically sodium and potassium ions. The key feature of principal cells is that their permeability to water and solutes is physiologically regulated by hormones. 2. Intercalated Cells When the acidity of the body increases, the intercalated cells secrete hydrogen ions into the urine to restore the acid/base balance of the body. The key feature of intercalated cells is their secretion of hydrogen ions for acid/base balancing. The key feature of intercalated cells is their secretion of hydrogen ions for acid/base balancing.

Micturition Once urine enters the renal pelvis, it flows through the ureters and enters the bladder, where urine is stored. Micturition is the process of emptying the urinary bladder. Two processes are involved: The bladder fills progressively until the tension in its wall is raised above a threshold level, and then A nervous reflex called the micturition reflex occurs that empties the bladder. The micturition reflex is an automatic spinal cord reflex; however, it can be inhibited or facilitated by centers in the brainstem and cerebral cortex.

stretch receptors Urine Micturition

Filling of the Bladder and Bladder Wall Tone - the Cystometrogram

1) APs generated by stretch receptors 2) reflex arc generates APs that
3) stimulate smooth muscle lining bladder 4) relax internal urethral sphincter (IUS) 5) stretch receptors also send APs to Pons 6) if it is o.k. to urinate APs from Pons excite smooth muscle of bladder and relax IUS relax external urethral sphincter 7) if not o.k. APs from Pons keep EUS contracted stretch receptors

overflow incontinence.
• Atonic Bladder and Incontinence Caused by Destruction of Sensory Nerve Fibers • the bladder fills to capacity and overflows a few drops at a time through the urethra. • common cause of atonic bladder is crush injury to the sacral region of the spinal cord. Automatic Bladder Caused by Spinal Cord Damage Above the Sacral Region micturition reflexes can still occur. However, they are no longer controlled by the brain. Uninhibited Neurogenic Bladder Caused by Lack of Inhibitory Signals from the Brain

Three basic renal processes
Introduction • Formation of urine by the kidney involves three main processes: 1. Glomerular filtration(180ltrs/day,20% of plasma filtered) 2. Tubular reabsorption(178.5ltrs) 3. Tubular secretion (80% of plasma is involved in exchange with the renal tubules) Filtration. The formation of urine begins with the process of filtration. Fluid and small solutes are forced under pressure to flow from the glomerulus into the capsular space of the glomerular capsule. • Reabsorption. As this filtrate passes through the tubules, specific substances are reabsorbed back into the blood of the peritubular capillaries. • Secretion. In addition, some solutes are removed from the blood of the peritubular capillaries and secreted by the tubular cells into the filtrate to “fine tune” the composition of the blood.

Glomerular Filtration Rate (GFR)
• The total amount of filtrate formed by all the renal corpuscles in both kidneys per minute is called the glomerular filtration rate, or GFR. In normal kidneys, the 17 millimeters of mercury of net filtration pressure produces approximately 125 milliliters of filtrate per minute. This translates to about 180 liters in 24 hours. Fortunately, 99% of this volume will be reabsorbed as the filtrate passes through the tubules. • The glomerular filtration rate is directly proportional to the net filtration pressure, so a fluctuation in any of the three pressures previously discussed will change the GFR. Prolonged changes in normal GFR will cause either too much or too little water and solutes to be removed from the blood.

Glomerular Filtrate • The fluid and solutes collecting in the capsular space is called glomerular filtrate. • The concentration of each of these substances in the glomerular filtrate is similar to its concentration in plasma. Damage to Filtration Membrane • How might the contents of the filtrate be altered if the filtration membrane is damaged or destroyed?

Forces Affecting Filtration
• There are three forces affecting filtration at the glomerulus: Forces Affecting Filtration • There are three forces affecting filtration at the glomerulus: 1. Hydrostatic Pressure within the Glomerular Capillaries • The blood pressure in the glomerulus averages 60 millimeters of mercury. This unusually high capillary pressure is the result of the short, large diameter afferent arterioles conveying blood at high arterial pressure directly to the glomerular capillaries. • The smaller diameter of the efferent arterioles leaving the glomerulus also helps maintain the pressure by restricting the outflow of blood. • However, the glomerular hydrostatic pressure is opposed by two forces that reduce the flow of fluid into the capsular space. 2. Back Pressure from Fluid Within the Capsule • Fluid already in the capsular space creates a “back pressure” that resists the incoming fluid. This capsular hydrostatic pressure averages 15 millimeters of mercury. 3. Osmotic Pressure within the Glomerular Capillaries • The second opposing force is the osmotic pressure of the blood in the glomerular capillaries. Remember that the capillaries retain proteins, which become more concentrated in the blood as the filtrate flows out. Because of these proteins, the osmolarity of the blood is higher than the osmolarity of the filtrate. The osmotic pressure of the blood, or its tendency to draw the fluid back in, averages 28 millimeters of mercury. • The algebraic sum of these three forces produces the net filtration pressure of 17 millimeters of mercury. Net Filtration Pressure = 60 mm Hg - (15 mm Hg + 28 mm Hg) = 17 mm Hg 1. Hydrostatic Pressure within the Glomerular Capillaries 2. Back Pressure from Fluid Within the Capsule 3. Osmotic Pressure within the Glomerular Capillaries Net Filtration Pressure = 60 mm Hg - (15 mm Hg + 28 mm Hg) = 17 mm Hg “kidney shut-down” or acute renal failure.

Glomerular Filtration Rate (GFR)
• The total amount of filtrate formed by all the renal corpuscles in both kidneys per minute is called the glomerular filtration rate, or GFR. In normal kidneys, the 17 millimeters of mercury of net filtration pressure produces approximately 125 milliliters of filtrate per minute. This translates to about 180 liters in 24 hours !!! Fortunately, 99% of this volume will be reabsorbed as the filtrate passes through the tubules. • The glomerular filtration rate is directly proportional to the net filtration pressure, so a fluctuation in any of the three pressures previously discussed will change the GFR. Prolonged changes in normal GFR will cause either too much or too little water and solutes to be removed from the blood.

Autoregulation of GFR During normal conditions, systemic blood pressure registers approximately 120 millimeters of mercury; the diameter of the afferent arteriole is normal, as is the glomerular hydrostatic pressure. These conditions provide a normal glomerular filtration rate of 125 milliliters per minute. During mild exercise  increase in GFR [of 21 milliliters per minute, to 146 milliliters per minute During periods of relaxation  reduction of glomerular hydrostatic pressure and GFR

GFR Regulation Mechanisms:
Myogenic Mechanism -inherent tendency of vascular smooth muscle cells to contract when stretched. • Stretching the arteriole wall(increasing blood pressure) causes a reflexive vasoconstriction. As long as pressure continues, the vessel will stay constricted. • When pressure against the vessel wall is reduced(decrease in blood pressure), the vessel dilates. Changes in blood pressure therefore directly affect the constriction or dilation of the arteriole, and so glomerular blood flow. Tubuloglomerular Mechanism • A second regulatory mechanism is the sensitivity of the macula densa cells of the juxtaglomerular apparatus to the concentration of sodium chloride in the filtrate, which is proportional to the rate of filtrate flow in the terminal portion of the ascending loop of Henle. High Osmolarity and High Rate of Filtrate Flow in Tubule.

Low Osmolarity and Low Rate of Filtrate Flow in Tubule
• A low rate of filtrate flow and, therefore, low sodium chloride in the terminal portion of the ascending loop of Henle is also sensed by the macula densa cells. This condition is usually the result of low GFR caused by low blood pressure. • In response, these cells initiate two effects: 1) They decrease secretion of the vasoconstrictor chemicals. This leads to dilation of the arteriole and so increases blood flow, glomerular hydrostatic pressure, and the GFR 2) The macula densa cells signal the granular cells of the afferent and efferent arterioles to release renin into the bloodstream. What is the Effect of Renin on the Regulation of the GFR ? 1- angiotensin II formed from renin causes constriction of the efferent arteriole 2- release of the hormone aldosterone

GFR Regulation Mechanisms: Sympathetic Nervous System Control
Sympathetic nerve fibers innervate all blood vessels of the kidney as an extrinsic regulation mechanism. During normal daily activity they have minimal influence. However, during periods of extreme stress or blood loss, sympathetic stimulation overrides the autoregulatory mechanisms of the kidney. • Increased sympathetic discharge causes intense constriction of all renal blood vessels. Two important results occur: 1) The activity of the kidney is temporarily lessened or suspended in favor of shunting the blood to other vital organs 2) The lower GFR reduces fluid loss, thus maintaining a higher blood volume and blood pressure for other vital functions. • Reduction in filtration cannot go on indefinitely, as waste products and metabolic imbalances increase in the blood. Autoregulation mechanisms are now ineffective in preventing acute renal failure. • When fluid is given intravenously, the blood volume increases. With increasing blood volume there will be gradual rise in blood pressure, reduction in sympathetic discharge, and restoration of renal functioning.

Introduction Three basic renal processes
• Formation of urine by the kidney involves three main processes: 1. Glomerular filtration(180ltrs/day,20% of plasma filtered) 2. Tubular reabsorption(178.5ltrs) 3. Tubular secretion Filtration. The formation of urine begins with the process of filtration. Fluid and small solutes are forced under pressure to flow from the glomerulus into the capsular space of the glomerular capsule. • Reabsorption. As this filtrate passes through the tubules, specific substances are reabsorbed back into the blood of the peritubular capillaries. • Secretion. In addition, some solutes are removed from the blood of the peritubular capillaries and secreted by the tubular cells into the filtrate to “fine tune” the composition of the blood.

Filtration Fraction (FF)
Glomerular Filtration Rate (GFR) • The total amount of filtrate formed by all the renal corpuscles in both kidneys per minute is called the glomerular filtration rate, or GFR. In normal kidneys, the 17 millimeters of mercury of net filtration pressure produces approximately 125 milliliters of filtrate per minute. This translates to about 180 liters in 24 hours !!! Fortunately, 99% of this volume will be reabsorbed as the filtrate passes through the tubules. Filtration Fraction (FF) using a value of GFR of 125 ml/min and ERPF = 700 ml/min, the fraction of plasma that is filtered is 125/700 = 18%. FF is typically in the range 15-25%. That is 15-25% of the plasma volume becomes filtrate in the nephrons of the kidney.

The Filtration Membrane and Glomerular Filtration
• Just as a filter keeps grounds out of your coffee, the glomerular filtration membrane keeps blood cells and proteins out of the urine passageways. • The filtration membrane is composed of three layers: 1. Fenestrated glomerular endothelium 2. Basement membrane 3. Filtration slits formed by pedicels of the podocytes • Passage through the filtration membrane is limited not only on the basis of size but also by charge. • Glomerular filtration is a process of bulk flow driven by the hydrostatic pressure of the blood. • Small molecules pass rapidly through the filtration membrane, while large proteins and blood cells are kept out of the capsular space. • If the filtration membrane is damaged, proteins will leak through and end up in the urine. • If the filtration membrane is very badly damaged, then blood cells will leak through. • Consequences of loss of protein in the urine: • Loss of albumin causes a decrease in osmotic pressure. Fluid will leak into the interstitial spaces and edema results. Eventually there will be a low circulatory volume and possibly shock. • Loss of blood clotting proteins can cause uncontrolled bleeding. • Loss of globulins and complement proteins make the individual prone to infection. • Passage through the filtration membrane is limited not only on the basis of size but also by charge. • Glomerular filtration is a process of bulk flow driven by the hydrostatic pressure of the blood. • Small molecules pass rapidly through the filtration membrane, while large proteins and blood cells are kept out of the capsular space.

Filtration barrier nephrotic syndrome Neutral molecule Anion Anion
Shape Filtration barrier Neutral molecule Anion Anion nephrotic syndrome proteinuria Glomerulonephritis: loss of negative charge on glomerular membranes

all other molecules and ions at ~same concentration as plasma
Glomerular filtration Afferent arteriole Efferent arteriole Glomerular capillaries no protein Bowman’s space all other molecules and ions at ~same concentration as plasma

Determinants of GFR The rate of filtration in any of the body's capillaries, including the glomeruli, is determined by the hydraulic permeability of the capillaries, their surface area, and the net filtration pressure (NFP) acting across them. Rate of filtration = hydraulic permeability x surface area x NFP Because it is difficult to estimate the area of a capillary bed, a parameter called the filtration coefficient (Kf) is used to denote the product of the hydraulic permeability and the area.

Net Filtration Pressure
• There are three forces affecting net filtration at the glomerulus: 1. Hydrostatic Pressure within the Glomerular Capillaries Forces Affecting Filtration • There are three forces affecting filtration at the glomerulus: 1. Hydrostatic Pressure within the Glomerular Capillaries • The blood pressure in the glomerulus averages 60 millimeters of mercury. This unusually high capillary pressure is the result of the short, large diameter afferent arterioles conveying blood at high arterial pressure directly to the glomerular capillaries. • The smaller diameter of the efferent arterioles leaving the glomerulus also helps maintain the pressure by restricting the outflow of blood. • However, the glomerular hydrostatic pressure is opposed by two forces that reduce the flow of fluid into the capsular space. 2. Back Pressure from Fluid Within the Capsule • Fluid already in the capsular space creates a “back pressure” that resists the incoming fluid. This capsular hydrostatic pressure averages 15 millimeters of mercury. 3. Osmotic Pressure within the Glomerular Capillaries • The second opposing force is the osmotic pressure of the blood in the glomerular capillaries. Remember that the capillaries retain proteins, which become more concentrated in the blood as the filtrate flows out. Because of these proteins, the osmolarity of the blood is higher than the osmolarity of the filtrate. The osmotic pressure of the blood, or its tendency to draw the fluid back in, averages 28 millimeters of mercury. • The algebraic sum of these three forces produces the net filtration pressure of 17 millimeters of mercury. Net Filtration Pressure = 60 mm Hg - (15 mm Hg + 28 mm Hg) = 17 mm Hg 2. Back Pressure from Fluid Within the Capsule 3. Osmotic Pressure within the Glomerular Capillaries NFP = (PGC – Л GC) – (PBC – Л BC) GFR = Kf (PGC – PBC – ЛGC). Net Filtration Pressure = 60 mm Hg - (15 mm Hg + 28 mm Hg) = 17 mm Hg “kidney shut-down” or acute renal failure.

(chronic renal failure)
Sum of filtration rates of all the nephrons = total glomerular filtration rate = total GFR = GFR If total number of functioning nephrons is reduced (chronic renal failure) GFR Measurement of GFR is the best single means of assessing kidney function quantitatively

Autoregulation Normally, renal blood flow doesn’t change much ml/min
Flow = Δ Pressure Resistance ml/min Renal blood flow 50 100 150 200 Mean arterial pressure (mmHg) 1500 500 1000 GFR 50 100 150 Autoregulation Renal blood flow and glomerular filtration rate are fairly constant across a wide range of mean arterial blood pressures. This phenomenon is called autoregulation. Total renal vascular resistance varies in direct proportion to renal arterial pressure so that flow remains roughly constant. This phenomenon continues in denervated kidneys, and so must be due to intrarenal mechanisms. Control of afferent arteriolar resistance is the key process. This occurs by a myogenic mechanism in the first instance. Distension of the wall of the afferent arteriole as flow increases results in contraction of the smooth muscle in the wall of the arteriole. Vascular resistance thus increases and blood flow is reduced to the normal rate. The myogenic mechanism is greatly augmented by tubulo-glomerular feedback (TGF)

Mechanism? PGC ↓ myogenic tubuloglomerular feedback
During autoregulation, as blood pressure increases, so does vascular resistance Afferent arteriole Efferent arteriole Arterial pressure PGC ↓ vasoconstriction Mechanism? myogenic tubuloglomerular feedback

Tubuloglomerular feedback
afferent arteriole adenosine A1 receptor Vasoconstriction ATP macula densa cell Na+ 2Cl- K+ macula densa NaCl delivery

A drug is noted to cause a decrease in GFR
A drug is noted to cause a decrease in GFR. Identify 4 possible actions of the drug that might decrease GFR. A person is given a drug that dilates the afferent arteriole and constricts the efferent arteriole by the same amounts. Assuming no other actions of the drug, what happens to this person's GFR A clamp around the renal artery is partially tightened to reduce renal arterial pressure from a mean of 120 to 90 mm Hg. do you predict RBF will change?

Renal clearance “The VOLUME of plasma rendered free of a given
Definition- The renal clearance of a substance is: “The VOLUME of plasma rendered free of a given substance in one minute” Substance x: Plasma concentration = Px Rate of excretion = Ux.V Clearance of x (Cx) = Ux.V Px = ml/min . The definition of renal clearance is given on the slide. Note that clearance is not the rate at which a substance appears in the urine (e.g. mg/min), it is a measure of the volume of plasma “cleaned” or “cleared” per unit time. Clearance methods involve measurement of urine flow rate and the concentrations of a substance in urine and plasma. The clearance of anything can be measured. Use of the clearance concept, when applied to certain substances, is still the most practical (and usually the only) way to measure glomerular filtration rate and to assess transport functions in humans. liters/day gallons/second

How much urea is excreted per min? What is the clearance of urea?
Questions: How much urea is excreted per min? What is the clearance of urea? Purea = 0.2 mg/ml Uurea = 6 mg/ml V = 2ml/min Answers: Urea excretion = 6 mg/ml x 2 ml/min = 12 mg/min Urea clearance = 12 mg/min = 60 ml/min 0.2 mg/ml i.e. 60 ml of plasma loses its urea into the urine in one minute

Representative Nephron
Glomerular capillaries Afferent arteriole Efferent arteriole Renal artery Filtration Peritubular capillaries Reabsorption Secretion Excretion Renal vein

Using Clearance to estimate/measure GFR
1. Freely filtered Need a substance (a) with special properties: (concentration in Bowman’s space = concentration in plasma) 2. Not reabsorbed 3. Not secreted H2O Inulin is a polysaccharide with a molecular weight of about It is normally present in small amounts in the diet, and must be infused in order to measure clearance. Inulin is small enough to pass freely through the glomerular filtration barrier, but is neither reabsorbed nor secreted by the nephron and cannot be metabolized. As such the rate of inulin filtration equals the rate of inulin excretion and the volume of plasma cleared is equal to the glomerular filtration rate. The slide shows that, because we can equate the rate at which inulin is filtered (glomerular filtration rate ´ plasma inulin concentration) and the rate inulin is excreted (urine flow rate ´ urine inulin concentration), we can rearrange this equation to obtain GFR = UinV/Pin, which is the clearance of inulin (Cin). Amount of a excreted per minute = amount of a filtered per minute Urine conc. of a x urine flow rate = glomerular filtrate conc. of a x GFR Ua x V = GFa x GFR C1 x V1 = C2 x V2 GFR = Ua x V GFa (GFa = Pa)

~180 liters/day! Inulin clearance = GFR
Very few substances meet the criteria required to measure GFR Best known: Inulin polysaccharide of fructose molecular weight ~5000 daltons molecular diameter ~3 nm Typical value for GFR ~120 ml/min ~180 liters/day! Inulin clearance = GFR Inulin is cleared from plasma by filtration alone. Since none of filtered inulin returns to the plasma, volume of plasma cleared of inulin per min must equal the volume of plasma filtered per min (= GFR)

Problems with measuring Cin clinically:
Must be infused intravenously Continual blood sampling required Chemical analysis cumbersome Useful alternative: Creatinine (not creatine) Endogenous (by-product of muscle metabolism) Released into blood at relatively constant rate (plasma concentration fairly stable; therefore only need one blood sample) Since inulin must be infused, it is not usually convenient to measure inulin clearance clinically. A suitable alternative is creatinine. Creatinine is a product of muscle metabolism. The rate of creatinine production is a function of a patient’s muscle mass, and so from day to day is quite constant. Creatinine is not a perfect substance for the measurement of GFR, because it is partially secreted by the proximal tubule (about 10% of its excretion comes from secretion). As such creatinine clearance is slightly higher than the true GFR, but is accurate enough for routine clinical application. Plasma creatinine concentration is in steady state where balance is achieved due to a constant production rate, matched by the renal excretion rate Freely filtered  Not reabsorbed  Not secreted ( true Ccr normally overestimates GFR by ~10-20%)

Patient (Jim) with suspected renal failure
24 hour urine volume = 600 mL Urine [creatinine] = 240 mg/dL ( mg/dL in males and mg/dL in females) Plasma [creatinine] = 10 mg/dL (0.5 to 1.0 mg/dL for women and 0.7 to 1.2 mg/dL for men) BUN = 80 mg/dL (normal mg/dL) Calculate his creatinine clearance BUN:creatinine ratio ?

Jim’s creatinine clearance (Ccr):
Ccr = Ucr x V / Pcr Ccr = 240 mg/dL x mL/day (0.42 ml/min) 10 mg/dL Ccr = 10ml/min = GFR for Jim. (normal = mL/min) Low GFR means renal insufficiency

GFR can be estimated from Pcr
Jim GFR is lower in young children and declines in old age. The Gault-Cockroft formula is used clinically to estimate GFR in the steady state from a measurement of plasma creatinine: GFR(ml /min) = [(140 - age)XWeight(kg)] (Pcr(mg / dL)x72) % plasma creatinine concentration is a function of GFR. The slide shows that, clinically, you can therefore use plasma creatinine concentration to estimate GFR.

Clearance of para-amino hippurate =
Renal clearance of selected substances provides special information Clearance of inulin = GFR Clearance of creatinine = ~ GFR Clearance of para-amino hippurate = renal plasma flow Para-amino hippurate (PAH) organic anion freely filtered avidly secreted by peritubular capillaries into proximal tubule at low plasma concentrations, the combination of filtration and secretion means that all PAH arriving in the renal plasma is excreted in the urine

all excreted in the urine
PAH handling by the kidney At low plasma concentrations: Volume of plasma cleared of PAH (= CPAH) = volume of plasma entering kidneys = renal plasma flow ~ 1/5 filtered enters in renal artery remaining 4/5 secreted ~ none in the renal vein all excreted in the urine

Urine flow rate = 1 ml/min
PPAH = 0.1 mg/ml UPAH = 65 mg/ml Renal plasma flow? RPF = CPAH = 65 mg/ml x 1 ml/min = 650 ml/min 0.1 mg/ml If CPAH = 650ml/min and the patient has a hematocrit of 45%, what is the rate of renal blood flow?

Quantifying tubular function
Useful data about the transport of a substance by the renal tubule can be obtained by applying a few simple calculations: Filtration = GFR x PZ (“filtered load”) Reabsorpn = (GFR x Pz) – (Uz x V) Secretn = (Uz x V) - (GFR x Pz) 1. How much of substance Z is filtered per unit time (“filtered load”)? Glomerular filtration rate (GFR) x Plasma concentration of Z (PZ) (units = mg/min) 2. How much of substance Z is excreted in the urine per unit time (“excretion rate”)? Urine flow rate (V) x Urine concentration of Z (UZ) 3. How much of substance Z was reabsorbed (i.e. if filtered load > excretion rate)? (GFR x PZ) - (UZ x V) 4. How much of substance Z was secreted (i.e. if excretion rate > filtered load)? (UZ x V) - (GFR x PZ) (units = mg/min) Excretion = UZ x V (“excretion rate”) Excretion = filtration – reabsorption + secretion

Fractional excretion Proportion of the filtered load was excreted = fractional excretion Fractional excretion of Z (FEZ) = rate of excretion of Z rate of filtration of Z i.e. excretion of Z as a percentage of the filtered load Fractional Reabsorption and Excretion These terms describe the rate of excretion or reabsorption that is occurring expressed as a proportion of the rate at which a substance is filtered. It may be expressed as a ratio, or in % units. So, if we were to say that the fractional reabsorption of sodium in the proximal tubule was 65%, this would mean that 65% of the amount of sodium filtered would be reabsorbed at this site. = CZ / GFR FEZ = UZ x V GFR x PZ

Where Does Na+ Reabsorption Occur?
FE = 10% [Na+] =145 FE = 3% FE = 35% The filtered load of sodium is far greater than the daily requirement for sodium excretion. Typically the fractional excretion for sodium is about 1-2%. Filtration and reabsorption are the only significant processes affecting NaCl and water excretion. Thus, regulation of excretion is achieved largely by varying the amount that escapes tubular reabsorption. The slide illustrates segmental handling of sodium (FE values for chloride are similar). The slide shows the proportion of filtered sodium remaining in the nephron at the point indicated (fractional excretion). For example, the proximal tubule extracts 65% of the filtered load of sodium, so that the fraction remaining at the end of this segment is 35%. The loop of Henle typically reabsorbs another 20-25% of the filtered load, so that around 10% of filtered NaCl enters the distal tubule. The % of filtered NaCl delivered to the distal nephron does not change much across a wide range of NaCl intakes. This design allows for fine regulation of NaCl excretion in the distal tubule and collecting duct, particularly by aldosterone. FE = % [Na+] units = mmole/L FE= Fractional excretion

B. Significantly below normal
The hospital lab reports that your patient's creatinine clearance is 120 g/day. This value is A. Normal B. Significantly below normal C. Not an interpretable number as presented List, in order of decreasing renal clearance, the following substances: glucose, urea, sodium, inulin, creatinine, PAH.

The following test results were obtained during a clearance experiment:
UIn = 50 mg/L PIn = 1 mg/L V = 2 mL/min UNa = 75 mmol/L PNa = 150 mmol/L What is the fractional excretion of sodium?

Micturition Once urine enters the renal pelvis, it flows through the ureters and enters the bladder, where urine is stored. Micturition is the process of emptying the urinary bladder. Two processes are involved: The bladder fills progressively until the tension in its wall is raised above a threshold level, and then A nervous reflex called the micturition reflex occurs that empties the bladder. The micturition reflex is an automatic spinal cord reflex; however, it can be inhibited or facilitated by centers in the brainstem and cerebral cortex.

stretch receptors Urine Micturition

1) APs generated by stretch receptors 2) reflex arc generates APs that
3) stimulate smooth muscle lining bladder 4) relax internal urethral sphincter (IUS) 5) stretch receptors also send APs to Pons 6) if it is o.k. to urinate APs from Pons excite smooth muscle of bladder and relax IUS relax external urethral sphincter 7) if not o.k. APs from Pons keep EUS contracted stretch receptors

REGIONAL TRANSPORT

LEARNING OBJECTIVES Describe the contribution of the major nephron segments to the reabsorption of the filtered load of solute and water. Describe the cellular mechanisms for the transport of Na+, Cl-, K+, HCO3-, Ca2+, phosphate, organic solutes (e.g., glucose, amino acids, and urea), and water by the major tubular segments.

Describe the function of the following renal transporters and their predominant localization along the tubules with regard to nephron segment and apical versus basolateral membranes Transport ATPases (Na+/K+-ATPase, H+/K+-ATPase, H+-ATPase, and Ca2+-ATPase) Ion and water channels (K+, ENaC, Cl-, Ca2+, aquaporins) Coupled transporters (Na+-glucose, Na+/H+-antiporter, Na+-K+-2Cl--symporter, Na+-phosphate symporter, Na+-Cl--symporter, Na+-HCO3 --symporter, Cl-/HCO3--antiporter)

Solutes that are reabsorbed by both active and passive processes include glucose, amino acids, urea, and ions such as (sodium), (potassium),(calcium),(chloride),(bicarbonate), and (phosphate). Secreted substances include hydrogen ions ,potassium, ammonium ions, creatinine, and certain drugs such as penicillin.

Reabsorption Routes

Reabsorption and Secretion in the Proximal Convoluted Tubule

Actions of Na/H + antiporters in proximal convoluted tubule cells.
(a) Reabsorption of sodium ions (Na and secretion of hydrogen ions via secondary active transport through the apical membrane; (b) reabsorption of bicarbonate ions via facilitated diffusion through the basolateral membrane.

Solute reabsorption in proximal convoluted tubules promotes osmosis of water. Each reabsorbed solute increases the osmolarity, first inside the tubule cell, then in interstitial fluid, and finally in the blood. Water thus moves rapidly from the tubular fluid, via both the paracellular and transcellular routes, into the peritubular capillaries and restores osmotic balance

Q Na +is reabsorbed from the basolateral surface of the renal epithelial cells by a. Na/H exchange b. Na-glucose cotransport c. Na-K pump d. Facilitated diffusion e. Solvent drag

Proximal Tubule Changes
1. Water and electrolytes Approximately 2/3 of the filtered sodium is reabsorbed in the proximal tubule by primary and secondary active transport. About two-thirds of the filtered H2O, K+, and almost two-thirds of the filtered Cl– follow the sodium (leaky system to these substances), and the osmolarity at the end of the proximal tubule remains close to 300 mOsm/L (isosmotic reabsorption).

As water leaves the tubular fluid, the concentrations of the remaining filtered solutes increase.
In the second half of the PCT, electrochemical gradients for Cl-,K+,Ca2+,Mg2+, and urea promote their passive diffusion into peritubular capillaries via both paracellular and transcellular routes.

The chloride concentration rises slightly through the proximal tubule because of the large percentage of bicarbonate reabsorbed here. Therefore, at the end of the proximal tubule, osmolarity and the concentrations of Na+ and K+ have not changed significantly from plasma, but only a third of the amount originally filtered remains.

2. Metabolites Normally, all carbohydrates, proteins, peptides, amino acids, and ketone bodies are reabsorbed here via secondary active transport (requires luminal sodium, linked to sodium reabsorption). Therefore, the concentration of the above should be zero in the tubular fluid leaving the proximal tubule (clearance is zero)

3. Bicarbonate About 80–90% of the filtered bicarbonate is reabsorbed indirectly here. Because the process simply recovers the amount filtered, there is no net gain or loss of bicarbonate by the body. The small amount of bicarbonate that leaves the proximal tubule is normally re-absorbed in subsequent segments.

Thus, for every H+ secreted into the tubular fluid of the proximal convoluted tubule, one HCO3 and one Na are reabsorbed.

Secretion in the proximal tubule
Many organic anions and cations are secreted and cleared from the circulation including PAH, penicillin, atropine, and morphine. Energy requirements All of the active processes are powered by the Na/K- ATPase primary active pump. It represents the most energy-demanding process of the nephron. The nephron also has a H-ATPase that contributes to the active H+ secretion.

Ratio of the concentration of the substance in the proximal tubular fluid (TF) to the concentration in the plasma (P)

Reabsorption in the Loop of Henle

Reabsorption in the Loop of Henle
The loop of Henle reabsorbs about 25% of the filtered electrolytes, which include Na+, Cl–, K+, Ca++and HCO3–. About 15% of the filtered water is also reabsorbed here. Again this is powered by the Na/K-ATPase located on the basolateral membrane.

The descending part of the thin segment
of the loop of Henle is highly permeable to water and moderately permeable to most solutes but has few mitochondria and little or no active reabsorption. The thick ascending limb of the loop of Henle reabsorbs about 25 per cent of the filtered loads of sodium, chloride, and potassium, as well as large amounts of calcium, bicarbonate, and magnesium. This segment also secretes hydrogen ions into the tubular lumen

This segment is impermeable to water

DISTAL TUBULE AND COLLECTING DUCT
Early distal tubule reabsorbs Na, Cl, and Ca. The NaCl crosses the apical membrane via a Na-Cl symporter. The Na is pumped across the basal membrane via the Na/K-ATPase proteins and the Cl diffuses down its electrochemical gradient through channels. This section is impermeable to water. Thus osmolarity decreases further.

Early DISTAL TUBULE Calcium transport is similar throughout the nephron. Calcium enters the cell from the luminal fluid passively through calcium channels. It is actively extruded into the peritubular fluid via Ca2+ATPase or a 3Na+ - Ca2+antiporter.

The early distal tubule has many of the same characteristics as the thick ascending loop of Henle and reabsorbs sodium, chloride, calcium, and magnesium but is virtually impermeable to water and urea. The late distal tubules and cortical collecting tubules are composed of two distinct cell types, the principal cellsand the intercalated cells. The principal cells reabsorb sodium from the lumen and secrete potassium ions into the lumen. The intercalated cells reabsorb potas-sium and bicarbonate ions from the lumen and secrete hydrogen ions into the lumen. The reabsorption of water from this tubular segment is controlled by the concentration of antidiuretic hormone

Late distal tubule and collecting duct
They are composed of principal cells and intercalated cells. Principal cells reabsorb sodium with some chloride and water. They secrete potassium. Intercalated cells are represented by 2 different populations of cells. Some secrete H+ and in doing so generate brand new bicarbonate, which is secreted into the circulation. The second population secretes bicarbonate into the lumen of the tubule. Both are involved in acid–base regulation. This is the section of the nephron responsible for eliminating fixed acids produced by body metabolism Late distal tubule and collecting duct – distal nephron

Reabsorption and Secretion in the Late Distal Convoluted Tubule and Collecting Duct
The principal cells reabsorb Na and secrete K; the intercalated cells reabsorb K and HCO3 and secrete H. In the late distal convoluted tubules and collecting ducts, the amount of water and solute reabsorption and the amount of solute secretion vary depending on the body’s needs.

Most of the glucose that is filtered through the glomerulus undergoes reabsorption in the a. Proximal tubule b. Descending limb of the loop of Henle c. Ascending limb of the loop of Henle d. Distal tubule e. Collecting duct

Which of the following substances will be more concentrated at the end of the proximal tubule than at the beginning of the proximal tubule? a. Glucose b. Creatinine c. Sodium d. Bicarbonate e. Phosphate

Endocrine and Synthetic functions

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