Editing Renal blood flow, glomerular filtration

*continued here from [[Kidney functions]] on 03/23/11


==Renal blood flow and glomerular filtration==

===Data for a resting, young adult, 70 kg man===
*A healthy man's blood flow distribution is like this:
**1200 ml / min to the liver
**1200 ml / min to the kidneys
**750  ml / min to the brain
**250  ml / min to the heart

*Note that the kidneys receive 25% of the cardiac output and the highest proportion of blood flow by weight.
*Also note that the kidneys use 20 ml of Oxygen / min.
**This is mostly to drive ATP production for active Na reabsorption.
**'''The kidneys have low oxygen extraction from their blood supply.'''

===Blood flow rate of the kidney===
*The blood flow rate can be described by the number of ml of blood that flow in a certain time (min) to a certain mass of tissue (g).
**ml / min / g
*The flow rate within the kidney is different depending on the location.
**In the cortex, blood flow rate is high because a high flow rate encourages filtration which is the job of the cortical glomeruli.
**In the medulla, the blood flow rate is lower because a low rate will not sweep away all the molecules of the interstitial fluid that are setting up the osmotic gradient that pulls nutrients out of the filtrate.
***Note that this low blood flow rate is still high enough to provide life-sustaining nutrients to the cells within the medulla.

===Autoregulation of renal blood flow and GFR===
*The kidney is engineered to have autoregulation of RBF and GFR.
*This autoregulation keeps small, normal changes in arterial blood pressure from changing the GFR.
**This is important because Na and H20 loss are a function of GFR (recall that as GFR increases, there is less time in the tubule to reabsorb Na and therefore less absorption of H20).
**So we don't want GFR to be changing all the time.
*There are two mechanisms by which GFR is regulated: myogenic and tubuloglomerular feedback.


*Myogenic GFR regulation
**This mechanism is not unique to the kidney; many vascular beds use it, including the brain.
**Recall that the point is to keep GFR at some constant levels and that an increased arterial blood pressure would increase GFR.
**So as arterial blood pressure increases, we want to myogenically decrease the blood pressure to maintain the same GFR.
**As arterial blood pressure increases, the vascular endothelial wall is stretched, stretch sensors on vascular smooth muscle cells open Ca channels, Ca enters the smooth muscle, muscle contracts, the lumen diameter decreases, and the vascular resistance increases.
**By this Stretch-Ca-based contraction of vascular smooth muscle and increased resistance, the ''renal blood flow (RBF)'' remains constant even when systemic blood pressure is elevated.


*Tubuloglomerular feedback
**Recall that the point is to keep GFR at some constant level because we don't want to lose too much Na or too much water (occurs when GFR is too high--not enough time in tubule to reabsorb the Na and H20).
**Note that there can be multiple afferent arterioles for a single glomerulus.
**The macula densa detects when NaCl levels ''in the filtrate'' are elevated.
**When filtrate NaCl levels are elevated, the macula densa cells release ATP which causes constriction of the afferent arterioles.
**Constriction of the afferent arterioles leads to '''decreased glomerular capillary hydrostatic pressure (P<sub>GC</sub>''' to that nephron) and therefore decreased GFR (in that nephron).
**Note that ATP is metabolized to adenosine in the interstitial fluid space between the macula densa and the smooth muscle cells of the afferent arteriole.
**'''Adenosine binds the A1 receptor''' on the afferent arteriole.

===Renal sympathetic nerves and RBF control===
*The two autoregulation control mechanisms for GFR are myogenic and tubuloglomerular; however, the body has a third for emergent situations: sympathetic nervous control.
**So, in these emergent situations, the blood pressure has drastically dropped for some very bad reason (trauma, et cetera).
*Sympathetic nervous control of the renal blood flow works by '''rapidly, temporarily constricting the afferent arterioles'''.
**This is a prioritization of water retention and continued blood flow to other organs over the proper function of the kidneys.
*Sympathetic nervous control is achieved through direct constriction, release of renin and release of catecholamines (epinephrine and norepinephrine).
**Direct innervation of the arterioles can cause constriction.
**Renin starts the angiotensin pathway which leads to angiotensin 2 and thus vasoconstriction, aldosterone release, and AVP release (all of which elevate blood pressure).
**'''Epinpehrine and norepi bind the a1-adrenoreceptors''' to directly cause vasoconstriction of the vascular smooth muscle.

===Hormomal control of RBF===
*In addition to autoregulation and sympathetic emergent control of RBF, there is long-term control via endogenous hormones.
*Renal vasodilators:
**Recall that vasodilation increases RBF, increases GFR, and increases loss of Na and H20.
**Prostaglandins, NO, dopamine, atrial natriuretic peptide
*Renal vasoconstrictors:
**Recall that vasoconstriction decreases RBF, decreases GFR, and decreases loss of Na and H20.
**Angiotensin 2, epi, norepi, throboxane A2, adenosine
***Thromboxane makes sense because it is activated when bleeding / clotting which is a good time to conserve water.
***Angiotensin 2 makes sense because it generally serves to conserve and reabsorb water, and decreasing RBF will slow filtrate flow and thus allow the tubule cells to reabsorb more of the H20.

===The dampening effect of prostaglandins on renal vasoconstriction===
*We have seen that sympathetic nerves cause vasoconstriction at the kidney (renin + epi / norepi -> vasoconstriction of the afferent arteriole).
*We have also seen that prostaglandins cause vasodilation at the kidney (vasodilation of the afferent arteriole).
*Finally, we know that '''NSAIDs decrease prostaglandin synthesis systemically'''.
*So, it makes sense that giving NSAIDs to a pt who is volume depleted (or otherwise has poor kidney function) is bad because it will reduce prostaglandin synthesis, therefore reduce the amount of vasodilation force on the afferent arteriole, and result in lower RBF, lower GFR, and less filtration.
*So, '''think of prostaglandins of the brake that slows vasoconstriction'''.
 Where do the prostaglandins come from?  Is there a local, renal source?

===Hallmark of glomerular disease===
*The hallmark of damage to the glomeruli is protein in the urine (proteinuria).
*Measuring protein in the urine underestimates the amount that is let into the filtrate at the glomerulus.
**This is because much of the filtered protein is metabolized or endocytized while it is part of the filtrate in the tubule.

===Glomerular filtration occurs over 3 layers===
*There are three cell types in the glomerulus:
**Endothelial cells of the capillaries
**Podocytes (visceral epithelial cells)
**Mesangial cells
***They hold stuff together
***Messangial cells are contractile; might be able to change filtration by covering up filtration slits or not.


*There are three major layers in the glomerulus through which a molecule must pass to get from the blood to the filtrate.
*The first layer is the capillary's endothelium.
**There are fenestrae through which most anything except cells can pass.
**However, we don't want proteins to pass through the endothelial barrier b/c they are large and will clog the glomerulus.
**The fenestrations of the endothelial cells are negatively charged to repel proteins (which are generally negatively charged).
**The fenestrae are about 70nm in diameter.
*The second filtration level is the basement membrane
**The endothelial cells of the arteriole sit on the basement membrane.
*The last specialization are the podocytes.
**Podocytes sit on the inside of the Bowman's capsule and send out feet from their cell body.
**The feet of neighboring podocytes rest very near to one another to form small slits through which only small molecules can pass.
**The slits formed by the podocytes are called '''filtration slits''' or '''slit pores'''.
**The filtration slits are about 4-14 nm in diameter.
**'''NEPHRIN''' is a critical structural protein for filtration slits.
***We believe NEPHRIN is a critical protein for proper filtration because when it is mutated, massive proteinuria occurs.

===Factors affecting filterability===
*Size, shape, deformability, and electrical charge are the major factors in deformability.
*Size: Albumin and hemoglobin rarely make it into the filtrate but myoglobin does readily enter the filtrate.
*Charge: albumin has a mass very similar to Hb but is found much less in the filtrate, probably due to albumin's negative charge.

===GFR is determined by Starling forces===
*Recall Starling forces which apply to all capillary beds of the body, including the renal capillaries and the glomeruli:
**There are four forces affecting flow from blood to interstitial fluid and ''vice versa''.
**In the case of GFR, the competing fluids are capillary blood and the filtrate, not blood and interstitial fluid.
**Blood colloid pressure (Pi<sub>GC</sub>) wants to keep stuff in the blood.
***Note that the blood colloid pressure (P<sub>GC</sub>) increases proximal to distal in the capillary as water is filtered out.
**Filtrate colloid pressure (P<sub>FC</sub>) wants to keep stuff in the interstitial fluid (and is nearly negligible b/c protein rarely enters the filtrate).
**Capillary hydrostatic pressure (P<sub>GC</sub>) wants to force stuff out of the capillary.
**Filtrate hydrostatic pressure (P<sub>BS</sub>) wants to force fluid into the blood.
***P<sub>BS</sub> is negligible.
*There is a constant called the '''glomerular ultrafiltration coefficient (K<sub>f</sub>) that accounts for the normal surface area and capillary permeability.
**Note that "ultrafiltration" is also the name for the overall filtration process that is occurring at the nephron.
**If there is vascular damage, the glomerular ultrafiltration coefficient may decrease.
*'''GFR = K<sub>f</sub> * (P<sub>GC</sub> - P<sub>BS</sub> - Pi<sub>GC</sub>)'''
**That is GFR = ultrafiltration coefficient * (capillary hydrostatic pressure - filtrate hydrostatic pressure - blood colloid pressure).

===Force differences along systemic capillaries and renal capillaries determine GFR===
*There is a distinct difference between systemic capillaries and the renal glomerular capillaries.
**Recall that systemic capillaries must pass nutrients from blood to tissue and pass waste from tissue to blood.
***This two-way exchange is facilitated by decreasing capillary hydrostatic pressure (over the distance of the capillary, the blood hydrostatic pressure decreases) and the static capillary colloid osmotic pressure (the amount of protein in the blood doesn't change as the blood passes through the capillary).
***At the proximal part of the systemic capillary, the hydrostatic pressure is greater than the blood colloid pressure so nutrients pass from the blood to the tissue.
***At the distal part of the systemic capillary, the hydrostatic pressure is less than the blood colloid pressure so wastes pas from the tissue to the blood.
*There are two separate sets of renal capillaries: the glomerular capillaries for generating filtrate and the renal peritubular capillaries for exchanging nutrients and wastes of the tubule cells.
*The glomerular capillaries function to generate filtrate and therefore do not have two-way exchange like the systemic capillaries:
**The capillary hydrostatic pressure (P<sub>GC</sub>) is much higher in glomerular capillaries than in systemic capillaries.
**Because the capillary hydrostatic pressure (P<sub>GC</sub>) is so much higher and changes so little from proximal to distal glomerular capillary, there is no point in the capillary where waste (filtrate) is brought into the capillary--'''the net force is always out of the blood at the glomerular capillaries'''.

====Afferent and Efferent arteriole pressures and GFR====
*The GFR can be controlled by changing the diameter of the afferent and efferent vessels.
*Recall that GFR = K<sub>f</sub> * (P<sub>GC</sub> - P<sub>BS</sub> - Pi<sub>GC</sub>)
**Note that the only variable in this equation that is dependent on the blood pressure is P<sub>GC</sub>.
*Afferent constriction
**Afferent constriction occurs when signaled by hormones (long term), sympathetics nerves (acute, via renin and epi), or via autoregulation (myogenic or tubuloglomerular).
**Upon '''constriction of the afferent arterioles there is decreased GFR because of decreased hydrostatic pressure P<sub>GC</sub>'''.
**Afferent dilation has the opposite effects: increased GFR and increased glomerular blood flow.
*Efferent constriction
**Efferent constriction occurs via even low angiotensin 2 levels.
**Upon '''constriction of the efferent arterioles there is increased GFR because of increased hydrostatic pressure P<sub>GC</sub>'''.
***In actuality, the GFR would go down if the degree of constriction is so severe that blood flow to the nephron is significantly reduced.
**Efferent dilation decreases the P<sub>GC</sub> and decreases GFR.


*It is important to recognize that the glomerular blood flow rate and the GFR are not directly related.
**See [http://editthis.info/iusmphysiology/Renal_blood_flow,_glomerular_filtration#Blood_colloid_pressure_(Pi<sub>GC</sub>)_and_GFR two headings later]
**It is the hydrostatic pressure of the capillary that determines the GFR.
**It is the pressure gradient of the afferent and efferent arterioles that determines the glomerular blood flow.

====Bowman space pressure (P<sub>BS</sub>) and GFR====
*Recall that the pressure of the Bowman space (P<sub>BS</sub>) opposes the hydrostatic pressure of the glomerular capillary blood.
*So, '''when P<sub>BS</sub> increases because of pathology, the GFR will decrease.'''
**Pathologies generally cause a backup or resistance in the tubule or ureter: kidney stones, prostatic hyperplasia, etc.

====Blood colloid pressure (Pi<sub>GC</sub>) and GFR====
*When adding saline to a pt's blood, the colloid osmotic pressure of the blood at the glomerular capillary will decrease (fewer proteins per ml).
*Recall that GFR = K<sub>f</sub> * (P<sub>GC</sub> - P<sub>BS</sub> - Pi<sub>GC</sub>)
*So when Pi<sub>GC</sub> (blood colloid osmotic pressure) decreases, GFR goes up.
*Does giving saline and therefore increasing GFR decrease mean that a higher dose or a more frequent administration of a drug must be given to be effective (because of increased clearance rate)?
**"makes sense – also depends on the stability/metabolism of the drug."

===Relationship of glomerular blood flow and GFR===
*The rate that blood flows through the capillaries of the glomerulus does affect how much filtration occurs.
*As blood flows through the glomerular capillary, stuff is lost to the filtrate but proteins (over 30kda) are not, thus '''blood colloidal osmotic pressure (COP = Pi<sub>CG</sub>) increases from proximal to distal in the glomerular capillaries'''.
*This increase in COP (Pi<sub>GC</sub>) is a function of the blood flow: the slower the blood flows the higher the COP of the blood.
**This makes because the longer the blood remains in the filtering area, the more filtrate will leave the blood (since hydrostatic pressure is forcing stuff out of the blood).
**Pi<sub>GC</sub> (the colloidal osmotic pressure) will rise until it is high enough to oppose the hydrostatic pressure (that is, until the sum of P<sub>GC</sub> and P<sub>BS</sub> is equal to P<sub>GC</sub>).
*When blood flow is too low, the equilibrium of P<sub>GC</sub> and (P<sub>BS</sub + Pi<sub>GC</sub>) occurs quickly and not all the surface area of the capillaries is used for filtration, which is bad because decreased filtration is like, well, kidney failure.

===Normal GFRs===
*Normal GFRs change with age and gender.
**Neonates: 20 ml / min / 1.73 m2
**Young adult, female: 110 +/- 15 ml / min / 1.73 m2
**Young adult, male: 125 +/- 15 ml / min / 1.73 m2
*GFR declines after 45.
**GFR is 30-40 lower at age 80 than 21.


*In healthy, young adults, the GFR is high primarily because:
**K<sub>f</sub> is high (there is a large surface area and there are many pores in the capillaries)
**P<sub>GC</sub> is high (blood pressure is as high as it should be, not higher, not lower)
**Glomerular blood flow is high (which results in a low Pi<sub>GC</sub> and therefore less counterforce to the hydrostatic pressure).

===GFR is an important metric===
*GFR is an important measure of renal function.
*Higher GFR at 12 months post-transplant is a good predictor of graft survival for 10 years.


*stopped here on 03/23/11.