BIOL 0800 - Physio Unit 3

Renal Functions

1. Regulate volume: isosmotic changes in volume

2. Regulate osmolarity: excrete more/less solutes; excrete more less/solvent

3. Regulate pH: net result of metabolism is acid load

   1. pH of urine reflects physiological response to ingestion

4. Excrete metabolic waste: urea, creatinine, uric acid

5. Regulate ECF ions: Na+, Cl-, K+, HCO3-, Ca++, Mg++

6. Regulate/Secrete Hormones: renin influences angiotensin/aldosterone hormones; erythropoietin is a hormone.

   1. Renin itself is not a hormone, BUT it does impact other hormones.

Anatomy of the Kidneys

ANYTHING INSIDE THE KIDNEYS IS OUTSIDE THE BODY

• 1 L of blood / min is received by the Kidney

• 1 mL of urine / minute is produced by Kidneys per minute

  • Majority of liquid is reabsorbed by the Kidneys

• After 500 minutes, the Kidneys reach capacity (500 mL) and are emptied through the Urethra

  • Outside of the Kidney = Renal Cortex

  • Inside of the Kidney = Renal Medulla

Nephrons

Plasma and Solutes are filed into Bowman’s Space (OUTSIDE THE BODY)

• 25% of the plasma that goes to your kidney is filtered here in this capillary bed.

  • Your Kidneys receive 1L blood / min

• Filtration is MUCH more favored than the typical capillary bed and is considered leaky.

• If this plasma was not recovered, you would lose 1 L plasma / 10 minutes, so this plasma must be recovered as it passes through the tubule system.

  • Most of the Plasma is reabsorbed as it goes through the system, with ultimately 1 mL leaving to fill the bladder.

The plasma is enriched with the goodies and the waste products like Urea. Large volumes of this are pushed into the kidneys: the body keeps everything that we need and throw all the bad stuff out into the Lumen.

• The Nephron is engineered similarly to the small intestine:

  • You eat food/drink water → stomach where it is broken down into solutes and water → transported into the body, nothing escapes into the large intestine

  • You dump a bunch of plasma into the nephron → trust transport mechanisms to transport into the body things we need, push out things we don’t need into the Lumen.

Renal Anatomy

Loop of Henly

• Thick ascending limb: a lot more cellular machinery and active transport occurring across the membrane

Renal Process

Tubule is a mini digestive tract

• Afferent arteriole carries blood in:

  • 500 mL of plasma enters

  • 375 mL/min of plasma is absorbed into the Efferent Arteriole

  • 125 mL/min of plasma is FILTERED OUTSIDE the body

    • As we have more and more reabsorption all along, this volume of plasma decreases as it travels through the PROXIMAL TUBULE.

    • Only 1 mL/min of plasma leaves to the bladder

• Ultimately, 499 mL/min of plasma returns through the Peritubular Capillaries to the Renal Vein.

Red blood cells are not filtered: they enter the Efferent Arteriole, pass through the Peritubular Capillaries, and are re-enriched with plasma as plasma is reabsorbed through the Efferent Arteriole.

* The difference between the volume that enters the renal artery and leaves the renal vein is found in urine

Renal Flow Rate

180 L/day travels through the body, with this passing through the Kidneys (this is roughly 36 times a day)

• Your blood is REPEATEDLY passing through the kidneys

• 1/5 of the 5L of blood that leaves your heart is filtered through the Kidneys every minute.

Amount Filtered - Amount Reabsorbed + Amount Secreted = Amount of Solute Excreted

180 L/day filtered = 1.5 L/day excreted

Glomerulus: the beginning of the Nephron

• 2,000,000 nephrons in our 2 Kidneys

  • We only need like 500 nephrons for proper functioning, so our renal system is overbuilt by a factor of FOUR.

• 500 mL of plasma/min to 2,000,000 Nephrons

• 125 mL plasma/min filtered = Glomerular Filtration Rate

• 125/2 million = 62.5 nL plasma/min filtered at each Glomerulus

Renal Terminology

• Afferent/Efferent Arteriole: lined with smooth muscles

  • Sympathetic nerve fibers innervate Afferent/Efferent Arterioles, with alpha receptors allowing for independent regulation of the resistance of arterioles.

    • This impacts how much filtration we have in the Glomerulus, and how much blood resistance (increased blood shunting away from the kidneys) to the Kidneys.

    • Increased blood resistance decreases the amount of blood that goes to the Kidneys

• Sandworm = Distal Convoluted Tubule:

  • In close approximation to the Afferent/Efferent Arterioles, allowing for Paracrine Signaling to the Arterioles between the Distal Convoluted Tubule.

  • The Distal Convoluted Tubule can sample the filtrate and release paracrine signaling for regulation purposes to adjust filtration rate through the Kidneys.

    • Maculadensal Cells at the front end can increase flow when filtration in the Distal Tubule is insufficient

Renal Terms

• Renal Blood Flow: 1000 mL/min

• Renal Plasma Flow (RPF): 500 mL/min

• Glomerular Filtration Rate (GFR): 125 mL/min

• Reabsorption: 124 mL/min

• Secretion: solutes effects concentration

• Excretion: 1 mL/min

  • Filtration Fraction: GFR/RPF = 125/500 = 0.25 mL/min

    • This is the #1 measure of Renal Function. If this drops (RPF increases), this indicates some disfunction.

Glomerular Histology

Bowman’s Space: the spaces that are continuous with the Proximal Tubule; these are the only parts of the Kidney that are OUTSIDE the body.

• Plasma in the Capillary Lumen have to pass through Endothelial cells → Podocytes → Enters Bowman’s Space outside the body

  • The junctions between endothelial cells are WIDE, allowing for leaky filtration out of the Capillary Lumen

• The basement membrane is necessary for EXCHANGE

  • RED BLOOD CELLS and LARGE PLASMA PROTEINS are not able to easily pass through the Endothelial Cell to reach Bowman’s Space, while waste products, ions, and water are EASILY able to pass through in order to filter as urine.

    • Plasma Proteins, such as Albumin (most numerous) can easily sneak through the Fenestrated Endothelium (endothelial cells), but the Extracellular Matrix has a net negative charge such that proteins are repelled at the Basement Membrane and are repulsed from passing through.

GFR Regulation

The Afferent Arteriole is a HIGHLY pressurized Arteriole, not far from the 100 mmHg of pressure in Aorta:

• This is a great driving force for FILTRATION out of the Glomerulus

  • P_H = Hydrostatic Pressure = 55 mmHg OUT

  • pi = Colloid Osmotic Pressure due to proteins in plasma = 30 mmHg IN

  • P_fluid = Fluid Pressure created by fluid in Bowman’s Capsule = 15 mmHg in

    • Net Filtration Pressure = 10 mmHg

• Kidney Stones can block filtration, leading to the accumulation of pressure in Bowman’s Capsule and ZERO filtration through the nonfunctioning Kidney.

  • Anything that blocks the Ureters can affect this.

10 mmHg results in a LARGE flow due to the LOW resistance and HIGH conductance of the Kidney, giving us HIGH flow and HIGH filtration

Nephron Circulation

Nephrons Include Tubule Components:

• Glomerulus, proximal, descending loop, thin ascending loop, thick ascending loop, distal tubule, collecting duct

  • Glomerular Capillary Bed: is necessary for FIILTRATION

  • Peritubular Capillary Bed: is necessary for REABSORBING filtrate put into the Lumen, actively secreting solutes, and actively undergoing O2/CO2 exchange.

and Blood Vessels:

• Arteries, Arterioles, Capillaries, Venules, Veins

Resistance, Pressure, and Flow in the Glomerulus

You can independently regulate the radius of the Afferent/Efferent Arterioles to regulate fluid flow:

• MAP from the Aorta is 100 mmHg → Pressure in Afferent Arteriole is 0 mmHg

• Resistance defined by the Precapillary Sphincter Muscle of Afferent Arteriole

  • Glomerular Capillary bed between Afferent/Efferent Arteriole results in a PRESSURE DROP due to Resistance. PROPORTIONAL

    • If the resistance of the Afferent Arteriole and Efferent Arteriole is equal, then half of the pressure drop occurs across the first resistor and half of the pressure drop occurs across the second resistor.

• Precapillary Sphincter Muscle on Efferent Arteriole induces Resistance as well.

• The Peritubular Capillary Bed receives blood from the Efferent Arteriole, with a relatively INSIGNIFICANT pressure drop with respect to the Glomerular Capillary Bed.

The Afferent/Efferent Arteriole System as Resistors

• The Afferent/Efferent Arteriole System is effectively two resistors in Series: R_total = R₁ + R₂

  • Under normal circumstances:

    • R₁ = ½ resistance

    • R₂ = ½ resistance

• Pressure is dropped across a resistance

• Amount of Pressure Drop is proportional to the amount of Resistance

Example:

• If we increase the resistance of the Afferent Arteriole above the Efferent Arteriole such that it is doubled, R₁ = 2/3 and R₂ = 1/3 of total Resistance.

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We have exquisite control over Filtration in our Glomerular Capillary Bed

• Anytime you constrict Afferently, you increase the resistance of the Kidneys and therefore decrease blood flow to the Kidneys.

• Anytime you constrict Efferently, you increase the pressure of the Glomerular Capillary bed, increasing GFR, decreasing RBF, but increasing the Filtration Fraction (GFR/RPF).

Regulation of GFR: regulation of pressure in Glomerular Capillaries

1. Sympathetic Stimulation

• a) Moderate to high - constriction of afferent and efferent arteriole

• b) Severe – even greater constriction of afferent arteriole

  • More constriction of the Afferent results in a pressure drop in the Glomerular Capillary, severely limiting renal blood flow and filtration of blood.

2. Autoregulation

• a) Myogenic Response (Renal baroreceptor-within kidney)

  • Stretch → ↑[Ca++]in

• b) Juxtaglomerular Apparatus

• Macula Densa Cells

  • 1. Release paracrine factors (afferent arteriole)

    • - ↑NaCl → purines (e.g.adenosine) → constriction

    • - ↓NaCl → Nitric Oxide → dilation

• 2. Release paracrine that release Renin from Juxtaglomerular Cells.

  • Renin activates hormones in blood (see endocrine)

3. Endocrine

• ↑Renin Angiotensin Aldosterone System (RAAS) = increase volume

  • Decrease RAAS = dump volume

• ↑Atrial Natriuretic Peptide (ANP) = decrease volume

  • Decrease ANP = increase volume

    • Peptide signaling molecule that causes Natriuresis, or loss of salt water from the body.

Endocrine Effects on GFR - Low Pressure Sensing Systems

Renin-Angiotensin-Aldosterone System (RAAS)

• ↓Blood Volume → JGA → ↑ renin → ↑ angiotensin II → ↑aldosterone

  • Angiotensin II vasoconstricts smooth muscle in blood vessels

Atrial Nariuretic Peptide (ANP) (low pressure sensing system in atria)

• ↑Blood Volume → ↑ Stretch of atria → ↑ Atrial Natriuretic Peptide (ANP)

  • - In kidney, vasodilates afferent arteriole; vasoconstricts efferent (↑GFR)

  • - ↓reabsorption of NaCl in distal tubule

  • - ↓release of Renin from JGCs

How does kidney handle solutes and water?

• 1. Dump plasma and most of the solutes (e.g. glucose, Na, Cl, K, Ca, etc.) outside the body into the lumen of the tubule.

• 2. Reabsorb what you want to keep: water, important solutes, etc. in a very regulated way.

  • If we need to adjust solute concentration, the kidney can regulate how much you do/don’t reabsorb or how much you do/don’t secrete.

• 3. Leave undesired plasma and solutes in lumen to form urine

• 4. Secrete some solutes from blood plasma into lumen of tubule (much smaller numbers of molecules handled this way)

  • (Kidney tubules are mini digestive tracts.

Renal Tubule Lumen

• Luminal Side of Tubule: apical membrane, facing the outside world.

• Basolateral Membrane: basal membrane, surrounded by extracellular fluid inside the body.

Concentration Gradients

• Na+ has strong gradient going inside of cell due to primary active transport. This is done via facilitated diffusion.

• Na+ gradient is used for co-transport of GLUCOSE molecules, amino acids, and other GOODIES.

  • WE NEVER WANT TO WASTE GLUCOSE IN URINE, SO WE MUST USE COTRANSPORT TO BRING BACK IN!!!

• K+ has a strong gradient out of the cell, transporting from the Basolateral membrane into the cell, across the Luminal membrane

Tight Junctions:

• Prevent the passive transport of molecules such that the kidneys can carefully regulate concentration gradients across the Basolateral/Apical membrane.

The movement of Water

Water can transport across the Apical Tubular Membrane through Aquaporin Channels

• Water permeability is variable across the Tubular Membrane, with Water following Osmotic gradients as ion concentration gradients are localized, drawing in Water WHEN it is permeable.

• Any water that is reabsorbed impacts Plasma in the Peritubular Capillaries (lots of free exchange here).

  • ABSORPTION is favored in these capillary beds.

Flow through Tubules

Flow Rate Along Nephron:

• For Water and Glucose:

  • At GFR = 125 mL/min and GFR = 250 mL/min

Flow Through Tubules:

• Most reabsorption of 125 mL/min of plasma occurs in the Proximal Tubule.

• Reabsorption continues in the Descending Loop.

• There are NOOOOOOO Aquaporins in the Thick Ascending Loop, so Water is NOT permeable.

• The Distal Tubule and Collecting Ducts contain Aquaporins such that reabsorption CAN occur here, but the flow rate is variable depending on how the body is sequestering water.

PROXIMAL TUBULE IS ALL ABOUT ABSORPTION

The normal concentration of Glucose is 100 mg/dL or 1 mg/mL of plasma

• If GFR = 125 mL plasma/min then flow rate of Glucose is:

  • 1 mg/mL x 125 mL/min = 125 mg/mL

ALL OF THE GLUCOSE MUST BE REABSORPED IN THE PROXIMAL TUBULE!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

• The massive machinery to bring Glucose back into the body allows it as such that NO Glucose will be passing beyond the Descending Loop and escaping into the Urine.

Sodium Reabsorption

Water follows (except for thick ascending)

• Thick ascending reabsorption of Na+ sets up osmotic gradient that results in more water reabsorbed.

  • Proximal Tubule (65 - 80%): 75%

  • Descending Loop (Na+ is used to set up osmotic gradient)

  • Thick Ascending Loop (10 – 20%): 15%

  • Distal Tubule (5 – 10%): 7%

  • Collecting Duct (3 – 5%): 3%

    • We have variability in the amount of water that is brought in here and is rather DYNAMIC.

Potassium Reabsorption

When you arrive at the Collecting Duct, Potassium can be ACTIVELY SECRETED, resulting in an INCREASED FLOW RATE.

• As opposed to static, or reabsorption of Sodium, Potassium is actively secreted.

• These two factors are yoked together:

  • In the Collecting Duct, the same mechanisms that pull Na+ back into the body are used to push K+ back out of the body.

Inulin and PAH Renal Transport

Inulin is filtered, but NOT reabsorbed or secreted from the Lumen

• Inulin is a good measure of the amount of Plasma that is being filtered every minute.

• Inulin remains constant in the Plasma, so if we can measure the amount of Inulin being secreted in Urine per minute, we can measure rates of Plasma filtration.

• 100 mg of Inulin in Tubule = 100 mg of Inulin in Urine

PAH is filtered in the Glomerulus, AND actively secreted along the Tubule

• PAH levels start of high in the Tubule and increase as we travel down the Proximal Tubule.

• PAH levels in Urine is a measure of Renal Plasma flow.

• 100 mg of PAH in Tubule = > 100 mg PAH in Urine

Big Picture

• 500 mL of Plasma enters the Glomerulus:

  • 375 mL is not filtered, 125 mL is filtered through the Tubule

  • 1 mL of Plasma is secreted in the Urine while 499 mL is transported through Renal Vein.

Flow Rate of Glucose, Inulin, and PAH through blood, filtrate:

• Renal Plasma Flow is 500 ml plasma/min

• Concentration of Glu., In. and PAH are all 1.00 mg/ml

• Flow rate for Glu., In. and PAH is 500 mg/min (= RPF x [solute]plasma)

  • GFR = 125 ml/min so filtration rate for all is 125 mg/min

• Glucose is reabsorbed so reabsorption is 125 mg/min and excretion are 0 mg/min

• Inulin is not reabsorbed or secreted, so reabsorption is 0 and excretion is 125

• PAH is not reabsorbed and remaining PAH in blood is actively secreted (375 mg/mi so excretion is 500 mg/min.

Inulin:

• If we have 100 mg/min of Inulin in the Urine:

  • 500 mg/min of Inulin enter the bloodstream

  • 375 mg/min of Inulin travels through the Efferent Arteriole through Renal Vein, 125 mg/min of Inulin is filtered through the Tubule.

PAH:

• If we have 500 mg/min of Inulin entering the bloodstream:

  • 125 mg/min is filtered through the Glomerular Tubular

  • 375 mg/min is NOT filtered as it flows through the Renal Vein.

    • Some mg/min from the 375 mg/min of PAH passes from the Renal Vein into the Glomerular Tubular, allowing for secretion of PAH and increased concentration of PAH through active secretion into urine.

Clearance:

The amount of blood plasma that is 100% cleared of a solute in one minute (mL/min)

• C_x = mL plasma/min

• V = urine flow rate (mL/min)

• U_x; P_x = Concentration (mg/mL)

  • Clearance of X (C_x) = U_x x V / P_x

Deriving the Clearance Equation:

• Some concentration of plasma times the volume of plasma that is cleared of that substance per minute.

  • [Plasma]_x x Clearance_x = [Urine]_x x V

• If 1 mg/mL is the concentration and we clear 100 mL plasma/min, we have:

  • 1 mg/mL x 100 mL plasma/min = 100 mg/min

    • 100 mg/min = [?]_x x 1 mL/min = [100 mg/mL] x 1 mL/min

• Clearance of Glucose from the Plasma should be ZERO as no Glucose

Clearance Rates of Glucose, Inulin, and PAH

C_Glucose: 1 mg/mL x 100 mL Plasma/min = 100 mg X/min = 100 mg/mL x 1 mL/min

• 100 mg X/min = 100 mg X/min

Only 91% of Plasma going to the Kidney is cleared of PAH:

• C_PAH = RPF(0.91)

• RPF = C_PAH/0.91

Transport Max of Glucose

• As Plasma Glucose levels rise, the Filtration rate of Glucose increases = more mg/min in Filtrate at the beginning of the Proximal Tubule into the Nephron.

  • How many mg/min of Glucose that show up in the Tubule is proportionally related to the GFR.

• How much is Reabsorbed? Normal rates are such that 125 mg/min is reabsorbed for every 125 mL/min that enter the Tubule.

The length of Tubule and the Density of Na/Glucose Cotransporters determine the Transport Max, or the maximum amount of Glucose that can be reabsorbed.

• When filtration exceeds reabsorption (TMax), we start to see Glucose appear in the Urine.

• The difference between reabsorption and filtration is measured as the rate of excretion.

• As the concentration of Glucose in the blood exceeds 300 mg/100 mL plasma, we begin seeing Glucose in the Urine.

Free Water Clearance

The set point for Osmolarity in the body is 300 mOsm/L

• Zero free water clearance (urine and plasma concentration equal)

  • Plasma renal artery (300 mOsm/L); plasma renal vein (300 mOsm/L); urine (300 mOsm/L)

• Positive free water clearance (dilute urine; more dilute than plasma)

  • Plasma renal artery (270 mOsm/L); plasma renal vein (280 mOsm/L); urine (50 mOsm/L)

    • We remove water from the blood, at it to urine!

    • Low concentrated Biliruben

• Negative free water clearance (concentrated urine; more concentrated than plasma)

  • Plasma renal artery (320 mOsm/L); plasma renal vein (310 mOsm/L); urine (1000 mOsm/L)

    • We add water to the blood, remove it from the urine!

    • Highly concentrated Biliruben

Why is Pee Yellow?

Bilirubin, resultant from the breakdown of red blood cells and the recycling of Hemoglobin.

• It make poo brown.