CV Biophysics & Kidney Flashcards
Major Functions of the Circulatory System
-Transporting nutrients to tissues
-Transporting waste products away from tissues
-Transporting hormones: signaling
Kidneys are an important part of this
Volume, Velocity, Pressure, Area
-Volume: Liters, ml, mcl
-Velocity: Distance/time (meters/sec)
-Pressure: Force; mmHg, cmH2O
-Area: Size, surface area (walls of a cyclinder)
Blood Flow Determinants
Blood Flow/ Vascular Resistance
-Blood Flow: Volume/time (ml/min, ml/sec, L/sec)
-Vascular Resistance: Typically determines what kind of BP we have. Increased resistance –> less flow
Blood Flow/Pressure & Resistance Example
The pressure will be highest between the source of blood flow and the area of resistance.
Immediately downstream from the area of resistance, the pressure should be much lower
Series vs Parallel
Blood vessels in a series: Blood vessels connected together end to end.
Ex: R1 + R2; will have double the resistance than just R1 or R2
Formula to determine resistance in series: Rtotal= R1 + R2 +R3…
Blood vessels in parallel: More pathways for the blood to flow through, stacked parallel to each other. Much lower resistance here
Cross Sectional Areas of Systemic Circulation
How does that affect velocity?
-Cross sectional area (cm2): Internal Diameter
-The lower the cross-sectional area, the faster the velocity of blood flow
-The higher the cross-sectional area, the slower the velocity of blood flow
Velocity of Blood Flow Formula
And cross-sectional diameters
Velocity= Blood flow/Cross-Sectional area
Small arteries- how do these influence blood pressure?
The further we get from the heart, blood pressure tends to decrease
-The small arteries and arterioles have a high resistance, and therefore are the determinants of our blood pressure.
If we look proximal to the small arteries, we should see a higher blood pressure
If we look distal to the small arteries, we should see a lower blood pressure
When giving phenylephrine, it increases the resistance of the small arteries, causing an increase in pressure upstream and a decrease in pressure downstream
Maintenance of pressure and resistance determines..
Circulatory Function
Blood flow is tightly controlled by..
-Blood flow is tightly controlled by tissue demands/ metabolic rate
-Maintenance of pressure and resistance determines what our blood pressure is going to be
Blood Flow Types
A) No flow
B) Laminar Blood Flow: The walls of the vessel are the resistance to movement. The blood closest to the walls of the vessel is flowing the slowest, whereas the blood in the middle in the vessel has less resistance and flows faster. Efficient. Doesn’t cause problems
C) Turbulent blood flow/disorderly: Blood is pushed into the walls of the blood vessels; slams Ca++ and cholesterol into the sides of the blood vessel causing it to be deposited into the wall. It usually caused from a blockage/narrowing in the blood vessel, causing blood to “shoot” through the narrow opening at a very fast velocity
Blood flow through the kidney? Why does it receive more than it needs?
-The kidney is one of the few organ systems that receives much more blood flow than it actually needs
-Kidneys receive about 1.1L/min of blood flow
-Without the extra blood flow, the kidney would not be an efficient filter
Ohm’s Law; Using it to solve for vascular resistance, delta P, or blood flow
-Solve for Delta P:
Delta P (change in pressure)= Flow (blood) x Resistance (Vasc.)
-Solve for Flow:
Flow= Delta P/ Resistance
-Solve for Resistance: Delta P/ Flow
Peripheral Vascular Resistance: How do we determine?
Aortic BP - R. Atrium BP / Total CO ml/min
R= Delta P/ Flow
How do we calculate this?
Vascular Conductance
If conductance is higher, what happens? If it’s lower?
-Conductance: The ease at which blood flows?
-If conductance is higher, resistance will be lower
-If conductance is lower, resistance will be higher
Conductance= 1 / Resistance
What are the functions of the capillary microcirculation?
How many capillaries do we have? Total surface area?
-Primary place of nutrient exchange and waste product collection in our circulation
-Arterioles are encased in smooth muscle, which is how blood flow through our capillaries is controlled
-Constriction of the smooth muscle will reduce blood flow at the arteriole. This causes an increase in pressure above the site of constriction, and a decrease in pressure distal to the constriction ultimately reducing blood flow
-Relaxtion of the smooth muscle will increase blood flow
- 10+ billion capillaries
- 500-700 square meters of surface area
What is significant about this picture? (Four layers)
-Area of high vascular resistance because it has four layers of smooth muscle cells. This gives our arterioles a high wall-thickness to internal diameter ratio
-This is what allows our arterioles to contract, relax, and control blood flow downstream
What determines constriction or relaxation of arterioles upstream of capillaries?
-Metabolic byproducts and gases being removed from the capillaries determines whether the upstream arterioles need to constrict or relax
- Decreased O2 delivery or increased tissue metabolism –> leads to a decrease in tissue O2 –> arterioles and precapillary sphincters relax to increase blood flow to the tissue downstream
Determine the velocity of blood flow through these vessels
CO is 5L/min
-Aorta: 1.11 L/min/cm2
-Arterioles: 0.0125 L/min/cm2
-Capillaries: 0.00111 L/min/cm2
-Venae Cavae: 0.28 L/min/cm2
5L/min divided by total cross-sectional area
Pressure of the arteriole and venous ends?
Capillary Dynamics
What area is responsible for filtration? Reabsorption?
-30mmHg on the arteriole end
-10mmHg on the venous end
-Arteriole side has forces that favor filtration; which is the process that describes movement of fluid out of the capillary and into the tissue
-Venous side has forces that favor reabsoprtion; a process of fluid being reabsorbed into the capillary bed
Capillary Starling Forces: “Pcap”
-Hydrostatic pressure in the capillary: ~30mmHg at the arteriole end of the capillary and 10mmHg at the venous end
-Physical blood pressure within the capillary
-This determines how blood flows from the arterial end to the venous end, and also plays a huge role in determining how much fluid is going to be pushed out of the capillary (filtration)
Capillary Starling Forces: Pisf
-This is the pressure outside of our capillaries and surrounding our cells
-Pressure can oppose filtration on the arteriole end and promote reabsorption on the venous end if the pressure is positive
-Typically -3mmHg. This pulls fluid out of the capillary on the arteriole end, and opposes too much reabsorption on the venous end.
-This negative pressure is due to our lymphatic system creating a “vacuum” effect and taking up extra fluid
What contributes to oncotic pressure?
Capillary Starling Forces: Plasma Colloid Osmotic Pressure; Oncotic Pressure
-There are plasma proteins (albumin, fibrinogen, immunoglobulins) mostly within the capillary
-The cell walls are not permeable to these proteins; however, they are permeable to fluid. This creates an osmotic pressure associated with the proteins within the cell and outside the cell
-Because there is a large amount of colloids dissolved in the blood within the capillary, the oncotic pressure here is higher than outside the capillary –> causing the fluid to stay within the capillary/ cardiovascular syste,
28mmHg
Conditions that cause the cell the be moer pourous?
What happens if plasma oncotic pressure is too low?
-Sepsis, liver failure, massive bleeding, or any condition that causes the cell to become more pourous than normal can cause these colloids to leak out of the capillary.
-The cell wall simply becoming permeable to the proteins causes a decrease in osmotic pressure (primary problem) and secondary is the proteins leaking out
-If we don’t have plasma proteins in the cardiovascular system, it becomes incredibly difficult to maintain a blood pressure
What kind of proteins are in the interstitial fluid?
Capillary Starling Forces: Interstitial Fluid Colloid Osmotic Pressure
-Very large strings of proteins that stay in the interstitial fluid (matrix proteins, proteoglycan filaments, hyaluronic acid, collagen)
-Osmotic pressure of 8mmHg
-Favors fluid movement into the interstial fluid ~a little~ but is outweighed by the plasma osmotic pressure
Capillary Starling Forces: Capillary Filtration Coefficient (Kf)
How do we use this to determine filtration rate?
-Secondary to all other capillary starling forces
-Related to capillary permeability and surface area (the more surface area we have, the more area for movement)
Filtration Rate = Kf (NFP)
Normal Kf is 12.5
What happens if our capillary cells are damaged in an unorganized way?
-If capillaries are crushed from some sort of trauma, the plasma proteins leak out into the interstial space causing significant swelling
-Crush injury, sepsis or severe acidosis, a condition where cells are dying/ imploding in an unplanned manner
Primary function? What happens if someone is sick?
Lymphatic system;
-Responsible for absorbing extra fluid and dumping it back into the top of the thorax, allowing it to be reabsorbed back into the cardiovascular system
-In a healthy person, the lymphatic system can increase it’s rate of work by 20-40x in terms of managing extra fluid
-After an injury where cell walls are damaged, the lymphatic system can absorb some of the extra fluid in the interstitial space but it is not specialied to pick up extra proteins.
-The lymphatic system typically increases its rate of action with increased muscle movement. If someone is immobile and in a hospital bed, the lymphatic system is not going to be able to do it’s job effectively
Capillary Oncotic Pressure: Components
Albumin: 4.5g/dl –> 21.8 mmHg
Globulins: 2.5g/dL –> 6.0mmHg
Fibrinogen: 0.3g/dL –> 0.2mmHg
Venous blood is returned back to the heart…
Via a one-way valve system that relies on our skeletal muscles compressing and relaxing against the lymphatic system
Without movement, fluid will accumulate in the legs and we are more prone to blood clots in the lower extremities.
Capillary Net Filtration Pressure: Arteriole End
Forces that favor filtration:
30mmHg
-3mmHg
8mmHg
Forces that oppose filtration:
28mmHg
NFP = Pcap - Pisf - Plasma Oncotic Pressure + Interstitial Oncotic Pressure
Gives us a NFP of 13mmHg
Favors filtration
Capillary Net Filtration Pressure: Venous End
Which pressure is the opposing force for both venous & arteriole ends?
Forces that favor filtration:
10mmHg
-3mmHg
8mmHg
Oppose Filtration:
28mmHg
NFP = Pcap - Pisf - Plasma Oncotic Pressure + Interstitial Oncotic Pressure
NFP: -7mmHg, favors reabsorption
Plasma oncotic pressure is the opposing pressure in both venous and arteriole ends
Average Capillary Blood Pressure in Systemic Circulation & Avg NFP
17.3mmHg
Capillaries get larger as we move from the arteriole end to the venous end
If we use this number in our NFP equation, we end up with an average NFP of 0.3mmHg throughout each capillary
Where is the exception for NaCl permeability?
General Capillary Permeability
What is the exception for NaCl?
The smaller the molecular weight, the more likely the membrane is permeable to that substane.
The exception for NaCl is the BBB.
Resistance & Blood Flow (Kidney Example)
Why does pressure decrease as blood flows past resistance?
-Renal artery pressure if ~100mmHg
-Blood encounters vascular resistance when traveling through the kidney, and by the time it reaches the renal vein, the pressure is around 0mmHg
-Energy/ATP is removed from the blood as it moves through resistance, causing a decrease in pressure as it continues to encounter resistance
Afferent Arteriole?
Glomerular Capillaries
Pressure here determines what? GFR?
-First set of capillaries in the kidneys
-Afferent arteriole is immediately upstream to the glomerular capillaries–> very important in determining how much pressure the glomerular capillaries have
-The pressure in the glomerular capillaries determines the glomerular filtration rate
-Normal pressure in the glomerular capillaries is around 60mmHg. This high pressure is used to push fluid out of the capillaries at a rate of about 125ml/min
Plasma Oncotic Pressure in the Glomerular Capillaries
-Plasma oncotic pressure is 28mmHg at the beginning of the glomerular capillaries
-As we move through the glomerular capillary, the plasma oncotic pressure increases ( 28mmHg –> 32mmHg–>36mmHg)
due to the fact that the glomerulus is filtering fluid, but the amount of colloids remains the same
What happens if someone is sick?
Autoregulation in the Kidney; Afferent Arteriole
How does this affect filtration? Autoregulation limits?
-If blood flow is too low, the afferent arteriole will relax to increase blood flow to the glomerulus
-Increasing renal blood flow increases GFR
-If renal blood flow is too high, the afferent arteriole constricts to reduce overperfusion
-Decreasing renal blood flow decreases GFR
Autoregulation typically occurs between 50mmHg and 150mmHg. The afferent arteriole is able to regulate RBF fairly well if BP is too high, but RBF and GFR starts to steeply drop off well before 50mmHg. If someone has had chronic HTN, the afferent arteriole will not be able to relax as well
Where does PCT empty? Filtration, secretion, excretion
Promixal Convoluted Tubule
Starling forces?
Ptubule- 18mmHg
-The fluid from filtration fills the PCT until it reaches a P of 18mmHg –> empties into ureters and bladder to be excreted or leaves the PCT –> renal interstitium –> reabsorbed PT capillaries
The body can physically pump things into the tubule (secretion). Leaves the PT capillaries –> renal interstitium –> P tubule
Ex: Toxins, K+, Na+
Oncotic pressure in the tubule should be 0mmHg because in a healthy person, we are not filtering protein
NFP in the Glormerular Capillaries
We need to compare against the numbers in the PCT
NFP = Pcap - Pisf - Plasma oncotic + Isf Oncotic
Take the Pcap from the glomerular capillar; 60mmHg
Use the Ptubule in place of Pisf; 18mmHg
Take the median plasma oncotic number from glomerular capillary
Isf Oncotic = PCT oncotic; 0mmHg
60mmHg-18mmHg-32mmHg= NFP of 10mmHg
Function, resistance, starling force
Efferent Arteriole
What is the pressure at the end of the E. arteriole? Why?
-Primary function is to regulate GFR
-If the efferent arteriole constricts, it will increase renal blood pressure in the glomerulus, causing an increase in GFR
-If the efferent arteriole relaxes, it will decrease renal blood pressure in the glomerulus, causing a decrease in GFR
-Higher vascular resistance in this arteriole than in the afferent
-Pressure at the end of the efferent arteriole is 18mmHg
Starling forces here? NFP/NRP?
Peritubular Capillaries
How does fluid that was filtered get here?
-Where the majority (99%) of our reabsorption takes place, so we should assume our NFP will favor that
Pcap: 13mmHg
Pisf: 6mmHg
Plasma Oncotic: 36mmHg –> 32mmHg –> 28mmHg
Oncotic Isf: 15mmHg (due to proteins in the renal intersitium)
NFP= Pcap - Pisf - Plasma Onc. + Onc. isf = -10mmHg OR NRP is 10mmHg
-Fluid that was filtered into the PCT will exit through or in between the cells lining the wall of the PCT, travel through the renal intersitium, and become reabsorbed at the PT capillaries in order to be returned to the CV system
What lives here?
Renal Interstitium
-Proteins
-Ions
-Electrolytes
-Large energy compounds
-Intermediary place between blood vessels and tubules
Filtration Fraction vs Osmotic Pressure
Efferent arteriole constriction or relaxation determines how much fluid is being filtered
-The more fluid we filter (higher filtration fraction), the higher the osmotic pressure will be on the efferent end
-The less fluid we filter (lower filtration fraction), the lower the osmotic pressure will be on the efferent end
This represents the change in osmotic pressure that we see along the glomerular capillary
Filtration Fraction; How do we determine what it is?
GFR/ RPF (Renal Plasma Flow)= FF
RBF = ~1100ml/min (~22% of CO)
If your HCT is 0.4, that means the remaing 60% of RBF is plasma
RPF= 660ml/min
125ml/min/660ml/min = 19%
Changes in Renal Vascular Resistance do what…?
In regards to afferent and efferent arteriole
-Increase in afferent arteriole resistance decreases Pcap in glomerulus –> Decreasing GFR–> Decreasing renal blood flow
-Decrease in afferent arteriole resistance causes an increase in Pcap –> Increase in GFR –>increase in renal blood flow
-Increase in efferent arteriole resistance causes and increase in Pcap in glomerulus –> increase in GFR –> decrease in renal blood flow
-Decrease in efferent arteriole resistance causes a decrease in Pcap –> decrease in GFR –> Increase in renal blood flow
Renal Autoregulation in Regards to UOP
Renal system favors…?
Normal UOP should be 1ml/min
-Increase in RBF –> Increase GFR –> Increase UOP –> Decreased BP
-Decrease in RBF –> Decrease in GFR –> Decrease in UOP –> Increased BP
Renal system favors fluid excretion and decreased pressures. It autoregulates better at a high pressure
A) Filtration Only: Happens when we don’t have any specialized transporters designed to retain or reabsorb whatever is being filtered
B) Filtration, Partial Reabsorption: Na+ is a good example. We typically eat more Na+ that we need. Reabsorb what we need, filter the rest
C) Filtration w/ complete reabsorption: Glucose in a non-diabetic patient. If glucose is present in the urine, BG is way too high or there is an issue with the transport system.
D) Filtration w/ secretion: A small portion of this was filtered, and the remainder of this was secreted. Paraminohippuric acid (PAH); a diagnostic compound that gives us an idea of what the renal blood flow is.
The higher the amount of PAH removed, the better the RBF
The lower the amount of PAH removed, the lower the RBF is
What is it? And function?
- Fenestrations: Specialized openings in the renal glomerular endothelium that allow the cell to be more permeable
- Epithelium/ Epithelial Cells: Specialized to provide support to the glomerular capillary bed. Pressure is high in the glomerulus, so this is important
- Baesment Membrane: Thick layer of connective tissue that is littered with negative charges in order to prevent other negatively charged particles from exiting through the slit pores (proteins)
- Endothelium
- Podocytes: What makes up the epithelium and provides structural support under the high pressure system in the glomerulus. Keeps the glomerular capillary from swelling due to chronic HTN (tries to). If you have chronic HTN and the pressure at the renal artery is 200mmHg instead of 100mmHg, this significantly increases the pressure within the glomerulus
- Slit Pores: “Foot processes” that are openings between podocytes.
How do size and charge affect filterability?
- Polycationic dextran: The charge on the sugar compound is positive, so the filtration rate will be higher
- Polyanionic dextran: The negative charged will be repelled by the basement membrane of the glomerulus, so it’s filterability is reduced
If the compound is larger, it’s less filterable
If the compound is smaller, it’s more filterable
Roles of the Kidney
BP, pH, RBC
-Long term regulator of BP: If someone has chronic HTN, their kidneys are not functioning properly
-Long term pH regulator: Produces HCO3- in response to excess protons, and the kidney also decides how much HCO3- to reabsorb
-Long term RBC/Hct regulator: O2 sensors deep inside the medullary portions of the kidney. If O2 levels are low, the kidneys release EPO–> increases the number of RBCs in circulation by stimulating the bone marrow.
Roles of the kidney
Electrolytes, Vit. D, Glucose
-Long term electrolyte regulator: Filtration & reabsorption of electroyltes
-Long term vit. D regulator: Vit. D is activated at the kidney
-Long term serum glucose regulator: Filtration & reabsorption of glucose. If there is excess glucose, kidney will typically reabsorb until it reaches the maxmimum amount that the kidney can reabsorb. If glucose is absurdly high, glucose will be filtered out
Roles of the Kidney
Drug clearance, metabolic waste, osmolarity
-Some drug clearance usually via secretion
-Long term metabolic waste removal: Nitrogenous compounds such as uric acid
-Osmolarity: Can decide how much water and NaCl to reabsorb independent of each other. Usually managed by ADH
Renal Blood Vessels
Renal artery –> Segmental arteries –> interlobar arteries –> arcuate arteries –> interlobular arteries –> afferent arterioles ->
Glomerular capillaries –> Efferent Arteriole–> peritubular capillaries
These are all located behind the PT capillaries:
–> Interlobular veins –> Arcuate veins –> Interlobar veins –> Segmental veins –> Renal veins
Arteries split into smaller arteries
Veins converge into larger veins
- Arcuate Artery
- Arcuate Vein
- Afferent Arteriole
- JG apparatus
- Efferent Arteriole
- Glomerulus
- Bowman’s Capsule
- Proximal Tubule
- Cortical collecting tubule
- Collecting Duct
- Loop of Henle
- Peritubular Capillaries
- Distal Tubule
Deep medullary capillaries are more sensitive to what?
Renal Blood Vessels; Two types of nephrons
Superficial vs Deep, difference between the vessels
90-95% of our nephrons are very superficial and are located in the cortex
-PT capillaries and renal vessels are in the outer medulla
5-10% of our nephrons are deep medullary nephrons
-Unequal number of descending and ascending PT capillaries here.
-Called descending and ascending Vasa Recta
-We have more ascending vasa recta than descending; causing the velocity of blood flow to slow as it ascends. This is important in maintaining a normal level of solutes in the deep interstitium; if the blood flow was too fast, it would “wash out” the solutes traveling through the renal interstitium
-Receive a limited supply of blood, so if BP is low, the deep medullary PT capillaries will be the most sensitive to those changes
Why is this important?
Renal Surface Anatomy
- R. Adrenal Gland
- L. Adrenal Gland
- Gastric surface of L kidney
- Splenic surface
- Pancreatic surface
- Descending colic (colon) surface
- Duodenal surface
- R colic flexure surface (colon)
- Hepatic Surface
Cancer in these other organs are likely to spread to the “surface” of the kidney that it touches
- Proximal convoluted tubule
- Afferent & Efferent Arterioles
- Straight Proximal tubule
- Descending Thin Loop of Henle
- Ascending thin Loop of Henle
- Thick ascending limb of Loop of Henle
- Macula Densa (Located in the TAL Loop of Henle)
- Glomerulus
- Bowman’s Capsule
- Distal convoluted tubule
- Cortical Collecting Duct
- Medullar Collecting Duct
-Outer MCD and Inner MCD - Papillary Duct
Function of the Macula Densa? Exact location?
-TAL of Loop of Henle
-Sits on top of the afferent and efferent arterioles entering the glomerulus
-Measures flow through the kidney.
-When flow is low, renin is released
-Increased Renin leads to increased Angiotensin II –> constricts the efferent arteriole, occluding outflow–> increases Pg
-Flow is too high –> decreased amounts of Renin released –> decreased Angiotensin II –> relaxation of the efferent arteriole
What is going on in this graph?
Concentration compared to location in tubule
-Creatinine is freely filtered, but not reabsorbed. The further along the tubule we go, the higher the concentration of creatinine becomes because water continues to be absorbed but creatinine is not
-All glucose reabsorption happens at the PCT. Concentration should be the same as plasma glucose once it’s filtered, but should completely be reabsorbed steeply decreasing the glucose concentration throughout the remained of the tubule
-Same for AA ^
-Na+ concentration is fairly consistent throughout the proximal tubule because as Na+ is being absorbed, water is also being absorbed
-Cl- tends to become slightly more concentrated than Na+ as we move through the proximal tubule. In the second half of the proximal tubule, Cl- is most concentrated, and this favors reabsorption
SGLT- Function? What happens if glucose is too high?
Glut transporter on basolateral side? Hyperfiltration of glucose does..?
-All filtered glucose should be reabsorbed in the PCT.
-The SGLT transporter brings 1 Na+ from the tubular lumen down it’s concentration gradient, into the tubular cells, and 1 glucose with it
-What happens if glucose is too high?
Hyperfiltration of glucose causes increased reabsorption of Na+. This causes increased renin release by the macula densa, increasing GFR. This increases the workload on the nephron and can destroy nephrons if hyperglycemia is chronically uncontrolled
-Because glucose is being packed into the tubular cells, the GLUT transporter on the basolateral side does not need ATP. Glucose moves down its concentration gradient
How are amino acids reabsorbed? What happens if plasma AA is too high?
-Small, filtered easily, and the body reabsorbs 100% of the AA that are filtered
-Sodium/Amino Acid transporter works the same way that the SGLT transporter does. 1 Na+ moves across it’s concentration gradient from the tubular lumen into the tubular cells, bringing one AA with it
-Hyperfiltration of AA is the same as glucose.
-AA are passively allowed out of the basolateral side of the cell in the same way as glucose
-Filtered load of glucose depends on GFR and plasma concentration of glucose
-Vertical axis is showing glucose filtered load, reabsorption, or excretion
-Horizontal axis is showing up plasma glucose concentration
-Threshold (Graph shows 200, Schmidt says <200mg/dL); the point where the PCT can no longer reabsorb 100% of the glucose, and some glucose will start to be excreted. As BG increases, excretion rate also increases
-Transport maximum is ~ 300mg/dL; at this point, there will be a rapid increase in the amount of glucose excrese
Primary effect & secondary affect. Which ion drives the Na/HCO3 pump
AT I Receptors
AT I receptors are located in which part of the tubule?
-Main effect: When Ang II binds to the AT I receptor, the speed of the Na+/K+/ATPase pump increases
1. Causing an increase in Na+ leaving the cell–> causing an increase in the concentration gradient –> Na+ will flow in faster at the NHE exchanger
2. Speeds the rate of reabsorption for HCO3- via the Na+/HCO3- cotransporter (secondary active transporter)
-HCO3- drives this pump, not Na+
Located in the PCT
Paraceullar vs Transcellular. What is reabsorbed via paracellular?
Tubular Reabsorption
-Paracellular reabsorptionm (passive) originates at the tight junction of the apical membrane of the tubular lumen. This pathway goes between cells
1. Cl- is reabsorbed this way –> moves into the renal interstitium because of the electrical gradient created by Na+
2. Water also moves this way
3. Areas of the kidney that are impermeable to water (Thin Ascending Loop) will have very tight junctions and will lack aquaporins
-Transcellular reabsorption happens via a transporter or channel within the cell wall
1. Water moves through aquaporins via the transcellular route. Follows solute traveling to the renal interstitium via osmosis
What is bulk flow? What is largely present in the renal interstitium?
-Bulk flow: Happens at the area of the tubule where filtration is very heavy, and reabsorption is also very heavy. NFP at the glomerular capillaries is about 10mmHg, and NRP at the peritubular capillaries is also 10mmHg
-When discussing bulk flow in regards to filtration and reabsorption, it takes place at the PCT
-Urea, a metabolic waste product, is somewhere stored within the renal interstitium and is used to help reabsorb water via osmosis
-Brush border on the apical side of the proximal tubule cells; increases the surface area of the cells lining the apical border of the tubule by ~20x. This allows for a large amount of the cell to be exposed to the fluid in the proximal tubule as well as a large area for the kidney to place transporters
What contributes to the Vrm in the tubular lumen?
Vrm in tubular cells and in the PCT tubular lumen
Vrm in the tubular cells is -70mV
Vrm in the tubular lumen is -3mV (due to a combination of K+, Na+ and Cl-)
Function of the NHE pump? H+ combines with what two compounds?
Acid-Base Management at the PCT
Carbonic anhydrase is located where? Walk thru the steps of the image
NHE: A form of secretion; secreting H+ ions at the PCT. This exchanger is also the primary reabsorption process for Na+ in the PCT
-H+ secreted into PCT, combines with HCO3- to form H2CO3
-Carbonic anhydrase dissociates H2CO3 into H2O and CO2
-H2O is easily reabsorbed via osmosis. CO2 easily diffuses across the membrane
-Carbonic anhydrase can be:
1. Tethered to the cell wall
2. Floating freely in the proximal tubule
3. Inside of the tubular cell
-Carbonic anhydrase then drives the reaction in the opposite direction once in the cell; CO2 + H2O = H2CO3
-Dissociates again into H+, HCO3-
-H+ is secreted into tubule, joins with HCO3-, or combines with NH4 (buffer for the urine)
-HCO3- is reabsorbed into the renal interstitium –> PT capillaries
What happens in the patient is in liver failure?
Production of new HCO3- in the PCT
-Glutamine produced in the liver can be converted into two different compounds in the PCT:
1. HCO3-
2. NH4+
1 Glutamine is turned into 1 glucose –> turned into 2HCO3- or into 2NH4+
The NH4+/ Na+ secretes NH4+ out into the tubular lumen, where H+ can attach to be excreted through the urine
This is another method for the body to buffer our blood by getting rid of extra protons. Liver failure means the person will not be able to produce glutamine as effectively
Other Buffers in the PCT
-NaHPO4- is a urinary buffer in addition to NH4+ and HCO3-
What happens to Ca if reabsorption rate is increased?
Ca++ Regulation in the tubule
Ca++ filtration heavily depends on what?
-Ca++ is reabsorbed in multiple areas of the tubule
-Follows both pathways of reabsorption;
- Paracellular: Ca++ is “dragged” along with water and other solutes via the paracellular route. If the reabsorption rate in the PCT increases for any reason, thats typically means that the reabsorption rate of Ca++ will also increase
- Transcellular:
-Ca++ channel on the apical side that allows Ca++ into the tubular cells (concentration gradient)
-Ca++ ATPase pump that directly pumps Ca++ out into the renal interstitium
-Ca++/Na+ exchanger (3 Na+ in, 1 Ca++ out)
Ca++ filtration heavily depends on acid/base balance. If Ca++ is bound to albumin (or something else that’s negatively charged), it’s not going to be filtered
H+ & Na+ Dependent Antiporters
Cation Secretion:
H+ Dependent antiporters bring one H+ ion into the cell in exchange for secreting a cation into the tubule
Anion Secretion:
This pathway uses an intermediary called alpha-ketogluterate
(a-kb). A transport system brings 3 Na+ with each 1 a-kb into the tubular cell. The increased concentration of a-kb in the tubular cells causes organic anions to be secreted into the tubular cells from the renal interstitium. Once in the tubular cell, the organic anion is secreted into the tubular lumen via a facilitated transporter
If two compounds are using the same transporter system, we can increase the levels of the one we do not want to keep around so that the transporter system secretes the compound in higher concentration
How much water is reabsorbed here? Renal interstitium becomes more what?
Descending Thin Loop of Henle
Impermeable to what?
-Tubular fluid moves through the descending thin loop of henle deeper into the kidney where the renal interstitium becomes more concentrated.
-Water should continue to be reabsorbed as we move deeper into the tubule provided that that portion of the tubule is permeable to water
-Impermeable to ions
- ~20% of our water is reabsorbed here
Transporter located here?
Ascending Thin Loop of Henle
-The more superficial the fluid travels, the more dilute the renal interstitium becomes
-Impermeable to water
-NaCl ATPase transporter; reabsorbs Na+ and Cl-
-Does this in relatively small amounts
What role does K+ play? Vrm in lumen allows what? Major pumps here?
Thick Ascending Loop of Henle
Ion transporter here is responsible for?
-Relatively impermeable to water
-Important area for cationic electrolyte reabsorption (Mg++ & Ca++ > Na+, K+) ~25% reabsorption here
-There are K+ leak channels here that allow K+ to move down it’s concentration gradient and out into the tubular lumen and into the renal interstitium
-There is enough K+ leaking out into the lumen that the Vrm in the tubular lumen here is +8mV
-The +8mV charge is what drive the paracellular reabsorption of Ca++ and Mg++
-NHE is here, acid/base balance takes place here as well
-Na+, 2Cl-, K+ transporter pushes 1 Na+, 2Cl-, and 1 K+ into the tubular cell
-The ion reabsorption that takes place here plays a very major role in the concentration of the renal interstitium. The ions reabsorbed here tend to settle in the deeper parts of the renal interstitium, contributing to the high osmolarity
The highest our osmo can be? What happens if the kidney is conserving?
Osmolarity in the Nephron
What happens if the kidney does not need to conserve water?
-Deepest part of the renal interstitium has an osmolarity of ~1200 mOsm/ml. This is the most concentrated that our renal interstitium can be. This is an example of a kidney that is conserving water
-Urine osmolarity should also be 1200.
-The limitation to concentrate our urine depends on how concentrated our renal interstitium is
-Our urine osmolarity should reflect what the osmolarity is in the deepest part of the renal interstitium- the collecting duct
PTH increases which three pumps? Ca++ pumps found here?
Transporters in the Distal Tubule
Na+ and Cl- reabsorption?
-Another area of the tubule where PTH can influence Ca++ reabsorption
-PTH can increase the number of Ca++ channels we have on the luminar side of the cell allowing Ca++ into the tubular cell
-This will also increase the amount of Ca++ pumps on the basolateral side of the cell to increase reabsorption into the renal interstitium. Ca++ ATPase and Ca++/Na++ (primary) exchanger are typically found together
-Simple reabsorption of Na+ and Cl- also takes place here. NaCl transporter on the apical side takes in 1 Na+ and 1 Cl-
Inhibits what? Secondary effect of thiazides?
Thiazide Diuretics
Inhibit the simple Na+/Cl- transporter in the distal tubule
-By blocking the Na+/Cl- transporter, we are decreasing the amount of Na+ entering from the tubular lumen.
-This will cause an increase in the rate of the Na+/Ca++ exchanger –> pushing more Ca++ into the renal interstitium for reabsorption
-Sometimes prescribed for patients with osteoporosis
-Need to be mindful of additional Ca++ intake in non-osteoporosis patients
-Useful in patients who have recurrent kidney stones; reducing the amount of Ca++ in the urine reduces the risk of it crystalizing
When thinking of principal cells, think…?
Late Distal Tubule/Early Convoluted- Principal Cells
-Sensitive to both ADH and aldosterone
-When thinking of principal cells- think K+ regulation
-Work via aldosterone receptors found inside the cell
-Aldosterone is a cholesterol derivative and has no problem making it through the cell wall
-This system is designed to mimic the actions of the Na+/K+/ATPase pump. Speeds up the pump cycling rate, increases the amount of Na+ and K+ channels on the apical side
-Increases the amount of K+ secretion by increasing number of K+ channels –> More k+ leaving the cell –> more K+ brought in via the Na/K/ATPase pump from the renal interstitium
-Increases the rate of Na+ reabsorption by increasing the amount of Na+ that leaks in through the ENaC Na+ channel –> pumped out into the renal interstitium via Na+/K+/ATPase pump
K+ Channels in the Principal Cells of the Distal Tubule/Early Collecting Duct
State of the cell wall during differnt phases of K+ excretion
-ROMK Channel: Renal Outer Medullary K+ Channel
-BK Channel: Big K+ channels. Secondary to ROMK
Low excretion state:
-ROMK is sequestered (inside the cell, inactive)
-Bk is closed
Normal excretion state:
-ROMK moves to cell wall (aldo mediated), opens
-BK is closed
High excretion state:
-ROMK is open
-BK is open (aldo mediated)
What is produced here?
Adrenal Glands
-Most superficial layer of the adrenal gland is the Zona Glomerulosa; aldosterone is secreted here
-Zona fasciculata is the next deeper portion
-Zona reticularis is deep to the fasciculata
-Cortisol and androgens are produced here; androstenedione, small amount of estrogen (fasciculata for estrogen)
-Medulla is the deepest
-Catecholamines are produced here. Epi/Norepi in a 4:1 ratio
V2 receptors are found where? ADH binds to V2 and…?
ADH/Vasopressin
ADH release in regards to water conservation/surplus. Only compound to?
-Both intercalated & principal cells are sensitive to ADH
-V2 receptors, found in the late distal tubule and collecting duct, bind ADH
-ADH binds to V2 –> activates protein kinase A –> phosphorylates aquaporin channel vesicles (AQP-2) —> move to the apical side of the cell wall –> increase H2O entry from the tubular lumen
-AQP 3, 4 on the basolateral side; non-ADH dependent and always present
If we need to conserve water, ADH is increased
If we need to secrete water, ADH is decreased
The only signaling compound that can control water reabsorption separate from salt reabsorption
3 factors that control ADH?
Vasopressin Control System
Factors that control ADH:
-Osmoreceptors: Sense osmolarity changes
-Baroreceptors: Blood pressure in high pressure side of circulation
-Blood volume sensors in the large veins & atria
Sensors send this information to two nuclei in the hypothalamus.
Both nuclei send ADH to the posterior pituitary gland –> enters blood stream here
- Osmoreceptors
- Paraventricular nuclei- Located on the sides of the third ventricle. 1/6th of ADH production
- Posterior pituitary/ neurohypophysis
- Anterior lobe/ adenohypophysis
- Supraoptic nuclei- Located above the eye, in front of the hypothalamus. Gives us 5/6th of our ADH production
Vasopressin & Changes in Osmolarity
Electrolytes responsible for osmolarity?
-A cell is in an isotonic solution; volume of cell will not change
-Cell is in a hypotonic solution; water will move into cell until the osmolarity of the cell equals the osmolarity of the solution
-This would cause a reduction of ADH released from the posterior pituitary
-Swelling of the osmoreceptor causes a reduction in action potentials sent to the ADH production areas (supraoptic & paraventricular nuclei)
-Cell is in a hypertonic solution; water will leave the cell until the osmolarity of the cell equals the osmolarity of the solution
-This would cause an increase in ADH released from the posterior pituitary
-Shrinkage of the osmoreceptor causes an increase in the firing rate of action potentials
Electrolytes responsible for osmolarity are typically Na and Cl
Osmolarity throughout the tubule
-PCT does not have any major shifts from normal osmolarity of ~300. H2O is reabsorbed along with NaCl
-Environment changes in the Loop of Henle; in the deep parts of the kidney there is a lot of protein, urea, electrolytes in the renal interstitium. Water leaves the descending thin loop of henle, electrolytes do not.
-Ascending Thin Loop is impermeable to water- NaCl is being reabsorbed, loop is becoming more and more dilute.
-Thick ascending loop & the early distal convoluted tubule are the diluting segment
-Osmolarity beyond the early distal tubule is completely dependant upon ADH
-
Physiologic Diuresis
-Drinking 1L of fluid should have a minor effect on our plasma osmolarity as long as we have a functioning ADH system
-Urine flow rate will begin to increase until plasma osmolarity has been restored to normal
-Urine osmolarity will be very dilute
Normal urine osmo should be about ~600mOsm/ml
What kind of conditions exist under these circumstances?
-Very dilute, means we are not conserving water
-Conditions that would cause this?
-Low ADH:
-High plasma volume
-High BP
-Low plasma osmolarity
-ETOH
-Haldol
What conditions would exist under these circumstances?
-Water conservation
-High ADH
-Low plasma volume
-Low BP
-High plasma osmolarity
-Nicotine, morphine
-Hypoxia, nausea
What’s going on?
This graph shows up the concentration changes of different compounds throughout the nephron
Why is PAH so much more concentrated than creatinine? Because it is being filtered AND secreted
Why are diuretics more efficient than an Alpha-1 blocker long-term?
Diuresis; Where does the excreted fluid come from?
-Diuresis- Di refers to both salt and water
-An increase in fluid excretion happens when taking diuretics
-This fluid typically comes from our ECF
-Plasma volume: 1/5th of ECF
-Interstitial fluid volume: 4/5ths of ECF
When exposed to the drug for the first time, patient will dump a lot of fluid. ECF volume decreases. The initial dose of the diuretic will keep this condition maintained- patient will not continue dumping additional fluid off
In this graph, about 1L of ECF fluid is removed. That would mean: -1/5th is coming from the plasma volume (~200ml)
- 4/5ths is coming from the interstitial volume (~800ml)
-The body will typically find away to compensate against a medication that solely relaxes blood vessels (alpha-1 blocker). Can help short-term
-Diuretics are able to maintain the change chronically
And what conditions cause these scenarios?
IF these conditions existed; how would they affect BP?
-Extra Na+ intake should match Na+ output in a person with healthy kidneys
-Chronically high circulating Ang II: Our BP will increase significantly with increased Na+ & water intake
-Conditions that can cause this: Renal artery stenosis, CKD
-Ang II blockade: Will probably also have low aldosterone. Causes a difficulty in retaining Na+, meaning it will very difficult to manage low BP in a patient like this
-ACE Inhibitors and ARBS
-Somebody with a horrificly unhealthy diet. Taking in a ton of salt everyday–> the body will decrease Ang II levels because we need to decrease Na+ reabsorption significantly
What is low when someone is affected by Salt-sensitive HTN? Drugs?
HTN: Salt vs Nonsalt-sensitive
-This graph shows that if our kidney’s are functioning normally, we should have minimal fluctuations in MAP when taking in excess Na+
-Essential HTN: Set-point for MAP is wrong. Higher than normal. Salt-sensitive vs nonsalt-sensitive
-Nonsalt-sensitive: Tends to handle excess salt intake slightly better than salt-sensitive HTN
-Salt-sensitive HTN: Renal vascular HTN, renal stenosis, anything that involves overexpression of the RAA system
-Effects african-americans, some of the asian population
-African-africans tend not to be effected by this
-African-american population affected by salt-sensitive HTN have a low renin form of HTN; which is the opposite of what we would expect to see considering high renin would help us get rid of excess Na
ACE inhibitors are useful even though there isn’t much to inhibit
Normal values, how do they change?
Renal Creatinine Handling: 2 Kidneys vs 1
What needs to happen for excretion to equal production rate?
Creatinine Clearance:
Px: 1mg/dL
Filtered Load: 1.25dL/min
Secretion (don’t really need to worry about this): 0.15mg/min
Adds up to 1.4mg/min excretion rate
Excretion rate must equal production rate
Typically have 2million nephrons. If we instantaneously lose half of our nephrons via unilateral nephrectomy:
Filtered load becomes: 0.625dL/min (62.5ml/min)
Px will initially be 1mg/dL
We are filtering and excreting half of what we normally do. Plasma concentration of creatinine will begin to rise up until to the point that excretion rate and production rate are now equal again. Px will need to double in order for our excretion rate to match our production rate
Main thing to consider here is pathologic hypertrophy & damaging workload
Normal Kidneys:
2 million nephrons
Each nephron filters about 62.5 nl/min
UOP: 1ml/min
Unhealthy loss of nephrons:
GFR is slightly higher than what would we would expect because of pathologic hypertrophy
The volume excreted per nephron here is the damaging workload
Body Fluid Compartments
TBW: 2/3rds of fluid is ICF
TBW: 1/3rd of fluid is ECF
Normal osmolarity is 300mOsm/ml- no corrections need to be made here
A. Adding Isotonic NaCl: Graph shifts to the right –> meaning ECF is increased, but no reason for NaCl to enter the cells
B. Add Hypertonic NaCl: Increase osmolarity. Decreasing ICF fluid and increasing ECF in order to balance osmolarity
C. Adding hypotonic NaCl: Decrease osmolarity, but increase volume in ECF and ICF in order to balance osmolarity
