Glomerular Filtration

Glomerular Filtration Study Notes

LEARNING OBJECTIVES

• Define the glomerular filtrate.

• Review the determinants of the glomerular filtration rate (GFR).

• Predict how renal plasma flow (RPF) and GFR are affected by auto-regulation.

• Identify the mediators of GFR regulation.

• Calculate clearance and estimation of GFR.

TAKE HOME POINTS

1. The glomerular filtrate is produced by Starling's forces and the intrinsic membrane properties:

   • Starling's Forces:

     • $P_{GC}$: Hydrostatic pressure in the glomerular capillary.

     • $P_{BS}$: Hydrostatic pressure in Bowman Space.

     • $ext{Π}_{GC}$: Oncotic pressure in the glomerular capillary.

   • Intrinsic membrane properties:

     • $S$: Surface area.

     • $L_p$: A permeability constant.

   • Small uncharged molecules pass across the glomerular basement membrane, while larger and especially anionic molecules are reflected.

2. GFR can be represented by the equation:
   $GFR = L_p imes S imes (P_{GC} - (P_{BS} + ext{Π}_{GC}))$

3. A glomerular filtrate is necessary for the kidney’s homeostatic and clearance functions. Despite wide fluctuations in renal plasma flow (RPF), GFR remains somewhat constant through adjustments in the filtration fraction (FF).

   • Filtration Fraction (FF):
     $FF = rac{GFR}{RPF}$

4. FF is controlled through a process called auto-regulation:

   • The afferent arteriole (AA) and the efferent arteriole (EA) can be independently adjusted to control $P_{GC}$:

     • During hypertension and high RPF, AA constriction lowers $P_{GC}$ (and FF) to maintain constant GFR.

     • During hypotension and low RPF, EA constriction increases $P_{GC}$ (and FF) to preserve GFR.

5. AA (like all arterioles) responds reflexively:

   • Constricts at high pressure.

   • Dilates at low pressure.

6. Hormonal influence on regulation:

   • Angiotensin II (AII) and the sympathetic nervous system preferentially constrict EA > AA at low blood pressure, preserving $P_{GC}$.

7. Prostaglandins dilate the AA and prevent AII/SNS-mediated constriction during volume depletion (e.g., Important note: Don't take NSAIDs before marathons).

8. Clearance: Volume of plasma completely cleared of a substance per unit of time calculated as: $C = rac{U imes V}{P}$

   • Where C is clearance, U is concentration of substance in urine, V is urine flow rate, and P is plasma concentration.

9. An ideal filtration marker is freely filtered by the glomerulus with no secretion or reabsorption, meaning its clearance equals GFR.

10. Creatinine clearance: Often used as a GFR marker despite some secretion by the tubule.

    • Several formulas can adjust serum creatinine concentration to estimate GFR (e.g., CKD-EPI, MDRD, Cockcroft-Gault).

GLOMERULAR FILTRATE

• The glomerular capillary features:

  • Increased hydrostatic pressure: highest pressure capillary bed in the body.

  • Increased permeability: nearly 50 times more permeable to water than other capillaries.

  • Interposed between two arterioles: afferent and efferent.

Pressures Involved in Glomerular Filtration

1. Net filtration pressure (PUF) at any point in a capillary equals the sum of opposing pressures:
   $PUF = ΔP - ΔΠ$

   • Where:

     • $ΔP = (P_{GC} - P_{BS})$

     • $ΔΠ = ( ext{Π}<em>{GC} - ext{Π}</em>{BS})$

   • Therefore,
     $PUF = (P_{GC} - P_{BS}) - ( ext{Π}<em>{GC} - ext{Π}</em>{BS})$,
     $PUF = (P_{GC} + ext{Π}<em>{BS}) - (P</em>{BS} + ext{Π}_{GC})$

2. Forces favoring filtration:

   • $P_{GC}$: Glomerular capillary hydrostatic pressure.

   • $ext{Π}_{BS}$: Bowman’s space oncotic pressure.

3. Forces opposing filtration:

   • $P_{BS}$: Bowman’s space hydrostatic pressure.

   • $ext{Π}_{GC}$: Glomerular capillary oncotic pressure.

4. Due to normal conditions (protein-free filtrate), the equation reduces to:
   $PUF ≈ P_{GC} - (P_{BS} + ext{Π}_{GC})$

5. Result from animal studies show:

   • $P_{GC} ext{ (average)} ≈ 49 ext{ mm Hg}$

   • $P_{BS} ≈ 14 ext{ mm Hg}$

   • $ext{Π}_{GC} ≈ 19 ext{ mm Hg}$

   • Hence,
     $PUF = 49 - (14 + 19) = 16 ext{ mm Hg}$

   • Values vary across species, e.g., dogs ≈ 24 mm Hg.

6. Changes in Glomerular Hemodynamics:

   • As protein-free filtrate is lost, oncotic pressure $ext{Π}_{GC}$ increases along the capillary, leading to a decline in PUF.

   • Hydrostatic pressures remain stable due to tubular efflux.

   • Consequently, PUF decreases from high at the afferent to low by the efferent.

MEMBRANE CHARACTERISTICS

1. The glomerular membrane is:

   • Highly permeable to water and low molecular weight solutes (electrolytes, such as $Na^+, K^+, Cl^-$).

   • Relatively impermeable to cells and larger molecules (plasma proteins).

2. Composition of Glomerular Filtrate:

   • Composed of water and electrolytes, with concentrations nearly equal to plasma.

   • Large molecules reflected due to narrow pores in the basement membrane and the slit diaphragm.

   • Anionic molecules reflected due to negative charges in the basement membrane.

3. The ultrafiltration coefficient (Kf) is expressed as:
   $Kf = L_p imes S$

   • Where $L_p$ is permeability and $S$ is surface area.

4. These factors are typically calculated when GFR, $ΔP$, and $ΔΠ$ are known, as Kf is dynamic, changing with mesangial cell contraction due to AII, which reduces S.

5. The GFR equation derived from hemodynamic forces is:
   $GFR = Kf imes PUF$
   or
   $GFR = Kf imes (ΔP - ΔΠ)$
   or
   $GFR = L_p imes S imes (P_{GC} - (P_{BS} + ext{Π}_{GC}))$

6. Filtration Fraction (FF):

   • Defined as the renal plasma flow (RPF) portion filtered by kidneys:
     $FF = rac{GFR}{RPF}$

   • FF tends to increase with reduced RPF due to efferent vasoconstriction maintaining GFR.

   • FF tends to decrease with increased RPF due to afferent vasoconstriction keeping GFR stable.

RELATIONSHIP OF RPF AND GFR

• Lack of GFR means no plasma processing and no homeostatic function.

• Adaptive mechanisms in the kidney aim to preserve GFR against systemic hemodynamic swings.

• Auto-Regulation permits regulation of $P_{GC}$ based on renal perfusion.

General Principles:

1. Factors dilating the afferent arteriole increase both $P_{GC}$ and RPF, consequently raising GFR.

2. Constricting the efferent arteriole reduces RPF but increases GFR via rising $P_{GC}$.

Auto-Regulation of GFR:

1. $P_{GC}$ preservation over various arterial pressures.

2. Importance of afferent tone at high pressures; efferent tone at low pressures.

3. GFR remains consistent through substantial renal artery pressure changes.

MEDIATORS OF GFR REGULATION

Local Factors:

1. Vascular Tone:

   • In the AA, vasoconstriction occurs with increased pressure and vasodilation when pressures drop, maintaining constant RPF and $P_{GC}$ (exact mechanisms are poorly understood).

2. Tubuloglomerular Feedback:

   • Macula densa senses filtrate composition and alters glomerular hemodynamics.

   • Slow flow with low Cl– leads to efferent vasoconstriction and increased FF; fast flow with high Cl– increases afferent constriction and reduces FF.

Hormonal Factors:

1. Angiotensin II (AII):

   • Released by juxta-glomerular apparatus in response to decreased Cl– at macula densa, lowered BP, and β1 sympathetic activity.

   • Activates renin which converts angiotensinogen to angiotensin I, then to AII (by ACE).

   • AII effects:

     • Efferent vasoconstriction enhances $P_{GC}$ and maintains GFR during RPF reductions.

     • Increased systemic vascular tone raises blood pressure.

2. Sympathetic nerves - norepinephrine and epinephrine:

   • Released in baroreflex low BP responses, causing systemic arteriolar constriction (including AA and EA).

   • Greater EA constriction increases $P_{GC}$, elevating GFR while limiting fall due to RPF drop, simulating renin release.

3. Prostaglandins:

   • Released under AII and sympathetic activation.

   • Causes vasodilation in AA, preserving GFR by increasing $P_{GC}$ and maintaining renal blood flow during systemic vasoconstriction.

   • NSAID blockade can substantially reduce GFR in hypoperfusion states (important note against taking NSAIDs pre-exertion).

4. Other Factors:

   • Vasoconstrictors such as vasopressin, endothelin, dopamine.

   • Vasodilators including nitric oxide, dopamine, kinins, ANP; uncertain roles in healthy conditions but critical in pathophysiological states.

MEASURING GFR

• GFR is crucial for kidney function; reductions correlate with kidney damage and uremic symptoms.

Clearance Concept:

• Clearance is the volume of plasma from which a substance is removed per time. Ideal filtration markers are freely filtered, not reabsorbed/secreated, making their clearance equal to GFR: $Filtered\,load = urinary\,excretion\,of\,x\, = P_x \times GFR$ $GFR = rac{U_x V}{P_x}$

  • Inulin, not insulin, is the standard.

1. Creatinine clearance is a common GFR estimate, since it's secreted and overestimates GFR.

2. When clearance equals total RPF, substances fully filtered and secreted are considered (e.g., PAH).

Estimating GFR:

1. Normal human GFR: 120 ml/min or 180 liters/day; ultrafilters plasma volume ~60 times daily.

   • GFR declines post age 35-40, varies between genders.

2. Techniques for Estimating GFR:

   • Ideal filtration marker criteria:

     • Freely filtered, not secreted or absorbed by tubule.

     • Inexpensive, readily available, non-toxic, measurable.

   • Inulin clearance:

     • Gold standard, but expensive and limited accuracy due to measurement precision, requires intravenous infusion.

   • Creatinine clearance:

     • Timed urine collection with plasma levels, overestimation due to secretion, but benefits from being endogenous and no infusion needed.

   • Serum creatinine:

     • Easy measurement; determined by muscle mass and diet, sharing creatinine clearance issues.

   • Formulas to estimate GFR:

     • $GFR ext{ (parabolic to linear conversion)} = rac{1}{ ext{serum creatinine}}$

     • Cockcroft and Gault:
       $Cr\,Cl = rac{(140 - ext{age}) imes ( ext{weight in kg}) imes (0.85 ext{ if female})}{72 imes ext{serum creatinine}}$

     • CKD-EPI 2021 equation:
       GFR = 142 imes ext{min}igg( rac{Scr}{κ},1igg)^ ext{α} imes ext{max}igg( rac{Scr}{κ},1igg)^{-1.200} imes 0.9938^ ext{age} imes 1.012 ext{ (if female)}

   • Radionucleotide scan:

     • Expensive, varied accuracy.

   • Cystatin C:

     • Endogenous molecule promoting filtration without appearing in urine; plasma levels correlate with GFR, less influenced by age/sex.

     • Earlier estimating equations wrongfully included race, but 2021 CKD-EPI equation maintained GFR accuracy while removing race from consideration.

SUMMARY

• Kidney functions depend on glomerular filtrate formation driven by local forces ($P_{GC}$, $ext{Π}<em>{GC}$, $P</em>{BS}$) and membrane intrinsic properties.

• GFR is maintained despite changes in perfusion pressure via local and systemic control systems involving vasoactive mediators at arterioles.

• Various measurement and estimation methods help assess GFR, critical in understanding renal disease and dysfunction.