Glomerular Filtration Rate (GFR)

Glomerular Filtration Rate (GFR)

• GFR represents the rate at which filtrate forms across all nephrons
• Normal GFR is 125 mL/min, equating to about 180L/day
• GFR can be estimated via inulin clearance measurements

Factors Influencing Glomerular Filtration

• Filtration is promoted by capillary hydrostatic pressure, which is enhanced by increased capillary hydrostatic pressure
• Afferent arteriole constriction reduces glomerular filtration
• Glomerular filtration is reduced by a marked decrease in blood pressure, such as during hemorrhage or shock
• Opposing effective filtration at the glomerulus due to pressure from plasma proteins and blood colloids
• Increased colloidal osmotic pressure in the afferent arteriole or glomerulus decreases GFR
• Reduced blood dilution, or hypoproteinemia, raises colloidal osmotic pressure, increasing effective filtration pressure and GFR
• Bowman's capsule hydrostatic pressure opposes filtration of fluid at the glomerulus
• Increased Bowman's capsule pressure, seen with urinary tract obstructions from renal calculi, reduces GFR
• The filtration rate is inversely related to the thickness of the filtration membrane; a thicker membrane means lower filtration

Filtration Membrane Surface Area

• Filtration rate depends on the membrane's surface area
• Increased surface area enhances filtration
• Conditions like renal diseases or partial nephrectomy that reduce the size of the glomerular capillary bed reduce glomerular filtration

Afferent and Efferent Arteriole Size

• Glomerular capillary hydrostatic pressure relies on the relative sizes of the afferent and efferent arterioles
• The efferent arteriole is normally narrower and longer than the afferent arteriole, restricting outward blood flow from glomerular capillaries
• Increased hydrostatic pressure in the glomerular capillary is due to anatomical differences
• Constricting the efferent arteriole while dilating the afferent arteriole enhances glomerular capillary hydrostatic pressure and GFR

Solute Size

• Electrolytes (like sodium) and organic substances (like glucose) are freely filtered
• Filtration rate is inversely proportional to molecule size where filtration declines with increasing molecule size

Sympathetic Stimulation

• Mild-to-moderate sympathetic nervous system stimulation has minimal impact on renal blood flow and GFR
• Strong sympathetic stimulation reduces blood flow and GFR by constricting renal arterioles
• During severe autonomic disturbances from acute hemorrhage and brain ischemia, the sympathetic system is key in reducing GFR

Protein Intake and Blood Glucose

• High protein intake and increased blood glucose levels increase renal blood flow, increasing GFR

Hormonal Control

• A significant increase in epinephrine and norepinephrine levels constricts both afferent and efferent arterioles
• This results in reduced renal blood flow

Barriers for Filtration

• Filtration has two significant barriers:
  • Mechanical or structural barrier
  • Electrical barrier

Mechanical Barrier

• The glomerular basement membrane is the primary mechanical barrier
• Larger particles are restricted by pores in the epithelial lining of the capsule and the endothelium of the blood vessel
• Smaller particles are filtered freely

Electrical Barrier

• Bowman's capsule cells and basement membrane have a negative charge, repelling negatively charged blood particles
• Albumin, a large, negatively charged protein, is repelled by this barrier, so only a minimal amount enters the filtrate
• Molecules larger than 4 nm cannot enter the filtrate due to these two barriers
• Proteinuria, caused by large amounts of filtered protein (mainly albumin), results from the loss of negative charge due to renal diseases or advanced diabetic nephropathy

GFR Measurement

• Inulin clearance measures GFR
• A substance used in GFR measurement should:
  • Be filtered freely
  • Not be secreted nor absorbed
  • Be nontoxic
  • Not alter kidney function

Inulin Clearance and Glomerular Filtration Rate

• Inulin is introduced intravenously and plasma levels are maintained with continuous infusion
• When the inulin reaches equilibrium, urine and plasma samples are collected
• Inulin concentration analysis informs GFR estimation

Principle

• Amount of inulin filtered (P x GFR) equals the amount excreted (U x V)
• P x GFR = U x V
• Where P is inulin concentration in plasma, GFR is glomerular filtration rate, U is inulin concentration in urine, and V is urine volume produced per unit time
• GFR = (U x V) / P

Creatinine Clearance

• Metabolism of muscle creatine and creatine phosphate produces Creatinine
• Urinary creatinine comes from endogenous sources
• Creatinine is not absorbed in the renal tubule, but a small amount is secreted there
• Creatinine clearance is slightly higher than inulin clearance
• Produced in the body and easy to measure, creatinine clearance is routinely used for GFR measurement
• Due to secretion in the nephron, creatinine clearance may exceed the actual GFR

Measurement of GFR Using Radioactive Tracers

• GFR can be accurately measured using radioactive substances, such as chromium-51 and technetium-99m

Variations in GFR

• Conditions that reduce GFR:
  • Blood pressure below 60 mm Hg
  • Circulatory shock
  • Erect posture
  • Emotion
  • Pain
  • Exercise
  • Cold
  • Blood loss
  • Pathological processes destroying the nephron
• Extracellular fluid and blood volume increases raise GFR, as happens with saline administration
• Infusion of saline dilutes plasma and reduces colloidal osmotic pressure

Filtration Fraction

• Filtration fraction, with a normal value of about 20%, is the ratio of glomerular filtration rate to renal plasma flow (RPF)
• Filtration fraction = GFR / RPF

Filtered Load

• The amount of any solute filtered per minute.

Renal (Plasma) Clearance

• Renal clearance of a substance in the volume of plasma fully cleared of that substance by both kidneys per unit time
• Clearance = Mass of substance excreted per unit time / Plasma concentration of the substance

Urea Clearance

• Urea clearance is the plasma volume from which urea is removed per minute, and can be:
  • Maximal (urine output exceeds 2 mL/min)
• Calculated as: Maximal urea clearance = (U x V) / P with a normal value of 75 mL/min
  • Standard (urine output less than or equal to 2 mL/min)
• Calculated as: Standard urea clearance = (U x V) / P with a normal value of 54 mL/min

Para-Amino Hippuric Acid Clearance

• Para-amino hippuric acid (PAH) clearance measures renal plasma flow
• PAH is freely filtered and fully excreted with its concentration measured in plasma and urine after intravenous infusion
• About 90% of PAH is cleared
• PAH clearance is calculated to derive effective renal plasma flow, with 90% or 0.9 extraction ratio
• Actual renal plasma flow = Effective renal plasma flow/ Extraction ratio

Renal Blood Flow

• Renal blood flow is calculated from the hematocrit value and the actual renal plasma flow
• Renal blood flow = RPF x [100 / (100 - Hematocrit)]
• Normal renal plasma flow is approximately 600-650 mL/min
• Normal renal blood flow is approximately 1100-1200 mL/min

Hydrogen Ions

• Hydrogen ions are also secreted in exchange for sodium ions, helping to retain sodium, which has physiological advantages and usefulness fot he body
• Secretion is carried out by secondary active transport called counter-transport
• During counter-transport, energy released by movement of one substance is used to transport another for something against the gradient
• It is done with a specific protein: Sodium-hydrogen exchanger

Drugs

• Some drugs are secreted in the PCT and removed quickly posing challenge to plasma concentration
• Penicillin and salicylates are cleared in the Kidney

Glomerular Function Alterations

• Damage of glomeruli destroys the basement membrane
• Kidney synthesizes bicarbonate ions
• Causes protein leakage in the filtrate and hence proteinuria

Renal Hypertension

• Reduced perfusion pressure is from the reduction of renal pressure that stimulates angiotensin II and the release of renin
• Increases the risk of hypertension
• Can lead to arteriosclerotic stenosis and administration of ACE Inhibitors which can lower levels of Angiotensin

Countercurrent Mechanism

• Using U-shaped tube system with fluid moving in opposite to concentrate urine