EVALUATION OF GLOMERULAR FILTRATION RATE

Among the many physiologic roles of the renal system, GFR is considered the best indicator of overall kidney function and therefore its assessment has become an important clinical tool in the daily care of patients. GFR cannot be measured directly, but instead it can be assessed by the renal clearance of filtration markers.¹ The total kidney GFR is the sum of the filtration rates of all single functional nephrons—that is, it is determined by the total number of functional nephrons. Because of its highly dynamic and adaptive nature, despite initial structural damage to the renal parenchyma (i.e., reduction in functional nephron number), an individual’s total GFR may not proportionally decrease because of the compensatory features of the remaining renal units, enabling the kidneys to maintain kidney function temporarily despite the loss of functional tissue. Moreover, the GFR may also be affected in the absence of parenchymal renal disease because of hemodynamic, pharmacologic factors, or both. The clinical assessment of GFR can aid the clinician in measuring the degree of renal dysfunction, progression of established kidney disease, or both; however, it is not informative in the determination of the cause of kidney disease, making it imperative to interpret the GFR in the context of the clinical setting.

The GFR can be determined from the renal clearance of a marker that achieves stable plasma concentration, is inert, and is freely filtered by the glomeruli but not reabsorbed, secreted, or metabolized.^1,² Such an ideal endogenous marker does not exist. Serum creatinine, one of the clinically useful analytes (others are serum urea and, more recently, serum cystatin C), has long been used by clinicians as a marker of renal function. However, it is important to emphasize that often the isolated use of serum creatinine concentration may not reflect the actual degree of kidney function of a particular subject. This is because multiple factors affect the concentration of serum creatinine (Table 1) and that the inverse relation between serum creatinine and GFR is nonlinear, particularly when patients have near-normal renal function (Fig. 1). An alternative to this approach is the measurement of creatinine clearance. This determination does not require highly trained personnel or expensive assays and can be performed by standard laboratories. However, this approach is limited by the difficulties in obtaining accurate urine collections and its potential misinterpretation because of the large biologic variability of creatinine metabolism in various clinical settings, including the unpredictable level of creatinine secretion at different levels of GFR. This method, however, is widely available and familiar to the health care community. On the other hand, more exact methods of GFR measurement, such as the clearance of exogenous markers such as inulin or renally excreted isotopes, are expensive and usually not readily available. More novel serum measurements of analytes, such as cystatin C, are under investigation and are not yet fully validated in all clinical settings; therefore, this approach remains a research tool at present.

Table 1 Factors Affecting Serum Creatinine Concentration

Factor	Effect on Serum Creatinine Level	Comment
Demographics
Aging	Decreased	Caused by decline in muscle mass
Female sex	Decreased	Reduced muscle mass
Ethnicity*
African American	Increased	Higher average muscle mass in African Americans
Hispanic	Decreased
Asian	Decreased
Body Habitus
Muscular	Increased	Increased muscle mass
Muscle wasting, amputation, malnutrition	Decreased	Reduced muscle mass ± decreased protein intake
Obesity	No change	No change in muscle mass
Diet
Vegetarian	Decreased	Decrease in creatinine generation
Ingestion of cooked meats	Increased	Transient increase in creatinine generation
Medications, Endogenous Substances
Cimetidine, trimethoprim, probenecid, potassium-sparing diuretics	Increased	Reduced creatinine tubular secretion
Ketoacids, ascorbic acid, glucose, some cephalosporins	Increased	Interference with alkaline picrate assay (Jaffé reaction) for creatinine
Bilirubin, hemoglobin	Decreased	Interference with alkaline picrate assay (Jaffé reaction) for creatinine
Flucytosine, praline, hemoglobin	Increased	Interference with enzymatic assays for creatinine
Metamizole, methyldopa, ethamsylate	Decreased	Interference with enzymatic assays for creatinine

* Whites used as reference group.

Figure 1 Relation between serum creatinine levels and measured glomerular filtration rate (GFR) by 125I-iothalamate GFR among black and white men (A) and women (B).

Note how a significant decrease in GFR can occur, despite normal or near-normal serum creatinine values.

(From Levey AS, Bosch JP, Lewis JP, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461-470.)

Rapid estimation of GFR by using creatinine-based mathematical equations is an attractive alternative to the clinician. These models rely on the inverse relation of serum creatinine with GFR, along with adjustment factors for measurable determinants of serum creatinine concentration (e.g., age, sex, body size, race).

CREATININE-BASED ESTIMATION EQUATIONS

Numerous kidney function estimation equations, used to estimate creatinine clearance or GFR, have been published over the past few decades. However, the most commonly used formulas, the Cockcroft-Gault formula and the modification of diet in renal disease (MDRD) study equation, have been recommended by the KDOQI practice guidelines to be used for the estimation of GFR. These equations rely heavily on the reciprocal relation between serum creatinine and GFR but also incorporate demographic and anthropometric variables to complement the GFR estimation derived from the use of serum creatinine alone. It is important to emphasize that these mathematical models will reflect the clinical setting used to originate them.³

Cockcroft-Gault Formula

The Cockcroft-Gault formula was developed in 1976 with data from 249 men, primarily in an inpatient setting, with a wide range of renal function.⁴ It uses age, the inverse of serum creatinine, and lean body weight to estimate creatinine clearance in milliliters per minute (Box 1); it was not originally intended to be adjusted for body surface area (BSA). The inclusion of the weight factor is intended to adjust for muscle mass, a determinant of serum creatinine concentration. This implies that in clinical situations in which a change in weight is not the result of a similar change in muscle mass (e.g., edematous states, pregnancy, third spacing, overweight, obesity), the weight factor will adversely affect the performance of this formula. Because the original mathematical model was derived from data obtained predominantly in a male population, an arbitrary adjustment for female sex by a factor of 0.85 was incorporated. This equation has become popular because of its simple mathematical formulation and bedside applicability. It is important to note that this formula estimates creatinine clearance; this is known to overestimate GFR because of tubular secretion of creatinine, which is not adjustable.

Box 1 Creatinine-based Glomerular Filtration Rate (GFR) Estimation Equations

Cockcroft-Gault formula = ([140 − age] × weight)/(72 × SCr)*

Abbreviated MDRD equation = 186 × (SCr^−1.154) × (age^−0.203)^†

Re-expressed MDRD equation ^‡ = 175 × (SCr^−1.154) × (age^−0.203)^†

Note: Weight in kilograms, age in years.

MDRD, modification of diet in renal disease; SCr, serum creatinine level, expressed in mg/dL.