Glomerular Pathophysiology
What factors alter arteriolar tone (i.e. control how dilated the arterioles are?)
Autoregulation by 1. ATII 2. Intrinsic Myogenic control 3. Tubuloglomerular feedback 4. And NE and prostaglandins. We can remember that NE will decrease GFR because this is the endogenous neurotransmitter released during flight or flight by sympathetic nervous system that directs blood away from kidney - i.e. it constricts both arteriolar afferent/efferents. However, it constricts afferent MORE leading to net decrease in GFR Prostaglandins essentially work to counterbalance this effect of NE and angiotensin II; they make sure we vasoconstrictor but not too much counteract by dilating afferent arterioles more than efferents. Can remember this in the context of sepsis/shock, where inflammation is rampant and prostaglandins are everywhere: although blood will be diverted from the kidney, you don't want too little filtration because you still want to get rid of wastes! The idea behind changing flow (via changes in arterial tone) is that increased flow leads to increased filtration, because this means that it will take longer time for the oncotic pressure in the capillary to reach its equilibrium where water will stop flowing out; thus, there is more SA in the glomerulus for filtration to occur). 5. Alterations in Kf. This can decrease when mesangial cells that surround glomerular capillaries contract, causing some of the capillary blood flow to be reduced (i.e due to acute injury to kidney, such as glomerulonephritis and sclerosis)
What is the goal of filtration in the glomerulus?
Goal is to keep protein and good stuff inside the blood, but we want to get rid of wastes, electrolytes and toxins. This is achieved through layers of filtration.
What are slit diaphragms made up of?
Slit diaphragms are essentially slits in the membrane that forms in between the podocyte's foot processes. These "slits" are formed by the presence of many different proteins that line up in a cross-hatch to create a net. This is important because if you lose one of them due to a genetic defect, they all go. The podocyte/filtration slits help maintain the glomerular ultra filtrate protein free. Note that the "slits" in the diaphragm that are formed between the pedicels are proteins that are cells of the PODOCYTES, i.e. these cells have proteins on their surface that form slits between their foot processes to create a network.
What is RPF and how is it determined?
This goes along with constriction of afferent or efferent capillaries, because this is determined by resistance at these two sites. RPF: (aortic pressure - renal venous pressure)/renal vascular resistance Thus, if there is an increase in vascular tone due to constriction on either side, this leads to an increase in resistance and RPF decrease (however, the change in GFR depends on direction; i.e. constriction of efferent increases GFR but decreases RPF).
What is tubuloglomerular feedback?
This is similar to RAA system because it involves macula dense, but the response is mediated by adenosine and not renin-angiotensin. The macula dense sense salt or chloride and if this is increased (i.e. suggesting there is increased rate of delivery of NaCl to TAl and thus increased pressure), then the response is to DECREASE GFR. Adenosine --> constricts afferent arterioles of same nephron, leading to decrease of GFR back to normal values.
What is the nephron's function?
This is the functional unit of the kidney which consists of a glomerular capillary network, PCT, loop of Henle, DCT, connecting segment, and collecting duct.
What is the myogenic mechanism?
This is the second mechanism of auto regulation, and is essentially the stretch of the afferent arteriole in response to HIGH flow which leads to constriction of the afferent. It just makes GFR get back to normal if it's elevated
What are the layers of filtration in glomerulus?
1. Endothelial cells 2. Glomerular capillary BM 3. Glomerular epithelial cell or podocytes with foot processes and filtration slits
Name the 3 main mechanisms of autoregulation
1. Renin-angiotensin-aldosterone system 2. Myogenic feedback 3. Tubuloglomerular feedback mechanism These work to keep renal blood flow (RBF) and glomerular filtration rate relatively constant despite changes in BP.
How much glomerular filtrate is produced by the kidneys each day, and what does this consist of? What is the normal GFR?
180 L, consisting of the INITIAL URINE. This urine is composed of wastes, water, and electrolytes that will be processed. Most of this is sucked back up. Normally we filter more than 90 mlx/min of fluid from 625-700 mls/min of plasma
While decreases in GFR are bad because they can lead to excess toxin/waste build up, why is too high of a GFR bad? In other words, why do we need auto regulation?
Autoregulation: keeping filtration CONSTANT despite swings in arterial pressure. This is important because if GFR is too high, you can filter too much Na and deliver to tubules, which can't reabsorb the filtered Na and you lose ECF volume. Think of the chocolate example: if the rate of conveyer is too fast, it surpasses the rate by which reabsorption occurs leading to excess Na in filtrate. Since water goes with, you lose water as well. Physically, increased pressure can damage kidney and lead to chronic kidney disease.
Based on the equation, what factors could you alter to alter an SNGFR?
Changes in driving pressure: Pressure in capillary (blood pressure), pressure in BS (obstruction, etc), and oncotic pressure in blood OR Changes in Kf
What is the most common means of altering driving pressure?
Changing glomerular hydrostatic pressure (if the glomerulus is NOT DAMAGED) Constrict afferent capillary or dilate efferent - decreases GFR Constrict efferent capillary or dilate afferent - increases GFR (like making a kink in a hose, and the part before that has high pressure) Pbs can increase if there is an obstruction to urinary flow (for ex, enlarged prostate or kidney stone in bladder)
What determines the GFR (conceptually)
Difference between the pressure driving excess fluid from glomerular capillary into the capsule (hydraulic), versus the oncotic pressure that's keeping the water in the blood (oncotic). This is because while movement across ICF/ECF is only due to osmotic difference, movement across capillary wall is determined by both osmotic pressure and oncotic. Thus, to calculate the rate of filtration, you must know the extent of the driving pressure of fluid and the permeability of the membrane to this fluid. The driving pressure is going to be determined by the difference between hydrostatic and oncotic pressure. Hydrostatic: Both the capillary and Bowman's capsule has hydrostatic pressure; the Pressure in capillary drives fluid in, while the pressure in the Bowman's capsule opposes movement out of the capillary. Normally, this interstitial (BC) pressure is 0 except for in the face of edema, so hydrostatic pressure will force fluid out of capillary. Oncotic: For the oncotic side, there is an oncotic pressure inside the capillary and outside the capillary in Bowman's space, since both areas have protein and the membrane is impermeable to it (remember, the membrane must be impermeable for the solute to exert an oncotic pressure). Oncotic pressure of the plasma is high, retarding moving of fluid outside of blood, while oncotic pressure (pressure retarding fluid flow) in Bowman's is basically 0 and isn't a factor. As a result of higher hydrostatic pressure driving fluid out of capillaries being greater than oncotic pressure pulling fluid in, there is net flow out into Bowmans
How do the layers of filtration in the glomerulus help it achieve its goal?
Endothelial cells have small fenestrations to permit the passage of macromolecules but not protein. Right outside the endothelial cells is the basement membrane; this is made up of collagen and is negatively charged (since most proteins are) and blocks the passage of other negatively charged plasma proteins. Above the BM are glomerular epithelial cells, which essentially can be thought of as shrink wrapping all the capillaries/endothelial cells (see previous pic), and sending off foot processes (hence their other name, podocyte) to cover the endothelial cells. These foot processes are little spidery extensions of the podocyte and in between processes is a thin membrane that has slits for the passage of everything except proteins.
Overall function of glomerulus?
Filter blood to make ultrafiltrate
What would the GFR be of a single nephron if the capillary hydrostatic pressure was 45, hydrostatic pressure in Bowman's was 10, and oncotic pressure in glomerular capillary was 18 at middle of capillary? Whats the significance of saying "in middle of capillary"?
GFR = 45-10-18 = 17 in middle of capillary. The significance of saying it's 18 in the middle of the capillary is because oncotic pressure increases throughout the length of the capillary as it loses fluid.
What is the GFR and what is considered normal?
Glomerular filtration rate tells us the rate by which plasma is being filtered to form urine, and it's usually above 90 ml/min
How does severe diarrhea and medications lead to alterations in the GFR rate?
If a patient is on ACE inhibitors for hypertension, these will prevent the production of ATII and thus reduce the efferent vasoconstriction that increases GFR, causing a decrease in GFR. If he's on NSAIDS, this blocks inflammation and thus prostaglandins, which dilate the afferent but constrict the efferent; thus, the patient would constrict afferent. Net result is reduced effered vasoconstriction and decreased afferent vasodilatation. So these dual effects cancel out to reduce perfusion pressure - can lead to acute kidney failure if perfusion is too low
What happens if the GFR is too low?
If filtration is lowered, this can lead to a fluid, waste/potassium/ and acid/medication buildup. Example: Excess fluid in lungs can lead to crackles Serum potassium and acid = lethal; medication buildup = toxic; accumulation of wastes = uremia (decreased appetite, nausea, vomiting, changes in mental state). Thus, we don't want GFR to be low!
How does the RAA system work for auto regulation?
RAA system: This is activated when volume is depleted. Volume sensors (located throughout body) increase rein, specifically in JG. The JG apparatus is located in the afferent/efferent aretiorles very close to the macula dense, or group of cells located in thick ascending limb of loop of Henle that is facing glomerulis. Renin is an an enzyme that cleaves angiotensinogen --> angiotensin 1. In the lung (or vascular endothelial cell, or glomerulus), ACE converts ATI to ATII and acts as a systemic vasoconstrictor. It also stimulates release of aldosterone, increasing sodium reabsorption and restoring extracellular fluid volume (i.e. plasma volume). Note that in the glomerulus, AT II constricts efferent more than afferent, causing an increase in Pgc in order to maintain normal glomerular filtration. The combo of 1) systemic vasoconstriction to increase BP, 2) aldosterone secretion/ATII inducing sodium reabsorption and increasing ECF aka plasma volume (aka you suck back salt so that you don't lose volume!) 3) Angio II causing more efferent than afferent constriction at glomerulus to maintain GFR.
What determines GFR (equation)?
Starling's equation: Kf(Pgc-Pbs) - s(oncotic pressure in plasma - onc pressure in bowmans) Since oncotic pressure in bowman's is 0, it's effectively just the hydrostatic pressure differences minus the difference in oncotic pressure that retaurds fluid flow. This must be multiplied by the permeability of the capillary wall to fluid flow (filtration coefficient). Note that Kf of glomerulus is MUCH more permeable than muscle capillary, which is why there is a high GFR. s = permeability of rote ins across capillary wall. If 0, then membrane is completely permeable and no oncotic pressure exists (this pressure is due to IM permeability). Most membranes are between 0 and 1, and we will consider s to be 1. In sum: Net filtration pressure = Puf (driving force) *Kf , where Pgc-Pbs-pigc (pressure in cap minus pressure in BS minus osmotic in cap)
What is Bowman's capsule, the glomerulus, and the purpose of this?
The PCT has an extension of epithelium (Bowman's capsule) that contains a bunch of capillaries, both the afferent arterioles and efferent arterioles. This capsule is essentially where urine gets filtered before going further down the PCT. This entire structure of capillary tufts +Bowman's capsule = glomerulus.
Can single nephron GFR cane overall GFR?
Yes. With the examples in class (woman with nausea, fatigue, blood in urin/pain) had NO holes in her damaged kidney, thus Kf is decreased which decreased her overall SNGFR and caused major systemic symptoms. In the other example, the man had a kidney stone in ureter cause obstruction and an increase in hydrostatic pressure in the Bowman's space, decreasing SNGFR and causing systemic problems.
