Estimating GFR

MDRD Study Equation

Because mild and moderate kidney injury is poorly inferred from serum creatinine alone, NKDEP strongly encourages clinical laboratories to routinely estimate glomerular filtration rate (GFR) and report the value when serum creatinine is measured for patients 18 and older, when appropriate and feasible. An estimated GFR (eGFR) calculated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) Study equation is a simple and effective way in which laboratories can help health care providers detect CKD among those with risk factors—diabetes, hypertension, cardiovascular disease, or family history of kidney disease. Providers also may use eGFR to monitor patients already diagnosed with CKD.

The following is the IDMS-traceable MDRD Study equation (for creatinine methods calibrated to an IDMS reference method)

GFR (mL/min/1.73 m²) = 175 × (S_cr)^-1.154 × (Age)^-0.203 × (0.742 if female) × (1.212 if African American)

The equation does not require weight or height variables because the results are reported normalized to 1.73 m² body surface area, which is an accepted average adult surface area.

Laboratories should program their information systems to use the MDRD Study equation to automatically estimate and report GFR for patients ages 18 and older, when appropriate and feasible.

Rationale for Use

There are several reasons for using the MDRD Study equation to estimate GFR, including:

• The normal serum creatinine reference interval does not necessarily reflect a normal GFR for a patient. Because the MDRD Study equation employs age, gender, and race, providers may observe that CKD is present despite a serum creatinine concentration that appears to fall within or just above the normal reference interval.
• The MDRD Study equation is the most thoroughly validated equation. The equation has been validated extensively in Caucasian and African American populations between the ages of 18 and 70* with impaired kidney function (eGFR < 60 mL/min/1.73 m²) and has shown good performance for patients with all common causes of kidney disease¹.
• The MDRD Study equation is currently superior to other methods of approximating GFR. Direct comparison of the MDRD to other equations such as Cockcroft-Gault^{1, 2} and to creatinine clearance measured from 24-hour urine collections has demonstrated this superiority³. Note that creatinine clearance should be considered when the patient's basal creatinine production is very abnormal. This may be the case with patients of extreme body size or muscle mass (e.g., obese, severely malnourished, amputees, paraplegics, or other muscle-wasting diseases), or with unusual dietary intake (e.g., vegetarian, creatine supplements).
• Measurement of kidney function (eGFR or creatinine clearance) is essential once albuminuria is discovered.

When Not to Use the MDRD Equation

The MDRD Study equation is not for all patients. Although an excellent tool for assessing kidney function, eGFR derived from the MDRD Study equation may not be suitable for all populations. MDRD-based estimates of GFR, like all creatinine-based estimates of kidney function (e.g., Cockcroft-Gault, reciprocal of serum creatinine), are only useful when renal function is stable; serum creatinine values obtained while kidney function is changing will not provide accurate estimates of kidney function.

Additionally, the equation is not recommended for use with:

• Nonadults. This includes all individuals under the age of 18. The Schwartz equation should be used to estimate GFR for infants, toddlers, children, and teens under age 18.
• Individuals with unstable creatinine concentrations. This includes pregnant women; patients with serious co-morbid conditions; and hospitalized patients, particularly those with acute renal failure. The MDRD Study equation should be used only for patients with stable creatinine concentrations.
• Persons with extremes in muscle mass and diet. This includes, but is not limited to, individuals who are amputees, paraplegics, bodybuilders, or obese; patients who have a muscle-wasting disease or a neuromuscular disorder; and those suffering from malnutrition, eating a vegetarian or low-meat diet, or taking creatine dietary supplements.

Application of the equation to these patient groups may lead to errors in GFR estimation⁴. GFR estimating equations have poorer agreement with measured GFR for ill hospitalized patients⁵ and for people with near normal kidney function¹ than for the patients in the MDRD Study.

*The equation has not been validated in patients older than 70, but an MDRD-derived eGFR may still be a useful tool for providers caring for patients older than 70.

As noted above, providers should exercise judgment regarding clinical status when presented with an MDRD Study-derived eGFR for a patient with an unstable creatinine level or other condition for which the equation is not suitable. Providers may not understand that estimating equations like the MDRD are derived from large populations of patients and provide the best estimate of mean GFR for a group of people of a certain age, race, gender, and serum creatinine value. Thus, the reported eGFR is the best estimate of a patient's GFR; it is not the patient's actual GFR.

Reduce Rounding Errors

NKDEP recommends using serum creatinine values in mg/dL to two decimal places (e.g., 0.95 mg/dL) OR values in µmol/L to the nearest whole number (e.g., 84 µmol/L) when calculating eGFR using the MDRD Study equation. This practice will reduce rounding errors that may contribute to imprecision in the eGFR value.

The CKD-EPI Equation

The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is a new equation, published in 2009, to estimate glomerular filtration rate (GFR) from serum creatinine, age, sex, and race for adults age ≥ 18 years ¹. The National Kidney Disease Education Program has not made a recommendation on general implementation of this equation. The equation is still being validated and, while offering some improvement for eGFR between 60 and 120 mL/min/1.73 m², it is not clear that implementing CKD-EPI in place of the Modification of Diet in Renal Disease (MDRD) equation would alter clinical detection or management of patients with CKD. However, a laboratory that reports eGFR numeric values > 60 mL/min/1.73 m² should consider using the CKD-EPI equation. Although the CKD-EPI equation is, on average, more accurate for values > 60 mL/min/1.73 m² than is the MDRD Study equation, the influence of imprecision of creatinine assays on the uncertainty of an eGFR value is greater at higher eGFR values and should be considered when determining the highest eGFR value to report.

The equation is based on the same four variables as the MDRD Study equation but uses a 2-slope "spline" to model the relationship between GFR and serum creatinine, age, sex, and race. The equation is given in the following table for creatinine in mg/dL (see Appendix for creatinine in µmol/L). The equation can be expressed in a single equation (see table legend) or as a series of equations for different race, sex, and creatinine conditions (see table rows).

Table 1: CKD EPI Equation for Estimating GFR Expressed for Specified Race, Sex and Serum Creatinine in mg/dL (From Ann Intern Med 2009;150:604-612, used with permission)

Race	Sex	Serum Creatinine, Scr (mg/dL)	Equation (age in years for ≥ 18)
Black	Female	≤ 0.7	GFR = 166 × (Scr/0.7)-0.329 × (0.993)Age
Black	Female	> 0.7	GFR = 166 × (Scr/0.7)-1.209 × (0.993)Age
Black	Male	≤ 0.9	GFR = 163 × (Scr/0.9)-0.411 × (0.993)Age
Black	Male	> 0.9	GFR = 163 × (Scr/0.9)-1.209 × (0.993)Age
White or other	Female	≤ 0.7	GFR = 144 × (Scr/0.7)-0.329 × (0.993)Age
White or other	Female	> 0.7	GFR = 144 × (Scr/0.7)-1.209 × (0.993)Age
White or other	Male	≤ 0.9	GFR = 141 × (Scr/0.9)-0.411 × (0.993)Age
White or other	Male	> 0.9	GFR = 141 × (Scr/0.9)-1.209 × (0.993)Age

CKD-EPI equation expressed as a single equation:

GFR = 141 × min (S_cr /κ, 1)^α × max(S_cr /κ, 1)^-1.209 × 0.993^Age × 1.018 [if female] × 1.159 [if black] where S_cr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of S_cr /κ or 1, and max indicates the maximum of
S_cr /κ or 1.

Equation Performance

As shown in the figure below, the CKD-EPI equation was as accurate as the MDRD Study equation in a subgroup with estimated GFR (eGFR) less than 60 mL/min/1.73 m² and more accurate in a subgroup with eGFR between 60 and 120 mL/min/1.73 m². However, the receiver operator curves (ROC) for detecting GFR categories less than 90, 75, 60, 45, 30 and 15 mL/min per 1.73 m² did not differ between the CKD-EPI and MDRD Study equations^{1, 2}.

Figure 1. Accuracy of the CKD-EPI and MDRD equations to estimate GFR for the validation data set (N=3896). Both panels show the difference between measured and estimated (y-axis) vs. estimated GFR (x-axis). A smoothed regression line is shown with the 95% CI for the distribution of results, using quantile regression, excluding the lowest and highest 2.5% of estimated GFR. From Ann Intern Med 2009;150:604-612, used with permission.

Limitations of the CKD-EPI Equation

• Limitations using creatinine as a filtration marker: both the MDRD study and CKD-EPI equations are based on serum creatinine. Despite modest reduction in bias with the CKD-EPI equation, estimates remain imprecise, with some people showing large differences between the measured and estimated GFR. Like all other creatinine-based estimation equations, they suffer from physiologic limitations of creatinine as a filtration marker^{3, 6}. The terms for age, sex, and race in both equations only capture some of the non-GFR determinants of creatinine concentration in blood plasma, and the coefficients represent average effects observed in the population used to develop the equations.

  All estimates of GFR based on serum creatinine will be less accurate for patients at the extremes of muscle mass (including frail elderly, critically ill, or cancer patients), those with unusual diets, and those with conditions associated with reduced secretion or extra-renal elimination of creatinine. Confirmatory tests with exogenous measured GFR or measured creatinine clearance should be performed for people in whom estimates based on serum/plasma/blood creatinine alone may be inaccurate.

• Populations not well represented in the development or validation cohorts: Elderly people and blacks with higher levels of GFR, racial and ethnic minorities other than blacks.
• The influence of creatinine measurement imprecision at low creatinine concentrations (high eGFR) has not been carefully studied but has likely contributed to the variability at higher eGFR values.

References

1. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.

2. Stevens LA, Schmid CH, Zhang YL, Coresh J, Manzi J, Landis R, et al. Development and validation of GFR-estimating equations using diabetes, transplant and weight. Nephrol Dial Transplant. 2010;25:449-57.

3. Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int. 1985;28(5):830-8.

4. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem. 1992;38(10):1933-53.

5. Rule AD, Teo BW. GFR estimation in Japan and China: what accounts for the difference? Am J Kidney Dis. 2009;53(6):932-5.

6. Rule AD, Bailey KR, Schwartz GL, Khosla S, Lieske JC, Melton LJ, 3rd. For estimating creatinine clearance measuring muscle mass gives better results than those based on demographics. Kidney Int. 2009;75(10):1071-8.

Appendix

Table 2: CKD EPI Equation for Estimating GFR Expressed for Specified Race, Sex and Serum Creatinine in µmol/L(Adapted from Ann Intern Med 2009;150:604-612, used with permission)

Race	Sex	Serum Creatinine, Scr µmol/L	Equation (age in years for ≥ 18)
Black	Female	≤ 61.9	GFR = 166 × (Scr/61.9)-0.329 × (0.993)Age
Black	Female	> 61.9	GFR = 166 × (Scr/61.9)-1.209 × (0.993)Age
Black	Male	≤ 79.6	GFR = 163 × (Scr/79.6)-0.411 × (0.993)Age
Black	Male	> 79.6	GFR = 163 × (Scr/79.6)-1.209 × (0.993)Age
White or other	Female	≤ 61.9	GFR = 144 × (Scr/61.9)-0.329 × (0.993)Age
White or other	Female	> 61.9	GFR = 144 × (Scr/61.9)-1.209 × (0.993)Age
White or other	Male	≤ 79.6	GFR = 141 × (Scr/79.6)-0.411 × (0.993)Age
White or other	Male	> 79.6	GFR = 141 × (Scr/79.6)-1.209 × (0.993)Age

GFR = 141 × min (S_cr /κ, 1)κ × max (S_cr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where S_cr is serum creatinine in µmol/L, κ is 61.9 for females and 79.6 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of S_cr /κ or 1, and max indicates the maximum of S_cr /κ or 1.