Physio Glomerular Filtration (37)

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  1. What key function do the kidneys play?
  2. 4 Functions of the Kidney
    • 1. Filtration
    • 2. Reabsorption
    • 3. Secretion
    • 4. Excretion
  3. Filtration
    • occurs in the glomerulus where blood is filtered to generate a fluid (that makes its way into the renal tubule) free of cells & most proteins
    • it looks like plasma MINUS the proteins
  4. Reabsorption
    • most of the filtered water & solutes (eg. Na+, Cl-, glucose, etc.) are reabsorbed from the tubular fluid
    • the vast majority of processing that occurs in the renal tubule IS reabsorption
    • what’s left behind in the tubular fluid are substances the body wants to excrete (via urine)
  5. Secretion
    • the selective process of transporting solutes into the renal fluid (in the renal tubule)
    • solutes (uric acid) & ions (K+, Fe) are some compounds along w/ other organic anions & cations that can be secreted INTO the tubular fluid
    • (the bulk of processing is reabsorption not secretion though)
  6. Excretion
    • excretion is what makes up the urine after all the processing has occurred
    • what’s excreted consists of the water & solutes that remain in the tubular fluid after passing through the renal tubule
    • *Excretion = Filtration - Reabsorption + Secretion
  7. What plasma electrolytes do the kidneys control the concentration of?
    • Na+
    • K+
    • Cl-
    • HCO3-
    • Ca2+
    • PO43-
    • (to name a few)
  8. What is the primary role the kidney plays in controlling plasma pH?
    • it can reabsorb filtered bicarbonate (HCO3-)
    • the vast majority of bicarb filtered by the glomerulus is REABSORBED in the proximal tubule
  9. What is a secondary way the kidneys help control plasma pH?
    • they can selectively secrete acid (H+)
    • this happens in the intercalating cells of the collecting duct (CD) - these cells have the capacity to secrete acid directly into the urine
  10. What two hormones are synthesized & released by the kidney?
    • Renin: increases blood pressure
    • Erythropoietin: regulates RBC production in bone marrow
  11. If a compound is filtered by the glomerulus & there’s no transporter to reabsorb it, what will happen to it by default?
    • it will be excreted into the urine - if something is filtered & not reabsorbed it WILL be excreted in the urine (even if it isn’t secreted into the tubule)
    • the kidneys dispose of compounds in the circulation by DEFAULT; there doesn’t HAVE to be a specific transport protein to get rid of a substance in the circulation
    • this is how the kidney can clear drugs/foreign compounds that shouldn’t be in the circulation
  12. Osmole (Osm, osmol)
    a unit of measurement that defines the number of moles of solute that contribute to the osmotic pressure of a solution
  13. What is the important different between the kidney cortex & medulla?
    • the concentration of solutes in each’s interstitial space differs
    • the interstitial osmolality in the cortex is close/nearly identical to plasma’s, ~300 milliosmoles
    • the interstitial osmolality in the medulla is MUCH HIGHER, can reach up to ~1200 milliosmoles
    • this is key for generating concentrated (↑solute ↓water) urine, especially when trying to conserve water
  14. Nephron
    • the basic functional unit of the kidney
    • it’s a blunt end tube w/ a glomerulus (where filtration occurs) → tubule that fluid makes its way through → empties into a collecting duct that continues into a series of larger and larger ducts that collect in the renal pelvis → ureter
    • Image Upload 1
    • e/a kidney has ~ 1.2 * 106 nephrons
    • if you have 2 kidneys there are ~2.4 million nephrons working to process all this fluid
  15. What percentage of the Cardiac Output (C.O.) do the kidneys receive?
    • ~25%
    • even though they only make up .5% of the body’s weight
    • they’re processing all this fluid - they don’t NEED 25% of the body’s O2 nor do they produce 25% of its CO2
  16. Glomerulus
    a capillary bed that (unlike others) has 2 arterioles: the afferent brings blood in → filtration occurs across the capillary bed → & the efferent takes blood away
  17. What percentage of blood that enters the afferent arteriole gets filtered by the glomerular membrane?
    • only 20% gets filtered into the Bowman’s Space - this fluid is free of cells & almost completely free of proteins
    • the other 80% that isn’t filtered exits via the Efferent Arteriole
  18. Composition of the Glomerular Filtration Bed (3 layers)
    1. capillary endothelial cells: fenestrated, so fluid can pass freely but cells cannot migrate across (700 Å)

    • 2. basement membrane: provides the MAJOR filtration barrier; allows water & small molecules (< 15 Å) to pass freely; contains fixed negative charges that electrostatically repel negatively charged proteins & those bigger than 20-40 Å (small positively charged proteins CAN get through)
    • 3. podocytes (sit on the side facing Bowman’s space): have foot processes that form additional filtration slits (250 Å in diameter)
  19. Proximal Tubule
    • filtered fluid from the Bowman’s Space then enters the proximal tubule (the “workhorse” of the operation)
    • this is where the majority of REABSORPTION occurs - where 2/3rds of the filtered, water, salt, Ca2+, etc. gets reabsorbed
    • species’ like AAs & sugars (glucose) are COMPLETELY reabsorbed here
    • organic anions/cations can be secreted here as well
  20. Loop of Henle
    • fluid leftover from the proximal tubule enters the loop of Henle

    • this is made up of 3 segments (in order): a (thin) descending limb → thin ascending limb → thick ascending limb

    • e/a of those segments have important properties related to their function

    • the thin descending limb is highly permeable to water

    • the ascending limbs are IMpermeable to water, but ARE permeable to salt

    • the driving force for such reabsorption is the high interstitial osmolarity in the medulla
  21. Distal Tubule
    in the early part of the distal tubule salt continues to be reabsorbed (W/O water) - its here that the renal tubular fluid becomes hypOosmolar (lower in osmolarity [more watery] than plasma)
  22. Collecting Duct
    • the final segment that reabsorbs both salt & water
    • the AMOUNT of water reabsorbed by the CD is tightly controlled by ADH (vasopressin)
  23. Antidiuretic Hormone (ADH)
    • the cells of the collecting duct are impermeable to water in the absence of ADH
    • w/ ADH, aquaporins (water channels) are upregulated on the CD cell membranes, allowing water to exit the renal tubule
    • this concentrates the provisional urine
  24. Cortical Nephrons
    • the majority of nephrons (90%) are cortical
    • have their glomeruli in the outer cortex
    • typically have short loops of Henle
    • & the efferent arterioles that exit the glomerulus form peritubular capillaries
  25. Peritubular Capillaries
    these surround the nephron & provide a proximal way for reabsorbed species to reenter the circulation
  26. Juxtamedullary Nephrons
    • make up only about 10% of total nephrons
    • they have their glomeruli at the border of the cortex & medulla
    • they have longer loops of Henle
    • & the efferent arterioles branch to form both peritubular capillaries & Vasa Recta
    • Image Upload 2
  27. Vasa Recta
    these provide blood to the deep parts of the medulla & also surround the long tubular segments to provide a route for reabsorbed water & solutes to reenter the circulation
  28. Juxtaglomerular Apparatus
    • found where the vascular pole of the renal corpuscle & the distal convoluted tubule CONTACT each other
    • it contains 3 cell types:
    • 1. JG cells
    • 2. macula densa cells
    • 3. lacis cells
  29. Macula Densa Cells
    • cells lining the wall of the distal tubule at the point where it returns to the vascular pole of its parent glomerulus (close to the afferent arteriole)
    • they’re chemoreceptors that monitor the NaCl concentration of the blood
    • when there's low salt/ion concentration, these cells signal nearby JG cells to release renin, initiating a cascade that ↑ BP
  30. Juxtaglomerular Cells (JG cells)
    • specialized smooth muscle baroreceptor cells lining the afferent & efferent arterioles: they physically monitor the BP
    • can release renin in response to low BP, which is a protease that cleaves angiotensinogen into angiotensin I
    • the general function of the cells/renin is to “help control the constriction of these arterioles”
  31. What renal disease occurs as a result of a defect in the nephrin protein?
    • Nephrotic Syndrome (loss of protein in urine)
    • is normally a transmembrane protein embedded in the podocyte membrane that makes up the filtration slits by interdigitating w/ each other (provide the way through which water/small molecules pass through the 3 layer capillary membrane)
    • if mutated, proteins from the plasma can get into the filtered fluid & get excreted in the urine (protein is NOT normally found in the urine)
    • it can cause edema & eventually renal failure
  32. Glomerular Filtration Rate (GFR)
    • the rate at which fluid is filtered through the glomerulus (mL/min)
    • total volume of fluid being filtered by the kidneys from all the working nephrons
  33. Renal Plasma Flow (RPF)
    • the rate at which plasma is delivered to the kidneys (mL/min)
    • both GFR & RPF are important indicators of renal function (aka how well the kidneys are working; abnormalities can be indicators of disease)
  34. Glomerulonephritis
    • renal disease often initiated by an immune response to a remote infection (eg. streptococcus bacteria) - 1 of the symptoms is a reduced GFR

    • person makes anti-streptococcal antibody, which combines with streptococcal antigen (immune complex) & gets stuck in the glomerular basement membrane

    • renal damage occurs 1-3 weeks after infection

    • WBCs also accumulate, leading to inflammation of the glomerulus & a breakdown of the permeability barrier → proteinuria
  35. What are the 2 forces causing filtration across the glomerulus?
    1. Hydrostatic Pressure (Pnet): this is the hydrostatic pressure within the glomerular capillary (PGC) minus the hydrostatic pressure in Bowman’s Space (PBS)

    2. Oncotic Pressure (πnet): this is the oncotic pressure within the glomerular capillary (πGC) minus the oncotic pressure in Bowman’s Space (πBS)

    • the idea is that a positive hydrostatic pressure IN the capillary is pushing filtration to occur, & any pressure in Bowman’s Space is pushing back

    • in contrast, a high πGC (oncotic capillary pressure) RETARDS filtration; it tends to pull fluid BACK into the capillary out of the Bowman’s space
  36. Why is there effectively no oncotic pressure within Bowman’s Space (πBS = 0)?
    • b/c protein can’t be filtered out of the plasma through the glomeruli membrane, meaning none gets into the Bowman’s Space (it all stays in the unfiltered plasma - shouldn’t be found in the urine)
    • Image Upload 3
  37. Relationship between GFR & Filtration Pressure (across the glomerulus)
    • GFR is equal to a filtration coefficient * net filtration pressure
    • GFR = Kf * net filtration pressure
  38. Net Filtration Pressure (PUF)
    • Pnet - πnet
    • (PGC-PBS) - (πGCBS)
  39. So GFR =
    • Kf * [(PGC-PBS) - (πGCBS)]
    • Kf * [(PGC - PBS - πGC]
  40. Pressure Values at the Afferent End of the Glomerulus (mmHg)
    • PGC: 60
    • PBS: 15
    • hydrostatic pressures facilitate fluid movement into BS, aka filtration (+ → -)
    • πGC: 28
    • πBS: 0
    • oncotic pressures prevents filtration (fluid movement into BS)
    • PUF: 17
  41. Pressure Values at the Efferent End of the Glomerulus (mmHg)
    • PGC: 58
    • PBS: 15
    • πGC: 35
    • πBS: 0
    • oncotic pressure preventing filtration has INCREASED (28 → 35)
    • PUF: 8
  42. Why has the oncotic pressure preventing filtration INCREASED (become more negative, 28 → 35) in the efferent arteriole end of the glomerulus?
    • b/c in the afferent end, filtration was promoted by hydrostatic pressure differences across the capillary membrane
    • filtration has decreased the amount of fluid dissolving solutes in the efferent plasma
    • the protein concentration has increased due to less fluid present (higher oncotic pressure results, preventing filtration from occurring)
  43. How does tubular obstruction (eg. kidney stones) affect filtration?
    • it increases the PBS (bowman’s space hydrostatic pressure) so that will RETARD filtration
    • fluid from inside the capillary will have to work harder to get into the Bowman’s space, less will eventually make it out
  44. Renal Blood Flow (RBF)
    • is typically around 1250 mL/min
    • this corresponds to ~25% of C.O.
  45. Hematocrit (Hct)
    • the fraction of blood volume occupied by cells
    • is typically about 0.45
  46. Renal Plasma Flow (RPF)
    • is the RBF * (1 minus the hematocrit)
    • RPF = RBF * (1 - Hct)
    • RPF = 1250 mL/min * 0.55 = 687 mL/min
  47. Filtration Fraction (FF)
    • the fraction of plasma filtered through the glomerulus; usually ~0.2 (the fraction of plasma that enters the glomerulus that ACTUALLY gets filtered)
    • FF = GFR/RPF, or
    • GFR = FF * RPF
    • GFR=0.2*687 mL/min=137 mL/min
  48. Typical Values
    • Renal Plasma Flow: 687 mL/min
    • Glomerular Filtration Rate: 137 mL/min
  49. Renal Clearance (mL/min)
    • the volume of plasma per unit time from which substance x has been completely removed & excreted (in the urine)
    • Cx = UxV/Px
    • the renal clearance of a given substance is equal to its excretion rate divided by its concentration in the plasma
  50. Values in Clearance Formula
    • Excretion Rate of x (mg/min): UxV
    • Ux: concentration of x in the urine (mg/mL)
    • V: urine flow rate (mL/min)
    • Px: concentration of x in the plasma (mg/mL)
  51. Clearance v. Excretion
    • NOT the same thing
    • clearance is a volume/time - volume of plasma that’s been CLEARED of some compound
    • excretion is a mass/time - how much of the compound is being eliminated in the urine
  52. The GFR can be measured using the CLEARANCE of a compound that has WHAT properties (4)?
    1. it’s freely filtered: not bound to plasma proteins

    2. not reabsorbed or secreted by the renal tubule: it has no transporter in either direction (the only way it gets into tubule is by filtration)

    3. not metabolized or produced by the kidney

    4. it DOESN’T alter the GFR

    • the idea is to get a compound that’s filtered in exact proportion to the plasma; if 20% of the plasma gets filtered, 20% of compound x gets filtered
  53. Inulin
    • a compounds that has the 4 aforementioned properties: a small polymer of fructose that isn’t metabolized
    • the amount of it that gets in the tubules gets excreted in the urine
  54. GFR = Cinulin
    • = UinulinV/Pinulin
    • = (125 mg/mL*1 mL/min)/1 mg/mL
    • = 125 mL/min
    • (the urine flow rate is typically 1 mL/min & the concentration being infused into said patient is 1 mg/mL)
  55. Why is the measured concentration of inulin in the urine (125 mg/mL) WAY higher than what it was in the plasma (1 mg/mL)?
    b/c the majority of water diluting inulin in the plasma is reabsorbed during passage through the renal tubules, leaving less water in the urine & a more concentrated value there for inulin
  56. Rate of Filtration of Inulin
    • that would be = to GFR * concentration of inulin in the plasma (GFR*Pinulin)
    • would give you the mass of inulin being filtered per minute
  57. Excretion Rate of Inulin
    • the concentration of inulin in the urine * urine flow rate (Uinulin*V)
    • that’s the mass of inulin excreted per minute
  58. Why do the Rate of Filtration & Excretion Rate of Inulin have to be equal?
    • b/c the only way inulin got INTO the urine is via filtration (there’s no secretion of it)
    • Image Upload 4
  59. What is typically used to measure GFR instead of inulin (b/c it requires infusion)?
    • CREATININE: produced endogenously in skeletal muscle at fairly constant rate by creatine breakdown of
    • is freely filtered & not reabsorbed
    • GFR = Ccreatinine
    • = UcreatinineV/Pcreatinine
    • (a small amount is secreted by the renal tubule (10%), this error is offset by a 10% overestimate in the assay for plasma creatinine)
  60. What kind of compound can be used to calculate Renal Plasma Flow (RPF)?
    1. freely filtered at glomerulus

    2. efficiently secreted from plasma into renal tubule

    3. not reabsorbed from the renal tubule back into the blood

    • eg. PAH (para-aminohippuric acid), a small organic anion that must be infused
    • Image Upload 5
  61. What is a complication of using PAH as an indicator of RPF?
    • not all of the PAH entering the afferent arteriole actually gets excreted in the urine
    • the transporter used to secrete it in the tubule isn’t efficient enough to clear it all; only ~90% of it is secreted into the tubule (extraction efficiency is 0.9) some ends up getting back into the circulation
    • therefore measurement of PAH clearance gives an effective renal plasma flow (ERPF) defined as CPAH = UPAH*V / PPAH
    • RPF = ERPF/extraction efficiency
  62. Tubular Secretion Rate Measurement
    • the tubular secretion rate (mg/min) for a freely filtered & secreted (NOT reabsorbed) compound is:
    • Ux*V - GFR * Px
    • aka the excretion rate of x minus the filtration rate of x
    • (*for PAH, more is getting into the urine via secretion than filtration)
  63. Tubular Reabsorption Rate (mg/min) Measurement
    • can be measured for a compound that is freely filtered & reabsorbed (NOT secreted)
    • = GFR*Px - Ux*V
    • aka the filtration rate (mg/min) minus the excretion rate (mg/min)
    • eg. used in lecture was glucose
  64. What is a typical plasma glucose (Pgluc) level?
    • 0.8-0.9 mg/mL
    • the highest it’ll ever go (unless you’re diabetic) is 2 mg/mL
    • (unless diabetic, urine glucose should be 0 - there should be no glucose in the urine)
  65. What happens to filtered, excreted, & reabsorbed glucose as you increase plasma glucose concentration (Pgluc)?
    • Image Upload 6
    • • Filtration increase as a linear function of plasma glucose

    • Reabsorption: increases linearly up until Pgluc = 3 mg/mL; at this point it levels off b/c the max reabsorption rate has been reached; transporters in the proximal tubule are saturated, so no more can be reabsorbed → glucose appears in urine

    • Excretion: none is excreted when Pgluc < 2 mg/mL b/c all of it is completely reabsorbed; above 3 mg/mL in plasma, excretion increases linearly
  66. Splay
    • the phenomenon that between a Pglucose of 2-3 mg/mL, some glucose is seen in urine before complete saturation of its proximal tubule transporters occurs
    • this is b/c some glucose escapes uptake & because of nephron heterogeneity
  67. Diabetes Mellitus
    • patients either fail to produce insulin in beta cells or fail to respond to insulin
    • this leads to blood sugar levels in excess of 16 mg/mL
    • high plasma glucose leads to high tubular glucose which saturates the Na+/glucose cotransporter in the proximal tubule
    • excess glucose appears in the urine of patients w/ uncontrolled diabetes mellitus
    • glucose that remains in the renal tubule acts to retain water in the tubule, leading to polyuria (more/higher urine volume)
  68. Clearance Ratio (CRx)
    • unitless ratio of the clearance of the compound being measured divided by GFR

    • Cx/GFR

    • • if Cx = GFR, then CRx = 1
    • - no net reabsorption or secretion [eg. inulin]

    • • if Cx > GFR, then CRx > 1
    • - secretion is occurring [eg. PAH]
    • - clearance must be occurring faster than by JUST filtration if Cx > GFR

    • • if Cx < GFR, then CRx < 1
    • - reabsorption is occurring [eg. glucose]

    • CRx tells you how the kidney is handling a given compound
  69. How are RBF & GFR regulated?
    • by constriction or dilation of the afferent & efferent arterioles
    • regulation of RBF & GFR are crucial to renal function
    • Image Upload 7
  70. What will a signal that selectively constricts the afferent arteriole result in?
    • ↓ RBF
    • ↓ GFR: conveying less arteriole pressure to the glomerulus, so PGC (hydrostatic pressure within the glomerular capillary) also ↓ (the force PUSHING renal filtration goes down)
  71. What will a signal that selectively constricts the efferent arteriole result in?
    • now the constriction is on the exiting end of the glomerulus
    • ↓ RBF
    • ↑ GFR: there is an ↑ in PGC (the force pushing filtration)
  72. What will a signal that selectively dilates the efferent arteriole result in?
    • ↑ RBF
    • ↓ GFR: PGC has been decreased
  73. What will a signal that selectively dilates the afferent arteriole result in?
    • ↑ RBF
    • ↑ GFR: more arterial pressure is conveyed to the capillary
  74. Norepinephrine
    • • a vasoconstrictor released by renal nerves in response to ↓BP or volume
    • • it constricts the afferent & efferent arterioles, ↓ both GFR & RBF
    • • this helps to return BP to normal & conserve fluid
  75. Nitric Oxide
    • • a vasodilator released by endothelial cells in response to ↑ intake of NaCl
    • • it dilates afferent & efferent arterioles, ↑ GFR & RBF (GFR increases b/c more arterial BP enters the glomerulus, increasing PGC)
    • • this helps ↑ water & NaCl excretion, reducing BP
  76. What are 2 intrinsic autoregulatory mechanisms that help to maintain renal blood flow & GFR over a fairly broad range of arterial pressures?
    1. Myogenic Mechanism: constriction of smooth muscle of afferent arteriole when stretched

    2. Tubuloglomerular Feedback: ↑ tubular flow sensed by the macula densa → signal from juxtaglomerular apparatus → constriction of afferent arteriole

    Image Upload 8

    *these can be regulated by extrinsic factors however
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Physio Glomerular Filtration (37)
Exam 4
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