Glomerular Filtration

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 Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. 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 Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. 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 Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. 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 Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. 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 Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface 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 Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm:
    • A unique form of intercellular junction
    • Consists of multiple proteins, including nephrin 
    • Assists in filtration function

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 Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of 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 Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim, cimetidine
  • Lab assay interference: acetoacetate (in diabetic ketoacidosis Diabetic ketoacidosis Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises ( DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises)), cefoxitin, flucytosine Flucytosine Flucytosine is a pyrimidine analog that disrupts fungal DNA and RNA synthesis. Flucytosine is always used in combination with other antifungal agents and is primarily used to treat cryptococcal meningitis. Flucytosine, Griseofulvin, and Terbinafine
  • ↑ 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 AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury or CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease:
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care:
    • 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 Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries, amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. 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 AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury 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 Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease Epidemiology Collaboration ( CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease-EPI)
  • Input variables: serum creatinine, age, sex, race (correlates with muscle mass)
  • Formulas are accurate only in steady-state conditions: 
    • Accurate in CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
    • Not accurate in AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury
  • 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 CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease 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 Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries of the glomerulus.
• Alport syndrome Alport Syndrome Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular and auditory findings. 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 Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss and ocular abnormalities.
• Anti-GBM disease (Goodpasture’s disease): This rare small-vessel vasculitis with polyclonal circulating antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins directed against antigens within the GBM results in a rapidly progressive glomerulonephritis Rapidly Progressive Glomerulonephritis Rapidly progressive glomerulonephritis (RPGN) is a syndrome of severe glomerular disease with progressive loss of kidney function within weeks to months. Histologically, crescents (the proliferation of epithelial cells and the infiltration of monocytes/macrophages in the Bowman space) are found in the glomeruli and arise from immunologic injury. Rapidly Progressive Glomerulonephritis and/or alveolar hemorrhage.
• Minimal change disease Minimal change disease Minimal change disease (MCD), also known as lipoid nephrosis, is the most common cause of nephrotic syndrome in children. The designation "minimal change" comes from the very little changes noticed in kidney biopsies under light microscopy. Hallmark clinical findings include edema, proteinuria, hypoalbuminemia, and hyperlipidemia. Minimal Change Disease: a major cause of nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. 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 Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids.
• Membranous nephropathy: a common cause of nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome resulting from thickening of the GBM due to immune deposits of IgG antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins directed against antigens on the podocyte foot processes.