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Clinical Pathology

Clearance Tests to Measure Glomerular Filtration Rate (GFR)

By Dayyal Dg.Twitter Profile | Updated: Saturday, 30 December 2023 00:09 UTC
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Free vector hand drawn urology illustration. Freepik / @freepik

Glomerular filtration rate (GFR) represents the rate in ml/min at which a substance is effectively cleared from the bloodstream by the glomeruli. The evaluative measure of the glomeruli's ability to filter a substance from the blood is conducted through clearance studies. If a substance is unbound to plasma proteins, undergoes complete filtration by the glomeruli, and experiences neither tubular secretion nor reabsorption, its clearance rate aligns with the glomerular filtration rate.

The clearance of a substance denotes the volume of plasma entirely purged of that substance per minute, calculated using the formula:

Clearance = UV⁄P

Here, U signifies the concentration of the substance in urine in mg/dl; V denotes the volume of excreted urine in ml/min; and P represents the concentration of the substance in plasma in mg/dl. Given that U and P share the same units, they mutually nullify, rendering the clearance value expressed in the same unit as V, i.e., ml/min. All clearance values are standardized to a standard body surface area of 1.73 m2.

The substances employed for gauging glomerular filtration rate (GFR) encompass:

  • Exogenous: Inulin, Radiolabelled ethylenediamine tetraacetic acid (51Cr- EDTA), 125I-iothalamate
  • Endogenous: Creatinine, Urea, Cystatin C

The selected agent for GFR measurement should exhibit the following properties: (1) Physiological inertness, preferably endogenous nature, (2) Unrestricted filtration by glomeruli without reabsorption or secretion by renal tubules, (3) No binding to plasma proteins and resistance to renal metabolism, and (4) Sole excretion by the kidneys. However, an entirely ideal endogenous agent remains elusive.

Conducting clearance tests proves to be intricate, costly, and not readily accessible. A significant challenge in clearance studies lies in the potential for incomplete urine collection.

Anomalous clearance patterns manifest in: (i) pre-renal factors such as diminished blood flow due to shock, dehydration, and congestive cardiac failure; (ii) renal diseases; and (iii) obstruction in urinary outflow.

Inulin Clearance

Inulin, an inert plant polysaccharide (a fructose polymer), undergoes glomerular filtration without reabsorption or secretion by the renal tubules, rendering it an ideal agent for GFR measurement. The procedure involves administering a bolus dose of inulin (25 ml of 10% solution IV), followed by a constant intravenous infusion (500 ml of 1.5% solution at a rate of 4 ml/min). Timed urine samples are collected, and blood samples are obtained at the midpoint of the timed urine collection. Widely recognized as the 'gold standard' or reference method for GFR estimation, this test is seldom employed due to its time-consuming nature, high cost, the requirement for continuous intravenous inulin infusion to maintain a steady plasma level, and challenges in laboratory analysis. The average inulin clearance is 125 ml/min/1.73 m2 for males and 110 ml/min/1.73 m2 for females. Clearance tends to be lower in children under 2 years and older adults. Primarily reserved for clinical research, this test is not commonly utilized in routine clinical practice.

Clearance of Radiolabeled Agents

Urinary clearance of radiolabeled iothalamate (125Iiothalamate) exhibits a close correlation with inulin clearance. Nevertheless, this technique is associated with high costs and potential exposure to radioactive substances. Alternative radiolabeled substances employed for similar purposes include 51Cr-EDTA and 99Tc-DTPA.

Cystatin C Clearance

Cystatin C, a cysteine protease inhibitor with a molecular weight of 13,000, is consistently synthesized by all nucleated cells at a constant rate. Unbound to proteins, it undergoes free filtration by glomeruli and is not reabsorbed into circulation post-filtration. Demonstrating greater sensitivity and specificity for impaired renal function than plasma creatinine, cystatin C serves as a marker unaffected by factors like sex, diet, or muscle mass. Many consider cystatin C superior to creatinine clearance as an estimator of GFR. Its measurement is typically conducted through immunoassay techniques.

Creatinine Clearance

The most widely employed method for assessing GFR is through creatinine clearance testing.

Creatinine, a continuous byproduct of muscle creatine, undergoes complete filtration by glomeruli and experiences negligible reabsorption by tubules, with a minor portion being tubularly secreted.

A 24-hour urine sample is the preferred collection method, mitigating issues related to diurnal variations in creatinine excretion and enhancing collection accuracy.

The procedure involves discarding the initial morning void and subsequently collecting all subsequent urine in the provided container. The next morning, the first voided urine is also collected, and the container is submitted to the laboratory. Simultaneously, a blood sample is drawn at the midpoint of the urine collection period to estimate plasma creatinine levels. Creatinine clearance is calculated using the following parameters: (1) creatinine concentration in urine in mg/ml (U), (2) volume of urine excreted in ml/min (V) – calculated as the volume of urine collected per the collection time in minutes (e.g., volume of urine collected in 24 hours ÷ 1440), and (3) creatinine concentration in plasma in mg/dl (P). The resulting creatinine clearance in ml/min per 1.73 m2 is derived from the formula UV/P.

Due to tubular secretion of creatinine, this formula tends to overestimate GFR by approximately 10%. In cases of advanced renal failure, where tubular secretion of creatinine is heightened, the overestimation of GFR becomes even more pronounced.

Jaffe's reaction, utilized for estimating creatinine (refer to serum creatinine), measures creatinine as well as other substances (non-creatinine chromogens) in the blood, resulting in a slightly elevated outcome. Consequently, the impact of tubular secretion of creatinine is somewhat counteracted by the minor overestimation of serum creatinine facilitated by Jaffe's reaction.

To yield values closer to the actual GFR, cimetidine, a substance that impedes secretion by renal tubules, can be administered before initiating urine collection, a method known as cimetidine-enhanced creatinine clearance.

Creatinine clearance, while widely used, possesses certain limitations for GFR estimation due to the following factors:

  1. A small amount of creatinine is secreted by renal tubules, a phenomenon accentuated in advanced renal failure.
  2. Urine collection is frequently incomplete.
  3. Creatinine levels are influenced by meat intake and muscle mass.
  4. Certain drugs, such as cimetidine, probenecid, and trimethoprim (which impede tubular secretion of creatinine), can affect creatinine levels.

Urea Clearance

Urea undergoes filtration in the glomeruli; however, approximately 40% of the filtered amount is reabsorbed by the tubules. The extent of reabsorption is contingent upon the rate of urine flow, leading to an underestimation of GFR. Urea's reliance on urine flow rate renders it less sensitive as an indicator of GFR.

When considered independently, Blood Urea Nitrogen (BUN) and serum creatinine lack sensitivity in detecting early renal impairment, as their values may register as normal. For instance, if the baseline value of serum creatinine is 0.5 mg/dl, a 50% reduction in kidney function would elevate it to 1.0 mg/dl. Therefore, clearance tests prove more beneficial in early-stage cases. In situations where biochemical tests yield normal results but renal function impairment is suspected, a creatinine clearance test becomes imperative. Conversely, if biochemical tests reveal abnormalities, clearance tests may be omitted.

What is the Difference Between GFR and eGFR?

GFR (Glomerular Filtration Rate) and eGFR (estimated Glomerular Filtration Rate) are both measures used to assess kidney function, but they have some differences. GFR is a direct measure of kidney function, while eGFR is an estimated value calculated using formulas based on serum creatinine and other factors. eGFR is more commonly used in clinical practice due to its convenience, but it's important to note that direct measurement of GFR is considered more accurate when feasible.

Difference Between GFR and eGFR.
AspectGFR (Glomerular Filtration Rate)eGFR (estimated Glomerular Filtration Rate)
Defination GFR is a measure of the volume of fluid that is filtered by the glomeruli per unit of time. It is considered the gold standard for assessing kidney function. eGFR is an estimated value of the GFR, often calculated using mathematical formulas that take into account serum creatinine levels, age, gender, and sometimes race.
Measurement GFR is usually measured directly through a clearance test, where a substance (such as inulin or creatinine) is introduced into the body, and its rate of clearance in the urine is measured. eGFR is calculated using formulas based on serum creatinine levels, age, gender, and other factors. Commonly used formulas include the Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
Accuracy Direct measurement of GFR is considered more accurate, but it may not be practical for routine clinical use. eGFR is an estimation and may not be as accurate as direct measurement. However, it is widely used in clinical practice due to its convenience and cost-effectiveness.
Clinical Use GFR is used to assess overall kidney function and is a crucial parameter in diagnosing and monitoring kidney diseases. eGFR is a commonly used clinical parameter for assessing kidney function, especially in routine blood tests. It is often reported alongside serum creatinine levels.

References

  • Gaw A, Murphy MJ, Cowan RA, O’Reilly DSJ, Stewart MJ, Shepherd J. Clinical Biochemistry: An Illustrated Colour Text (3rd Ed). Edinburgh: Churchill Livingstone 2004.
  • Johnson CA, Levey AS, Coresh J, Levin A, Lau J, Eknoyan G. Clinical practice guidelines for chronic kidney disease in adults: Part II. Glomerular filtration rate, proteinuria, and other markers Am Fam Physician 2004;70:1091-7.
  • Stevens LA, Coresh J, Green T, Levey AS. Assessing kidney function-measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473-83.
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