Filtration and Clearance

Question 1

Glomerular Filtration

Answer 1

• the process by which plasma is filtered across the glomerular capillaries to form a protein-free ultrafiltrate in Bowman’s space
• differences in the oncotic and hydrostatic pressure (Starling Forces) across the glomerular capillaries drive the net efflux of a plasma ultrafiltrate
• except plasma protein, organic and inorganic anionic and cationic solutes are freely filtered across the glomerular capillaries and exist in the same concentration in plasma and ultrafiltrate

Question 2

Glomerular Filtration Rate

Answer 2

• approximately 125 ml/min or 180L per day, which is more than 10-fold the extracellular fluid volume (14L/70 Kg body weight) and equivalent to filtering the entire ECF volume every 2 hrs
• this rapid turnover of ECF through the kidneys serves the purpose of maintaining ECF volume and solute composition within narrow limits by rapidly responding to correct changes ECF volume and solute composition

Question 3

Filtration rate

Answer 3

=Kf[(Pgc-Pbs)-(Pigc- Pibs)]

• Kf is filtration coefficient of the glomerular capillary and is the product of the capillary hydraulic conductivity and the surface area available for filtration
• (Pgc-Pbs) is the difference in hydrostatic pressure inside the glomerular capillary and Bowmans space
• (Pigc- Pibs) is the difference of oncotic pressure across the glomerular capillary
• Pgc is 45-50 mmHg at the beginning and decreases to 41-47 at the end of the glomerular capillary
• this small decrease in pressure occurs despite efflux of plasma and is due to post capillary efferent arteriole contriction
• Pi GC is 25 (oncotic pressure) at the beginning of the glomerular capillary and increases to 35 mmHg at the end of the glomerular capillary due to plasma filtration and concentration of the plasma protein
• Pbs is 10 mmHg and Pi bs is zero
• Pi bs is significantly increased in nephrotic syndrome due to filtration to plasma protein

Question 4

Starling Forces Drive Glomerular Filtration

Answer 4

-where the driving force favoring and opposing glomerular filtration become equivalent toward the efferent end of the glomerular capillary bed, glomerular filtration will cease

Question 5

Glomerular Barrier to Filtration

Answer 5

• endothelial cells of glomerular capillaries restrict passage of cellular elements into Bowman’s space, contain fenestrations ~70 nm in width
• capillary basement membrane-restricts filtration of solutes larger than ~ 1 kDa. An anionic charge favors filtration of cations and restricts filtration of anionic proteins
• visceral epithelial layer of Bowman’s capsule- podocytes have foot process that cover glomerular capillaries, foot processes separated by filtration slits connected by a thin diaphragm with pores ranging in size from 4-14 nm
• glycoproteins with negative charges also cover podocytes, filtration slits and slit diaphragms favoring filtration of small cationic solutes

Question 6

Glomerulus and Bowman’s Capsule

Answer 6

• permselectivity of the glomerular barrier is determined by the size and charge of the solute
• water and solutes with a diameter < 4 nm (effective molecular radius of < 2nm) are freely filtered

Question 7

Size Dependence of Solute Permselectivity at the Glomerular Barrier

Answer 7

• dependence of glomerular permeability on molecular size
• the Y axis is the ratio of the solute concentration in Bowman’s space (Bs) to that in plasma
• a solute freely filtered exists at the same concentration in plasma and filtrate or a concentration ratio of 1
• [S]Bs/[S] plasma
• H20, glucose NaCl are are 1.0, inulin is right under 1
• myoglobin 0.75
• hemoglobin 0.30
• albumin is 0

Question 8

Dependence of Filterability On Charge and SIze

Answer 8

• the clearance ratio on the Y axis is a quantitative index of solute filterability relative to inulin, which is freely filtered
• the negative charge on the basement membrane and foot processes impedes the passage of negatively charges solutes (proteins) while allowing passage of neutral solutes and positively charged solutes

Question 9

Dependence of Filterability of Anionic Dextrans On Charge of Glomerular Barrier

Answer 9

-removal of the negative charge from the glomerular barrier increases the passage of anions such as occurs with increased filtration of plasma proteins in nephrotic serum nephritis

Question 10

Renal Hemodynamics

Answer 10

• CO (HR x SV): 5-6 liters per minute, 7200-8640 liters per 24 hours
• Renal blood flow (RBF)- 1-1.2 liters per minute, 1440-1728 liters per 24 hours
• Renal plasma flow (RPF)- 600-720 ml per minute, 860-1040 liters per 24 hours
• Glomerular filtration rate (GFR)- 125 ml per minute, 180 liters per 24 hours
• Urine output 10 ml/min

Question 11

Filtration Fraction

Answer 11

-Glomerular filtration rate (GFR)/ Renal plasma flow (RPF)

=125ml/min/ 600 ml/min = 0.2

Question 12

Daily filter

Answer 12

• kidneys filter 180 L of plasma per day which is more than 10 fold the ECF volume (14 L/70 Kg man)
• the kidneys serve to maintain constant volume and solute composition of the ECF (homeostasis) by acting upon the enormous volume and solute composition of the glomerular filtrate to form urine
• GFR remains constant and the rate of volume of urine excretion varies according to the rate and volume of fluid consumed, which changes the volume and solute concentration of the ECF

Question 13

Increases with Renal Plasma Flow (RPF)

Answer 13

• FF= GFR/RPF
• GFR increases with increasing RPF
• FF decreases with increasing RPF
• as plasma flow increases through the glomeruli, an increasingly greater surface area is filtering plasma and a maximal rate of glomerular filtration is achieved
• a normal GFR of 125 ml/min is measured at a normal plasma flow of 600 ml/min indicating a normal FF of 20%
• the curvilinear relationship if GFR to RPF indicates a greater fraction of RPF is filtered at lower rates of RPF and a smaller fraction of RPF is filtered at higher rates of RPF
• this maintains GFR at levels necessary for renal function when RPF is compromised due to disease

Question 14

Afferent arteriolar constriction

Answer 14

• lowers RPF (renal plasma flow)
• lowers GFR
• this will decrease the hydrostatic pressure driving force for filtration and depending on the magnitude of the decrease in RPF, may decrease the capillary surface area of filtration

Question 15

Efferent arteriolar constriction

Answer 15

• lower RPF
• increase GFR
• a decrease in RPF will occur and an increase in glomerular capillary hydrostatic pressure will occur on the upstream side of the efferent arteriolar constriction
• in this instance, the effect of increasing glomerular capillary hydrostatic pressure to increase GFR exceeds the effect of a decrease in RPF until RPF becomes very low where the surface area of the glomerular capillary mediating filtration begins to decrease at low RPF flow rates below the normal 600 ml/min

Question 16

Afferent and Efferent arteriolar constriction

Answer 16

• a decrease in RPF will occur and glomerular capillary hydrostatic pressure will remain constant, maintaining GFR constant, as long as RPF is at a level where filtration occurs across the entire length of the glomerular capillary
• therefore the RPF dependence of GFR wis a function of the glomerular capillary surface area mediating filtration, which is more or less maximal at normal or above normal rate of RPF

Question 17

Increase plasma protein

Answer 17

• N/C in RPF

- decrease GFR

Question 18

Decrease plasma protein

Answer 18

• N/C in RPF

- increase GFR

Question 19

Obstruct ureter

Answer 19

• N/C in RPF

- decrease GFR

Question 20

Fluid Reabsorption in Post-Glomerular Pertitbular Capillaries

Answer 20

• Starling forces drive fluid reabsorption from the interstitial space into the peritubular capillaries
• the peritubular capillary oncotic pressure difference (Pi PC- Pi IS) driving fluid absorption exceeds the peritubular capillary hydrostatic pressure difference (P PC- P IS) opposing fluid absorption
• P PC= 20 mmHg (constriction of preceding efferent arteriole)
• Pi PC= 35 mmHg (filtration of plasma concentrates plasma proteins)
• P IS= 6-10 mmHg
• Pi IS = 4-8 mmHg
• net pressure difference driving net fluid: (20- 35) - (8 - 6) = -17 mm Hg
• a negative sign indicates a net pressure driving fluid movement into the peritubular capillary and a positive sign indicates a net pressure driving fluid movement out of the peritubular capillary
• the peritubular capillary network lies adjacent to the basolateral side or blood side of the tubular epithelial cells
• water and solute transported across the tubular epithelial cells from the luminal side to the basolateral side are returned to the circulation by absorption or uptake into the peritubular capillaries

Question 21

Glomerular Filtration Rate

Answer 21

• measurement of GFR can provide an index of the number of functioning nephrons when assessing kidney disease. Renal failure begins when GFR decreases to below 20 ml/min or a loss of function of 85% of nephrons
• the renal clearance of a substance is the virtual volume plasma from which a solute is completely removed from the plasma by the kidney per unit of time
• the renal clearance of a solute can be used to measure GFR if it freely filtered at the glomerulus, not reabsorbed along the length of the nephron, not secreted into the tubular fluid along the length of the nephron, not synthesized by the kidney, not metabolized by the kidney
• excreted = filtration - reabsorption +secretion

Question 22

Renal handling

Answer 22

-amount of solute filtered/time = Ps X GFR = moles/time
-amount of solute excreted/time = Us x V = moles/time
-amount solute filtered/time = amount solute excreted/time
Ps x GFR = Us x V therefore GFR = Us x V/ Ps

Question 23

Solutes Used to Measure GFR

Answer 23

• Inulin- an exogenous fructose polymer, infused to maintain constant plasma concentration, can be measured very accurately even at low concentration
• creatinine- a product of creatine phosphate metabolism in skeletal muscle, formation is low but constant in the absence of strenuous exercise or disease, minor secretion in kidney results in 10 % over estimation of GFR
• where creatinine production and excretion are constant, an increase and decrease inGFR will be reflected by a proportional decrease and increase in plasma creatinine. Thus a measurement of plasma creatinine may indicate an increase or decrease in GFR due to disease
• renal clearance of a substance is the virtual volume of plasma from which the solute is completely removed per unit of time. The renal clearance of inulin and creatinine measures GFR because ALL the inulin that is filtered into Bowman’s space is excreted in the urine and the kidneys are clearning the plasma of inulin or creatinine at a rate of 125 ml/min

Question 24

Clearance Ratios

Answer 24

• the clearance of any solute may be more or less than the clearance of inulin
• a solute may be only reabsorbed, only secreted or both reabsorbed and secreted, in any given segment or segments of the nephron
• where both solute reabsorption and secretion occurs, the difference in solute reabsorption and secretion determines either net solute reabsorption or net solute secretion
• a solute clearance less than the clearance of inulin indicates the solute is not freely filtered at the glomerulus or, if freely filtered, net solute reabsorption occurs from the tubular fluid in the nephron
• a solute clearance greater than the clearance of inulin indicates net solute secretion into the tubular fluid of nephron

Question 25

Fractional Excretion of Water

Answer 25

• the fractional excretion of water is the fraction of the glomerular filtrate NOT reabsorbed from the tubular fluid along the nephron and therefore, appearing as urine
• the FEH2O is the ration of urine flow rate to GFR
• FeH2O= V/GFR where GFR = Cln = Uln x V/ Pln
• FeH2O - V/Cln = V x Pln/ Uln x V = Pin/ Uln
• may be estimated from the plasma to urine inulin concentration ratio
• inulin is neither reabsorbed from nor secreted into the tubular fluid and its concentration in the urine arises directly from the amount of water reabsorption occurring in the nephron. If the inulin is 100X more concentrated in the urine than plasma
• Pin/Uin = 1/100 =0.01 1% of the filtered water is eliminated in the urine
• the renal handling of the endogenous metabolite cretinine can be substituted
• assess renal function by drawing blood and collecting urine

Question 26

Fractional Excretion of Solute

Answer 26

• for any solute filtered at the glomerulus, the fractional excretion of solute is the fraction of filtered solute which appears in the urine. That FEs may be estimated as the ratio of solute clearance to GFR. Using the clearance of creatinine to estimate GFR, the fraction of filtered solute appearing in the urine may be easily determined by measurement of solute and creatinine concentration in plasma and urine
• FEs = Cs/Ccreat = Us x V/Ps / Ucret x V/ P creat = Us x Pcreat/ Ucreat x Ps
• when in water and Na balance, approximately 1% of the filtered water and Na appears in the urine. In neg water balance FeH20 < 1 while FeNa = 1. In positive water balance FeH20 > 5 while FENa = 1%
• fractional reabsorption is the fraction of filtered water or solute, which is reabsorbed and does not appear in the urine. Fractional reabsorption may be simply quantified as 1- FE. Thus in water and Na balance, approximately 99% of filtered Na and water are reabsorbed

Question 27

Autoregulation of Blood Flow

Answer 27

• renal blood flow is autoregulated across a wide range of mean arterial pressures keeping GFR relatively constant over a wide range of MAP’s. Recall the first principles from the previous hemodynamics lectures
• blood flow in the blood vessels is determined by the ratio of Blood Pressure divided by the Resistance to flow, where resistance to flow is determined by the diameter of the blood vessel BF= BP/R
• when BP rises, BF is kept constant by an increase in resistance to flow or a decrease in the diameter of blood vessel
• low BP is opposite
• myogenic response to increased or decreased pressure resulting in a decrease or increase diameter of the blood vessel
• tubuloglomerural feedback at the macula dense cells sensing an increase or decrease in GFR and causing decreased or increased constriction the afferent arteriole
• autoregulation of renal blood flow is intrinsic to the blood vessels in the kidney and occurs in the absence of kidney innervation