Glomerular Filtration

Renal Anatomy and Physiology Overview

Overview

The GFR is the rate of filtration of plasma through the glomerular membrane. Filtration is 1 of 4 primary mechanisms involved in the regulation of water, electrolytes, and waste excretion:

1. Filtration: Plasma is filtered in the glomerular capillaries, creating a filtrate that passes through the renal tubules.
2. Reabsorption: Desirable solutes and water are reabsorbed from the tubule lumens back into the blood.
3. Secretion: Waste products are intentionally secreted.
4. Excretion: Remaining filtrate is excreted as urine.

Other renal functions:

• Hemodynamic regulation (renin, prostaglandins, bradykinin)
• RBC production (erythropoietin)
• Bone metabolism

Kidney layers

• Cortex: 
  • Outer layer
  • Location of the glomeruli and proximal and distal convoluted tubules
  • Lowest osmolality (approximately 300 mOsm/kg)
• Outer medulla: middle layer, between the cortex and inner medulla
• Inner medulla:
  • Deepest layer
  • Contains the loops of Henle
  • Highest osmolality (up to 1200 mOsm/kg)

Blood flow

The renal blood flow is as follows (in order):

• Aorta → renal artery → interlobar artery → arcuate artery → interlobular artery  
• Afferent arteriole  
• Glomerular capillaries:  
  • Blood is filtered in the glomerular capillaries.
  • The filtrate enters Bowman’s space (ultimately becomes urine).
• Efferent arteriole  
• Peritubular and vasa recta capillaries:  
  • Peritubular capillaries: surround the proximal and distal tubules
  • Vasa recta: surround the loops of Henle
  • Peritubular and vasa recta capillaries are the beginning of venous circulation.
• Interlobular vein → arcuate vein → interlobar vein → renal vein → vena cava

Nephrons

Nephrons are the functional units of the kidney

• Nephron segments (in the order through which the filtrate flows):
  • Bowman’s capsule
  • Proximal convoluted tubule
  • Proximal straight tubule
  • Loop of Henle, further divided into:
    • Thin descending limb
    • Thin ascending limb
    • Thick ascending limb
  • Distal convoluted tubule
  • Collecting duct
• Types of nephrons:
  • Cortical (or superficial): Loops of Henle penetrate only as deep as the outer medulla.
  • Juxtamedullary: 
    • Nephrons whose loops penetrate all the way into the inner medulla
    • Allow for ↑ concentration of the urine (due to ↑ osmolality in the inner medulla)

Definitions

• Renal blood flow (RBF):
  • Rate at which systemic blood is delivered to the kidney
  • Roughly equals 1000 mL/min, or 20%–25% of the cardiac output 
  • The entire blood volume is delivered to the kidneys about every 5 minutes.
• Renal plasma flow (RPF):
  • Portion of RBF that is only plasma (not cells or proteins)
  • This portion of the blood is filtered across the glomerular membrane.
  • RPF (approximate) = RBF × (1 – hematocrit)
  • Approximately 600 mL/min (assuming an RBF of 1000 mL/min and a hematocrit of 40%)
• Filtration fraction (FF):
  • Fraction of the RPF that actually moves across the glomerular membrane 
  • FF = GFR / RPF 
  • Approximately 20% under normal circumstances

Glomerular Filtration Rate

Glomerular filtration rate

The GFR is the volume of plasma filtered by the glomerulus per unit of time. It is the most important laboratory indicator of kidney function.

• Normal GFR = 90–120 mL/min in healthy people
  • Varies with age, sex, and muscle mass
  • Often standardized for body surface area 
  • Is the sum of all filtration rates in all functioning nephrons:
    • Is a rough assessment of the number of functioning nephrons
    • ↓ GFR indicates renal disease.
• Process: 
  • Plasma moves from the glomerular capillaries through the glomerular barrier.
  • The resulting filtrate (the primary urine) collects in Bowman’s space and exits through the tubule lumen.
  • The remaining blood within the capillaries exits through the efferent arteriole.
• Equation 1: GFR = RPF × FF
  • Assume normal parameters: 
    • RPF = 600 mL/min
    • FF = 20%
  • GFR = RPF × FF →  600 mL/min × 20% = 120 mL/min
• GFR is a function of:
  • Renal capillary forces (Starling forces): hydrostatic and oncotic pressure within the capillaries and Bowman’s space
  • Properties of the glomerular barrier 

Starling forces

Equation 2: GFR = K_f [ (P_GC – P_BS) – (π_GC – π_BS) ]:

• K_f: filtration barrier; measure of surface area and glomerular permeability
• P_GC: glomerular capillary hydrostatic pressure
• P_BS: Bowman’s space hydrostatic pressure
• π_GC: glomerular capillary oncotic pressure
• π_BS: Bowman’s space oncotic pressure

Glomerular barrier

The glomerular barrier is the filtration structure of the nephron that surrounds the glomerular capillaries and includes the following 3 layers:

• Capillary endothelium: 
  • Walls of the capillary vessels
  • Fenestrated: contain small windows, approximately 100 nm in size
  • Coated with anionic glycosaminoglycans and glycoproteins
• Glomerular basement membrane (GBM): 
  • Intermediate layer formed by the capillary endothelial and podocyte basal laminas
  • Negatively charged → favors filtration of cations
• Epithelium (podocytes): 
  • Attached to the GBM with multiple foot processes
  • Foot processes interdigitate, forming gaps (or pores) approximately 40 nm in size.
  • Pores are covered by a membrane called the slit diaphragm:
    • A unique form of intercellular junction
    • Consists of multiple proteins, including nephrin 
    • Assists in filtration function

Regulation of the Glomerular Filtration Rate

The kidney has multiple levels of regulatory mechanisms on the GFR: 

• Autoregulation of the renal blood flow overall
• Relative constriction and dilation of the afferent and efferent arterioles
• Tubuloglomerular feedback
• Fine-tuning mechanisms: paracrine, endocrine, and neural

Autoregulation of Renal Blood Flow

Renal blood flow is autoregulated through a localized reflexive process called the myogenic response. 

• Myogenic response: ↑ BP stretches afferent arterioles → activates inward-directed ion channels → depolarization → arteriole contraction
  • ↑ Systemic BP → afferent arteriole vasoconstriction → ↓ RBF
  • ↓ Systemic BP  → afferent arteriole vasodilation → ↑ RBF
• Maintains relatively constant RBF within a range of normal mean arterial BPs (the autoregulatory range)
• Stable RBF allows the other regulatory mechanisms (rather than systemic BP) to regulate the GFR.

Glomerular hemodynamics

The primary regulation of glomerular filtration occurs within the glomerulus itself by constricting and dilating the afferent and efferent arterioles. This affects the hydrostatic pressure within the glomerular capillaries.

• Main parameters:
  • RBF
  • Ultrafiltrate pressure (P_UF), which correlates with glomerular capillary hydrostatic pressure (P_GC)
  • GFR
  • Tubular flow: refers to filtered primary urine leaving Bowman’s space
• Afferent arteriole: 
  • Think in terms of how changing the inflow of blood affects forward pressure.
  • Constriction: 
    • Decreases all parameters 
    • ↓ Inflow → ↓ RBF → ↓ P_UF →↓ GFR → ↓ tubular flow
  • Dilation: 
    • Increases all parameters 
    • ↑ Inflow → ↑ RBF → ↑ P_UF → ↑ GFR → ↑ tubular flow
• Efferent arteriole: 
  • Think in terms of how changing outflow affects backward pressure
  • Constriction: ↓ outflow → ↑ P_UF →  ↑ GFR → ↑ tubular flow but ↓ RBF
  • Dilation: ↑ outflow → ↓ P_UF  → ↓ GFR → ↓ tubular flow but ↑ RBF
• Renin–angiotensin–aldosterone system (RAAS):
  • ↓ BP → ↓ afferent arteriole stretch → triggers release of renin from the juxtaglomerular cells within the afferent arterioles
  • ↑ Renin → ↑ angiotensin I → ↑ angiotensin II:
    • Systemic vasoconstriction → ↑ BP to maintain RBF
    • Vasoconstriction of both the afferent and efferent arterioles but with more constriction of the efferent → ↑ P_GC → ↑ GFR but ↓ in RBF
    • Stimulates aldosterone → ↑ Na and water reabsorption → ↑ in systemic BP and RBF
  • ↑ BP has the opposite effects.

Tubuloglomerular feedback

Macula densa cells within the tubules can sense tubular flow and adjust secretion of substances that affect GFR. This process is called tubuloglomerular feedback.

• Macula densa cells (located in distal tubules):
  • Sense the relative flow of NaCl, which correlates directly with GFR
  • ↑ NaCl flow = ↑ GFR
  • Macula densa cells can:
    • Secrete adenosine
    • Independently stimulate juxtaglomerular cells to secrete renin (activate the RAAS)
• Adenosine: ↓ GFR
  • Constricts afferent arterioles 
  • Dilates efferent arterioles 
• Renin: ↑ GFR (see RAAS above)
• Examples:
  • ↑ GFR → ↑ tubular NaCl flow → macula densa cells sense ↑ flow → release adenosine (and inhibit renin) → GFR ↓ (normalizes)
  • ↓ GFR → ↓ tubular NaCl flow → macula densa cells sense ↓ flow → stimulate the release of renin (and inhibit adenosine) → GFR ↑ (normalizes)

Fine-tuning mechanisms

• Paracrine mechanisms:
  • Arteriole vasoconstrictors (↓ RBF):
    • Endothelins
    • Leukotrienes
  • Arteriole vasodilators (↑ RBF):
    • NO
    • Prostaglandins
• Endocrine mechanisms:
  • Angiotensin II: ↑ glomerular hydrostatic pressure due to preferential constriction of the efferent arteriole → ↑ GFR but ↓ RBF
  • Atrial natriuretic peptide (ANP): vasodilation of the afferent arteriole → ↑ GFR and ↑ RBF
• Neural mechanisms:
  • Sympathetic nervous system–mediated vasoconstriction of arterioles → ↓ RBF
  • Epinephrine, norepinephrine

Clearance

Clearance describes the amount of plasma volume that is completely cleared of a particular substance per unit of time. Clearance equals GFR with substances that are freely filtered (not blocked by the glomerular barrier), not reabsorbed, and not secreted.

Renal clearance formula

C_x = U_x ⋅ V/P_x 

• C_x is the clearance of substance x (e.g., creatinine).
• U_x is the urine concentration of substance x.
• P_x is the plasma concentration of substance x.
• V is the urine flow rate.

Substances used to measure clearance

• Inulin: 
  • A nonendogenous polysaccharide (must be given IV)
  • An ideal indicator for GFR because it is:
    • Freely filtered 
    • Not reabsorbed
    • Not secreted
  • Used for research purposes, but not commonly used in clinical practice

• Creatinine:
  • A by-product of muscle metabolism
  • Good indicator for GFR:
    • Freely filtered
    • Not reabsorbed
    • Small amount secreted: slight tendency to overestimate GFR (because some is cleared by secretion rather than filtration)
  • Clinical standard for GFR estimation and overall kidney function:
    • Endogenous product of muscle metabolism
    • Easily measured on routine blood tests (e.g., basic metabolic panel)
    • Can easily adjust for slight inaccuracy from secretion effect  
• Para-amino hippurate (PAH): 
  • Ideal indicator for RPF (freely filtered, not reabsorbed, fully secreted)
  • Not endogenous (must be given IV)
  • Not commonly used in practice

Clinical Assessment of GFR

24-hour urine collection for creatinine clearance

• Clinical gold standard for GFR assessment 
• Can be impractical: 
  • Patient must be motivated to collect all urine for 24 hours.
  • Takes several days to get results
  • Common to have incomplete urine collections, which are difficult to interpret
• Sometimes done if very accurate GFR measurement is desired (e.g., prior to starting dialysis)

Serum creatinine

Serum creatinine is typically what is used for GFR determination, owing to its ease of collection and rapid turnaround time.

• An inverse logarithmic relationship exists between serum creatinine and GFR.
  • Increase in Cr from 1 to 2 = approximately 50% decrease in GFR, but
  • Increase in Cr from 4 to 5 = relatively small decrease in GFR 
  • Clinical implications:
    • Small changes in serum creatinine must be attended to vigilantly.
    • Dialysis/transplantation are often considered once serum creatinine is consistently > 4 mg/dL.
• Serum creatinine can be falsely elevated: will not have corresponding ↑ in serum BUN
  • ↑ Tubular secretion of creatinine: trimethoprim, cimetidine
  • Lab assay interference: acetoacetate (in diabetic ketoacidosis (DKA)), cefoxitin, flucytosine
  • ↑ Production of creatinine: excessive intake of creatine (dietary supplement), injury to skeletal muscle
• Serum creatinine can have true changes in several common circumstances other than AKI or CKD:
  • Pregnancy:
    • Decreases slightly during 1st and 2nd trimesters
    • Returns to prepregnancy value in 3rd trimester
  • Aging: 
    • Rises very slowly with age
    • GFR can decrease by 0.5–1 mL/min/year in healthy adults.
  • Diabetes:
    • Serum creatinine decreases early in the disease course owing to hyperfiltration.
    • Over time, hyperfiltration causes damage and results in elevated serum creatinine.
  • Very low muscle mass: cirrhosis, malnutrition, amputation: 
    • Often have serum creatinine < 0.5 at baseline
    • GFR equations will overestimate true kidney function.
    • Small changes (e.g., serum creatinine 0.5 → 1) represent severe AKI in these patients (commonly missed by clinicians).

Estimated glomerular filtration rate from serum creatinine

• Most common clinical indicator of GFR
• Several formulas have been developed and validated: 
  • Cockcroft–Gault, Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
  • Input variables: serum creatinine, age, sex, race (correlates with muscle mass)
  • Formulas are accurate only in steady-state conditions: 
    • Accurate in CKD
    • Not accurate in AKI
  • In practice, simple online calculators are used for this formula.
• eGFR is used to stage chronic kidney disease:
  • Stage 1: GFR ≥ 90 mL/min/1.73 m²
  • Stage 2: GFR 60–89 mL/min/1.73 m²
  • Stage 3: GFR 30–59 mL/min/1.73 m²
  • Stage 4: GFR 15–29 mL/min/1.73 m²
  • Stage 5: GFR < 15 mL/min/1.73 m²
• eGFR is also commonly used to adjust drug dosages for kidney function.

Clinical Relevance

Glomerular filtration is most commonly used to assess overall kidney function and to stratify CKD into stages. Additionally, there are specific disease processes of the glomerulus that impair filtration. Diseases are typically categorized as nephrotic (primarily proteinuria) or nephritic (primarily hematuria).

• ANCA vasculitis: This vasculitis is a necrotizing vasculitis affecting small vessels, including the capillaries of the glomerulus.
• Alport syndrome: a genetic condition resulting in abnormal type IV collagen, which affects the GBM, in addition to the cochlea and eye, leading to progressive renal dysfunction, sensorineural hearing loss and ocular abnormalities.
• Anti-GBM disease (Goodpasture’s disease): This rare small-vessel vasculitis with polyclonal circulating antibodies directed against antigens within the GBM results in a rapidly progressive glomerulonephritis and/or alveolar hemorrhage.
• Minimal change disease: a major cause of nephrotic syndrome caused by fusion (retraction, widening, and shortening) of the foot processes in podocytes: The underlying cause of minimal change disease is unclear, but evidence suggests that T-cell dysfunction may play a causative role. Treatment generally involves glucocorticoids.
• Membranous nephropathy: a common cause of nephrotic syndrome resulting from thickening of the GBM due to immune deposits of IgG antibodies directed against antigens on the podocyte foot processes.