3 - Renal Blood Flow and Glomerular Filtration

ADVANTAGES OF ↑ GLOMERULAR FILTRATION RATE

Allows kidneys to rapidly remove waste products from the body that depend mainly on GFR or filtration for their excretion. Allows body fluids to be filtered and processed by the kidneys many times each day; for a precise and rapid control of the volume and composition of bodily fluids; homeostasis.

The glomerular capillary hydrostatic pressure is determined by 3 factors:

> Renal arterial pressure at the glomerulus > Afferent arteriolar resistance > Efferent arteriolar resistance The 3 factors mentioned above can be depicted in an analogy of a leaking garden hose: ● If pressure in the pipes leading to the faucet of the hose goes up or down, this directly affects pressure in the hose, hence the rate of leak. This represents the renal arterial pressure. ● If we kink the hose upstream from the leak, pressure at the region of the leak falls and less water leaks out. This represents the afferent arteriolar resistance. ● If we kink the hose beyond the leak, this raises pressure at the region of the leak and increases the leak rate. This represents the efferent arteriolar resistance.

FACTORS AFFECTING RENAL CIRCULATION: Sympathetic Nerve Fibers

All blood vessels of the kidneys, including afferent and efferent arterioles are richly innervated by sympathetic nerve fibers. ● Increased sympathetic activation → can constrict renal arterioles → increasing the resistance in arterioles → decrease renal blood flow → decrease GFR An important mechanism since sympathetic nerve stimulation helps in reducing GFR in acute disturbances such as defense reaction, brain ischemia or severe hemorrhages.

Forces Opposing Filtration (mmHg)

An increase here would decrease GFR ● Bowman's capsule hydrostatic pressure = 18 ● Glomerular capillary colloid osmotic pressure = 32 ● Net Filtration pressure = 60 - 18 - 32 = 10 mmHg

Forces Favoring Filtration (mmHg)

An increase here would increase GFR ● Glomerular Hydrostatic pressure = 60 [primary driving force for filtration - pressure inside the capillaries] ● Bowman's capsule colloid osmotic pressure = 0 [negligible]

RENAL CLEARANCE

Clearance: Reading the body of a substance Renal Clearance: ● Substance that was removed from the body and excreted from the urine ● Measurement of the excretory function of the kidney ● Tells the volume of plasma from which a substance has been completely excreted in the urine per unit time based on fixed principle of conservation of mass (e.g. What flows into the kidneys via the renal artery, must flow out of the renal vein or the urine). Assuming that substance x is completely excreted and not reabsorbed along the nephron. ● Unit is volume per time

Kidney Structure: Inner medulla

Composed of 8-10 pyramids, each pyramid has an apical end called papilla which: ●Empty urine into the minor calyces then each drains to major calyx. ●Contains collecting ducts concentrated in the pyramids. There are 3 major calyces in each kidney which drain into the renal pelvis: ●Renal pelvis ●Ureter ●Urinary bladder

Determining Factors for Solute Penetration of the Glomerular Membrane

Despite the high filtration rate, the glomerular filtration barrier is selective in determining which molecules to filter Selectivity of the barrier of the filtered solute is based on ● Molecular size ( small molecules, larger molecules) ● Electrical charge or ionic charge ●Smaller molecules are solutes that are filtered more than larger molecules ●Positively charged molecules , are readily filtered because of the strong negative charge of the filtration barrier

MYOGENIC AUTOREGULATION OF RBF AND GFR

Direct reaction of the vascular smooth muscles to stretch or relaxation ● Increase in blood pressure - cause vasoconstriction> Decrease in blood pressure - cause vasodilation so that blood flow downstream remains steady If we increase the arterial blood pressure, we increase the afferent arterial blood pressure also and there would be an arterial wall stretch → sensed by the myogenic cell receptors which opens the voltage gated Ca²⁺ channels which causes contraction of these vascular smooth muscles When the smooth muscles contract, it causes vasoconstriction and minimizes the afferent arteriole blood flow which will tend to decrease the GFR

Angiotensin II Effect on Renin-Angiotensin System

Direct vasoconstricting effects Stimulate Na reabsorption by the proximal convoluted tubule Stimulates thirst, antidiuretic release, catecholamines release (e.g. epinephrine and norepinephrine), aldosterone release and secretion

Efferent arteriolar constriction effect on GFR

Efferent arteriolar constriction → has a biphasic effect on GFR ● At moderate levels of constriction → slight increase in GFR ● At severe constriction → decrease in GFR ● Slight increase in efferent arteriolar resistance or vasoconstriction of the efferent arteriole → increases glomerular hydrostatic pressure → increasing the glomerular filtration rate ● Very severe resistance in the efferent arterial → increase in glomerular capillary oncotic pressure is greater than the increase in the glomerular capillary hydrostatic pressure → filtration cease → decreasing GFR

Filterability of solutes: Electrical Charge

Electrical charge is a second variable determining filterability of macromolecules Negatively charged large molecules are filtered less easily than positively charged molecules of equal molecular size ● This is because the surface of all the components of the filtration barrier contains fixed polyanions which repel negatively charged macromolecules during filtration ● Almost all plasma proteins give negative charges ● Electrical repulsion plays an important restrictive role ● Certain diseases that cause glomerular capillaries to become leaky do so by eliminating negative charges in the membrane such as diseases where we can see manifestation of proteinuria or albuminuria

GLOMERULAR FILTRATION

Glomerular capillaries are relatively impermeable to proteins Composition of the Filtrate ●Protein free and cell free ●Salts and organic molecules are similar to those in plasma ●Does not include calcium and fatty acids that are bound to proteins

GLOMERULAR CAPILLARY MEMBRANE: 3 Layers

Endothelium perforated by small holes called fenestrations serving as a size barrier: ● Contains proteins that are richly endowed by fixed negative charges that hinder the passage of plasma proteins Basement membrane: ● Contains a lot of collagen and proteoglycans including heparan sulfate that contributes to the strong negative electric charge Epithelial cells with foot like processes called podocytes: ● Foot processes or podocytes which interdigitates to form slit pores through which the glomerular filtrate moves ● Have negative charge and also provides additional restrictions to filtration of plasma proteins 3 step process through the fenestrae, basement membrane, and the slit pores between podocyte foot processes

Function of Kidney: Regulation of body fluid osmolality and electrolyte concentrations.

Excretion of electrolytes must match intake to maintain homeostasis which is governed by eating and drinking habits. In times of deficiency, the kidneys reabsorb most of what is filtered. At times of excess, the kidneys excrete.

TUBULOGLOMERULAR FEEDBACK

Feedback mechanism from the tubules back to the glomerulus. As the filtration rate in an individual neutron increases or decreases the amount of Na that escapes reabsorption in the proximal tubule and the loop of henle also increases or decreases (direct relationship) ● ↓filtration rate filtered, ↓Na remains in the lumen of the nephron, ↓Na flowing from the thick ascending vein into the distal tubule because of increased reabsorption

Filterability of solutes: Inverse Relationship for Size

Filterability of solutes is inversely related to their size Filterability of 1 means that the substance if filtered as freely as water which means plasma concentration of a certain substance is equal to the concentration in the filtered grove found in the lumen ● Filterability of 0.75 means that the substance is filtered only 75% as rapidly as water ● This is dependent on the molecular weight of the substance ●Molecular size of a substance is indirectly proportional to its filterability; thus, as the molecular weight approaches that of albumin, filterability rapidly decreases approaching zero

RENAL HANDLING OF SOLUTES

For any molecule X that is freely filtered at the glomerulusIf filtration rate is greater than excretion rate, there is net reabsorption if X. ● If excretion rate is greater than filtration rate, there is net secretion of X. ● If filtration rate and excretion rate are the same, X passes through the nephron without net reabsorption or secretion ● If clearance of X is less than inulin clearance, there is net reabsorption of X. ● If clearance of X is equal to inulin clearance, X is neither reabsorbed nor secreted. ● If the clearance of X is greater than inulin clearance, there is net secretion of X.

DETERMINANTS OF GFR (Overview)

GFR is determined by: > Glomerular capillary filtration coefficient / Kf - Product of permeability and filtering surface area of capillaries or filtration coefficient ● GFR = Kf x Net Filtration Pressure > Net filtration pressure: - Hydrostatic + Colloid osmotic forces across the glomerular membrane ● Glomerular capillary have higher rate of filtration because of a high glomerular hydrostatic pressure and a large filtration coefficient ● The normal value of net filtration pressure is 10 mmHg ● The normal value of GFR is 125 ml/min

EXAMPLE OF SUBSTANCE USED FOR GFR MEASUREMENT

Glomerular Filtration Rate (GFR) is measured using either: 1. Creatinine (Endogenous) ● by product of skeletal muscle metabolism ●fairly produced at a fairly constant rate ●proportional to the body muscle mass ●freely filtered in the glomerulus and not reabsorbed nor secreted (mostly) in the tubular system. ●not a perfect estimation in the proximal tubule 2. Inulin (Exogenous) ● a polysaccharide with a molecular weight of 5200 ● it fits all requirements as a substance used to measure GFR ●freely filtered in the glomerulus and not reabsorbed nor secreted in the tubular system ●all the insulin that is filtered flows through the nephron and appears in the urine, this it is considered as the gold standard for measuring GFR ●To determine inulin clearance to measure GFR, we can use the clearance equation.

ABILITY OF SOLUTE TO PENETRATE GLOMERULAR MEMBRANE

How do the podocytes surround the capillaries to form slit pores? Both the slit pores and basement membrane are composed of an array of proteins ● Integrity of slit pores essential to prevent excessive leak of plasma proteins including albumin ● Some protein wasting diseases are associated with abnormal slit pores structures

RENAL AUTOREGULATION

How does the kidney maintain adequate GFR in the face of systemic arterial pressure changes? AUTOREGULATION ● Major function: autoregulation in the kidneys > Maintain a relatively constant GFR > Allow precise control of renal excretion of water and solutes ● Without autoregulation, an increase of blood pressure from 100-125 (difference of 25 mmHg) would cause an increase in 25% in the GFR → 180-225 L per day > Depletion of blood volume occurs ● Autoregulation is important because it will relatively conserve or maintain a constant GFR and precise control of excretion of water and solutes

GLOMERULAR CAPILLARY OSMOTIC PRESSURE

INCREASED GLOMERULAR CAPILLARY OSMOTIC PRESSURE DECREASES GFR ● Oncotic pressures in the plasma, at the very beginning of the glomerular capillaries, is simply the oncotic systemic arterial plasma. ● Oncotic pressure in glomerular capillaries is identical to arterial oncotic pressure only at the very beginning of the glomerular capillaries (or the afferent end). ● The glomerular capillary oncotic pressure then progressively increases along the glomerular capillaries as protein free fluid filters out of the capillary, concentrating the protein left behind. ● This means that the net filtration pressure and filtration decrease along capillary length towards efferent end. ● Anything that causes a rise in glomerular capillary oncotic pressure will lower the average net filtration pressure and GFR.

CLEARANCE RATIO

If the clearance will be expressed as a ratio, it is usually expressed as clearance of any substance compared with the clearance of inulin. Net handling of other substances can be determined depending on whether the clearance is greater than inulin clearance. ● If clearance ratio = 1.0, the substance approximates GFR ● If clearance ratio = 1.0, the substance approximates GFR > ● If clearance ratio < 1.0, There is net reabsorption of the substance

GLOMERULAR CAPILLARY MEMBRANE (Overview)

In order to form a glomerular filtrate, filtered fluid must pass through the glomerular filtration barrier The filtration barrier separates the blood from the urinary space that connects to the outside world via the renal tubules, ureters, bladder, and urethra

Aldosterone Effect on Renin-Angiotensin System

Increase Na reabsorption as water follows salt, blood volume increase along with blood pressure

JUXTAGLOMERULAR APPARATUS

JG apparatus is composed of JG cells ● JG Cells - modified smooth muscles of afferent arterioles, macula densa, and the extraglomerular mesangial cells ● Apparatus secrete renin in response to decrease renal blood pressure, decreased NaCl delivery to the distal tubule, and increase in sympathetic tone ● Important component of the tubuloglomerular feedback mechanism

Function of Kidney: Regulation of acid-base balance

Kidneys excrete acid and regulate the body fluid buffer stores. This is the only means of eliminating sulfuric and phosphoric acids which are generated by the metabolism of proteins.

Function of Kidney: Regulation of arterial pressure.

Long term: Excreting variable amounts of sodium and water. Short term: Secreting hormones and vasoactive factors such as Renin

Structures within Tubular System

Macula densa - Unique segment containing specialized epithelial cells where it has a delineation between the cortex in the medulla.

CLINICAL CORRELATIONS FOR NEGATIVE CHARGES AND MOLECULAR WEIGHT

Negative charges on the basement membrane are lost even before there are noticeable changes in kidney histology. Some of the lower molecular weight proteins especially albumin, are filtered and appear in the urine known as proteinuria or albuminuria

NEPHRON

Nephron - most basic structural and functional unit of the kidney. ● About 800,000-1,000,000 in each kidney. ● Cannot regenerate and gradually decrease with renal injury, disease or normal aging.

NET FILTRATION PRESSURE (NFP)

Net filtration pressure = Net Hydrostatic pressure - Net oncotic pressure There are four pressures (Starling Forces) that we need to understand: ● Two hydrostatic pressures: > Glomerular hydrostatic pressure (PG) : hydrostatic pressure inside the capillaries. Usually 60 mm Hg > Hydrostatic pressure in the Bowman's Capsule (PB) : Usually 80 mm Hg. ● Two oncotic pressures: > Glomerular colloid oncotic pressure (πG): Usually 32 mm Hg. > Bowman's space oncotic pressure (πB): negligible under normal conditions, since there is normally little protein in the Bowman's capsule.

Kidney Structure: Renal corpuscle

Only found in the cortex.

Kidney Structure: Kidneys

Paired retroperitoneal organs weighing 150g each and about the size of a clenched fist.

HORMONAL AND AUTACOID CONTROL OF RBF & GFR: Endothelin

Released by damaged vascular endothelial cells and other tissues (e.g., vascular injury in acute renal failure, etc) Potent vasoconstrictor

HORMONAL AND AUTACOID CONTROL OF RBF & GFR: Endothelial-derived NO

Released by vascular endothelium Vasodilator

HORMONAL AND AUTACOID CONTROL OF RBF & GFR: Epinephrine, Norepinephrine

Released from adrenal medulla Increased with sympathetic stimulation → constricts afferent and efferent arterioles

Autoregulation of Renal Arterial Pressure

Renal blood flow is autoregulated over a wide range of renal arterial pressure ● Renal arterial pressure vary from 80-200 mmHg, YET renal blood flow will be kept constant ● ↓renal arterial pressure (80 mmHg), ↓renal blood flow The intrinsic response of the kidney changes in blood pressure is of independent of innervation ● Autoregulation is an intrinsic response of the kidney The only way to maintain the constancy of blood flow in the phase of a changing arterial pressure is by varying their resistance of some of the arterioles The two internal autoregulatory mechanisms that operate without outside influence are: 1. Tubuloglomerular feedback mechanism 2. Myogenic mechanism

RENAL BLOOD FLOW Equation

Renal blood flow is determined by the difference between renal vein artery pressure and renal vein pressure divided by the total renal vascular resistance. ● Renal artery pressure = usually 100 mmHg ● Renal vein pressure = 2 - 4 mmHg

Vascular Resistance in the interlobular arteries, afferent arteries, and efferent arterioles

Resistance of these vessels is controlled by the sympathetic nervous system, various hormones, and local internal renal control mechanism. ● Increase in resistance in these vessels → reduced blood flow ● Decrease in resistance → increased blood flow Arterial pressure is maintained between 80 - 170 mmHg via autoregulation. ● Mean arterial pressure as little as 40 mmHg → cease glomerular filtration → arterial pressure in the glomerulus needs to be autoregulated The cortex receives most of the blood since the majority of the function nephron resides in this area. While the vasa recta receives only 1-2% that plays an important role in allowing the kidneys to form concentrated urine

GLOMERULAR CAPILLARY COEFFICIENT -> Diabetes and Obesity Application

Some diseases lower the filtration coefficient by reducing the number of functional glomerular capillaries; thereby, reducing the surface area for filtration ● They also increase the thickness of the glomerular capillary membrane and reduces its hydraulic conductivity ● For example, chronic uncontrolled hypertension and diabetic mellitus, gradually reduce Kf by increasing the thickness of the glomerular capillary basement membrane ● Eventually damaging the capillary so severely that there is loss of capillary function

FUNCTIONS OF THE KIDNEY: EXCRETION

The exit of substances in final urine form produced by the kidneys from the body. Urinary excretion rate : filtration rate - reabsorption rate + secretion rate. ● Normally, glomerular filtration rate is 180 L per day; tubular reabsorption is 178.5 L per day. ● 1.5 L per day excreted as urine. ● Usual plasma volume is 3 L and GFR = 180 L per day. Thus, the entire plasma can be filtered and processed about 60 times each day.

Function of Kidney: Regulation of water and electrolyte imbalances.

Such as urea, creatinine, uric acid, hemoglobin breakdown products, toxins, pesticides, drugs & food additives

Kidney Structure: Hilum

Surrounded by a tough capsule that has an outer cortex and inner medulla ●Enter: Renal artery and renal nerve. ●Exit: Renal vein, lymphatics and ureter.

Function of Kidney: Gluconeogenesis

Synthesize amino acids and precursors during prolonged fasting.

TUBULOGLOMERULAR FEEDBACK: Macula Densa Roles

The macula densa cells sense the amount of Na and Cl in the lumen and act as salt detectors Decrease in NaCl concentration initiates signal from the macula densa has 2 effects: 1. Decreases the resistance to blood flow i the afferent arterioles which raises glomerular hydrostatic pressure, returning GFR back to normal 2. Increases renin release from the JG cells of the afferent & efferent arterioles (major storage sites of renine) which in turn, increases angiotensin II and increased efferent arteriolar resistance → normalization of the GFR ● Clinical practice: tubuloglomerular feedback mechanisms are useful for patients with severe hemorrhage

FUNCTIONS OF THE KIDNEY: REABSORPTION

The process by moving the substances from the lumen across the epithelial layer into the surrounding interstitium. (In most cases, reabsorbed substances move from the interstitium into the surrounding blood vessels.)

FUNCTIONS OF THE KIDNEY: FILTRATION

The process by which water and solutes in the blood leave the vascular space through the filtration barrier and enter Bowman's space.

FUNCTIONS OF THE KIDNEY: SECRETION

The process of moving the substances into the tubular lumen from cytosol of epithelial cells that form the nephron walls. (Secreted substances may originate by synthesis within the epithelial cells, or more often by crossing the epithelial layer from the surrounding renal interstitium)

RENAL HANDLING OF SUBSTANCES

The renal handling of any substance consists of some combination of filtration, reabsorption, and secretion. ● The substance is freely filtered but not reabsorbed nor secreted. ● The substance is freely filtered and reabsorbed back in the blood. ● The substance is freely filtered but is fully reabsorbed. ● The substance is freely filtered and is not reabsorbed but is secreted.

HORMONAL AND AUTACOID CONTROL OF RBF & GFR: Angiotensin II

Vasoconstrictor, particularly of renal efferent arteriole

HORMONAL AND AUTACOID CONTROL OF RBF & GFR: Prostaglandins, Bradykinin

Vasodilators May dampen renal vasoconstrictors effects of sympathetic nerves or angiotensin :: NSAIDs that inhibit prostaglandins synthesis may cause significant decrease in GFR under stressful conditions (e.g., hypovolemia, post-surgery)

Why do you think that almost ¼ of the cardiac output is delivered to the kidneys?

● In a 70 kg man, renal blood flow is 1100mL/min or 22% of cardiac output ● Kidneys → consume oxygen at twice the rate of the brain > Have 7x the blood flow of the brain > Means that O2 delivered to the kidneys far exceeds their metabolic needs. ● It is due to oxygen consumption in relation to active sodium reabsorption in the tubular system ● Decrease in the renal blood flow → decrease in sodium filtration and reabsorption → less O2 will be consumed

BOWMAN'S CAPSULE HYDROSTATIC PRESSURE (PB)

● About 18 mmHG in normal conditions ● Normally changes as a function of GFR, not a physiological regulator of GFR ● The major pathological cause of an increase in hydraulic pressure in the Bowman's capsule is obstruction such as: > Tubular obstruction (anywhere along the tubules): ● Kidney Stones ● Tubular necrosis > Urinary tract obstruction (in the external portion of the urinary system) ● Prostate Hypertrophy ● Bladder Cancer ● The effect of these obstructions is an increase in tubular pressure everywhere proximal to the occlusion, all the way back to the Bowman's capsule. > Increases the Bowman's capsule hydrostatic pressure → opposes filtration → decrease in glomerular filtration rate.

Segments of the Tubular System: Collecting Ducts

● Absorbs only a small percentage of the filtered fluid ● Has a unique sensitivity to wide range of hormonal stimuli (e.g. Aldosterone & Antidiuretic Hormone that alter its permeability to water and particles)

Blocking of Angiotensin II Action

● Administration of drugs that block angiotensin II called angiotensin converting enzyme inhibitors or drugs that block the action of angiotensin II (ARBs) may cause greater reduction in the GFR than usual when the renal arterial pressure falls below normal ● This happens in hypertension in young children secondary to renal artery stenosis, giving ACE inhibitors (ARBs) might result to severe decrease in GFR (in some cases causing acute renal failure) > Do NOT give ACE inhibitors (ARBs) to patients with renal artery stenosis, especially in children

Renal Circulation Overview

● Approximately, 22% - 25% of cardiac output reaches the kidney about 1100 mL/min. ● Blood moves from the aorta through the renal artery and enters the hilum of the kidney, then percolates through smaller and smaller vessels, creating a cul-de-sac of a capillary loop. ● The renal circulation is unique in having 2 capillary beds separated by the afferent arteriole and are arranged in series which helps in regulating hydrostatic pressure.

INCREASED GLOMERULAR CAPILLARY OSMOTIC PRESSURE INCREASES GFR

● Changes in the glomerular hydrostatic pressure serves as a means for physiological regulation of the glomerular filtration rate (GFR). ● If you increase the glomerular hydrostatic pressure, you will also increase the glomerular filtration rate, and vice versa. ● Increased arterial pressure tends to raise glomerular hydrostatic pressure, and therefore increase the GFR. ● Increased resistance or vasoconstriction of the afferent arteriole tends to reduce glomerular hydrostatic pressure, and decrease the GFR. ● Conversely, if we dilate the afferent arteriole , we will increase both hydrostatic pressure and GFR.Increased resistance or vasoconstriction of the efferent arteriole tends to increase capillary hydrostatic pressure, and increase the GFR.

Multiple Functions of Kidney (Overview of 7 Functions)

● Excretion of metabolic waste products and foreign chemicals. ● Regulation of water and electrolyte imbalances. ● Regulation of body fluid osmolality and electrolyte concentrations. ● Regulation of arterial pressure. ● Regulation of acid-base balance. ● Secretion, metabolism, and excretion of hormones such as erythropoietin, calcitriol. ● Gluconeogenesis

Filtration Fraction (FF)

● Filtration Fraction (FF): ratio of GFR to RPF

CELLS OF THE JG APPARATUS: JG Cells

● Form the vascular part of the apparatus in the wall of the afferent and efferent arterioles ● Receive input from the macula densa cells

CELLS OF THE JG APPARATUS: Macula Densa

● Forms the tubular part of the JG apparatus ● Found in the wall of the distal tubule ● Function: salt sensor → senses sodium concentration, and tubular fluid flow in the tubular filtrate which feedbacks to the JG accordingly

FILTRATION FRACTION (In-Depth)

● Fraction of the substance entering the kidney that is filtered, normally 0.20 or 20% for a freely filtered substance ● Filtered Load (mg/min) = GFR (mL/min) x plasma concentration (mg/mL) ● Filtration Fraction (FF) = GFR/RPF > Typical GFR = 125 mL/min > 625 mL of plasma that enters the glomeruli by afferent arterioles ● FF = GFR/RPF ● FF = 125 mL/min/ 625 mL/min ● FF = 20% filtered into the Bowman's space ● Remaining 80% passes via the efferent arterioles into the peritubular capillaries

Glomerular Filtration Rate (GFR)

● Glomerular Filtration Rate (GFR): amount of plasma filtered through the glomerulus each minute; around 20% of RPF

Renal Circulation: Capillaries Regulating Hydrostatic Pressure

● Glomerular capillaries - High hydrostatic pressure that promotes filtration. ● Peritubular capillaries - Low hydrostatic pressure which permits repaid fluid reabsorption.

Structures within Renal Corpuscle

● Glomerular capillaries are covered by epithelial cells which have foot-like processes called podocytes. ● The total glomerulus is encased in a bowman's capsule which is where fluid filtered from the glomerular capillaries flows into the bowman's space and into proximal tubules

Components of Kidney Structure

●Kidneys ●Hilum ●Inner medulla ●Minor calyces ●Major calyx ●Renal pelvis ●Ureter ●Urinary bladder ●Renal corpuscle

Changes in GFR determinants (Effects of Changes)

● Increase in glomerular capillary filtration causes an increase in GFR ● Increase in Bowman's capsule hydrostatic pressure causes a decrease in GFR ● Increase in glomerular capillary colloid osmotic pressure causes a decrease in GFR ●Increase in glomerular capillary hydrostatic pressure causes an increase in GFR

Efferent arteriolar constriction

● Increases resistance to outflow from the glomerular capillaries ● A mechanism that raises the glomerular hydrostatic pressure ●As long as the increase in efferent resistance does not reduce blood flow too much, GFR increases slightly. ● Reduces the following: ●Renal blood flow ●Filtration Fraction ●Glomerular Colloid Osmotic Pressure In cases where constriction of efferent arterioles are severe and the rise in colloid osmotic pressure exceeds the increase in the glomerular capillary hydrostatic pressure, the net force for filtration decreases, causing a reduction in GFR.

CELLS OF THE JG APPARATUS: Extra mesangial cells

● Interstitial cells of the apparatus ● Receive input from the macula densa cells ● When they contract they reduce the glomerular capillary surface "area" which ultimately can lead to lower GMR

Kf

● Kf: glomerular capillary filtration coefficient, cannot be measured directly; estimated by: GFR/net filtration pressure

Cortical Nephron

● Located in the outer renal cortex that is formed by 70-80% of nephrons ● Contains shorter loops of henle that penetrate only a short distance into the medulla ● Surrounded by an extensive network of peritubular capillaries ● Distribution of nephrons affects the distribution of blood flow within the kidney. Majority of which is in the cortex because of the 70-80% of cortical nephrons

Net Filtration Pressure

● Net Filtration Pressure: sum of the hydrostatic and colloid osmotic forces that either favor or oppose filtration across the glomerular capillaries

FACTORS AFFECTING RENAL CIRCULATION: Hormones and Autacoids

● Norepinephrine, Epinephrine, and Endothelin → potent vasoconstrictors → decreases GFR ● Endothelial-derived nitric oxide, and Prostaglandins → vasodilators → increases GFR ● In practice, NSAIDs such as Aspirin inhibits prostaglandins → reducing GFR ● Angiotensin II is unique since in most physiologic condition it preferentially vasoconstricts the efferent arteriole → increases GFR > Afferent arterioles are relatively protected by Angiotensin II mediated vasoconstriction due to the release of nitric oxide and prostaglandins in these vessels. > Increase in Angiotensin II formation → occurs in circumstances associated with decreased arterial pressure or volume depletion → decrease GFR. In this condition, Angiotensin II helps prevent decrease in glomerular hydrostatic pressure and GFR

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS)

● Part of the tubuloglomerular feedback mechanism ● Volume regulating system which involves the kidney: Kidney synthesizes and secretes renin in response to decreased blood pressure, and decreased fluid volume or decreased Na and increase hydrogen in the plasma ● Renin secretion results in conversion of angiotensinogen → angiotensin I > Conversion of angiotensin I → angiotensin II in the lungs, and is considered as a potent vasoconstrictor and stimulator of aldosterone from the adrenal gland ● Angiotensin Converting Enzyme (ACE) converts angiotensin I → angiotensin II; released from the lungs > Usual targets of ACE inhibitors which is a class of antihypertensive medication ● Angiotensin II & Aldosterone stimulate NaCl & water reabsorption in the proximal convoluted tubule and collecting ducts, respectively

GLOMERULAR CAPILLARY COEFFICIENT (Kf)

● Product of the hydraulic conductivity and surface area of the glomerular capillaries ● Cannot be directly measured ● Estimated experimentally by this formula Kf = GFR/Net Filtration pressure = 125ml/min/ 10mmHg = 12.5ml/min/mmHg ● Changes in the value of the filtration coefficient is directly proportional to glomerular filtration rate > Increased KF increases GFR and Decreased KF decreased GFR > However changes in KF do not provide a primary mechanism for the normal day to day regulation of GFR

Renal Blood Flow (RBF)

● Renal Blood Flow (RBF): blood perfusing the kidneys each minute; around 22% of the cardiac output

Renal Plasma Flow (RPF)

● Renal Plasma Flow (RPF): plasma flow rate to the kidneys each minute. Renal Plasma Flow is different from Renal Blood Flow.

2 Functional Parts of Nephron

● Renal corpuscle - Consists of glomerulus, bowman's capsule & bowman's space that forms the ultrafiltrate. ● Tubular system - Receives the filtered fluid and converts it into urine.

Segments of the Tubular System: Proximal Convoluted Tubule

●Approximately reacquires 75-80% of filtered fluid from the glomerulus ●Contains a lot of mitochondria as well as basal infoldings in the cell membranes that are vital in the reabsorption of fluid and particles ●Connected to the Loop of Henle ("loop" hairpin structure) with a Thin Descending Limb and a Thick Ascending Limb that contributes to 5-10% of water reabsorption and pumps out ions against the concentration gradient of the cells of the mitochondria which are high in concentration

FACTORS AFFECTING GLOMERULAR CAPILLARY OSMOTIC PRESSURE (𝜫G )

●Arterial plasma colloid osmotic pressure > A decrease in arterial protein plasma concentration (occuring in liver disease) will lower arterial colloid osmotic pressure ● An increase in arterial oncotic pressure (and glomerular oncotic pressure) will decrease GFR ● In the glomerulus, there is a steep increase in oncotic pressure as blood flows from the afferent end to the efferent end (from a value of 28mmHg to 36mmHg) ● Filtration fraction > Filtration fraction = GFR / Renal Plasma Flow > The glomerular capillary oncotic pressure is directly proportional to the filtration fraction. > Meaning the higher the volume that is filtered from plasma, the higher is the rise in glomerular capillary oncotic pressure.

Segments of the Tubular System: Distal Convoluted Tubule

●Connects with the Macula Densa ●Connects with the Collecting Tubules/Ducts

Juxtamedullary Nephron

●Formed by 20-30% of nephrons ●Has a glomerulus that has long loops of henle that extend deep into the medulla ●Has long efferent arterioles that extend down the outer medulla that divides into specialized peritubular capillaries called Vasa Recta ●Medulla receives much less blood than the cortex since only 1-2% of total renal flow reaches the deep medulla

BLOOD FLOW OF THE KIDNEYS

●Renal artery -> segmental arteries -> interlobar arteries -> medulla -> corticomedullary junction -> arcuate arteries -> interlobular arteries / radial arteries -> afferent arterioles ->afferent arterioles -> cortex -> glomerular capillaries -> efferent arterioles -> peritubular capillaries -> vasa recta ●Efferent arterioles have smaller diameter than afferent arterioles forming further two capillary system called peritubular capillaries and vasa recta ●20% of blood is filtered off by the glomerulus; 80% passes through efferent arteriole ● Venous circulation of kidneys mirrors that of the arterial. ● Peritubular capillaries and arcuate vein empty into the interlobular vein ● Interlobar vein will drain into the segmental vein and towards the renal vein which will ultimately drain into the inferior vena cava.

Vasa Recta

●Tubular system of the Juxtamedullary Nephron ●Extends downward into the medulla lying side by side with the loop of henle ●Enclosed proximately along the whole length of the loop of henle for reabsorption of substances ●Conduits for blood ●Exchanges water and solutes between the plasma and the interstitium