Abstract
Glomerular filtration rate (GFR) is generally considered the best overall assessment of kidney function. The normal level for GFR is 120 to 130 mL/min per 1.73 m 2 but varies according to age, sex, body size, and other factors. Reductions in GFR can be due to either a decline in the nephron number or a decline in the average single nephron GFR (SNGFR), resulting from either physiologic or hemodynamic alterations. GFR is measured with plasma or urinary clearance of filtration markers. Because of the difficulties in measuring GFR, GFR is often estimated with serum levels of endogenous filtration markers. The main limitation is that the serum level of filtration markers is also influenced by generation, tubular secretion and reabsorption, and extrarenal elimination (“non-GFR determinants”) of these markers. Estimating equations incorporate demographic and clinical variables as surrogates for the non-GFR determinants and provide a more accurate estimate of GFR than the serum level alone. Serum creatinine is the most commonly used endogenous filtration marker in clinical practice, and serum cystatin C currently shows promise. In the past, urea was widely used. The KDIGO CKD 2013 clinical practice guidelines recommend eGFRcr using the Chronic Kidney Disease Epidemiology (CKD-EPI) 2009 equation as the primary test with eGFRcr-cys or eGFRcys using the CKD-EPI 2012 equations or a clearance measurement as confirmatory tests.
Keywords
creatinine, cystatin C, measured GFR, glomerular filtration rate
Glomerular Filtration Rate
GFR is the product of the average filtration rate of each single nephron (the filtering unit of the kidneys) multiplied by the number of nephrons in both kidneys. The normal GFR level varies considerably according to age, sex, body size, physical activity, diet, pharmacologic therapy, and physiologic states such as pregnancy. For GFR to be standardized for differences in kidney size (kidney size is proportional to body size), GFR is typically indexed for body surface area, which is computed from height and weight, and then expressed per 1.73 m 2 surface area, which was the mean body surface area of young men and women at the time indexing was first proposed. Normal average GFR values are approximately 130 and 120 mL/min per 1.73 m 2 for young men and women, respectively.
Reductions in GFR can be due to a decline in the nephron number or a decline in the average single-nephron GFR (SNGFR) resulting from physiologic or hemodynamic alterations. However, a rise in SNGFR due to increased filtration pressure (e.g., increased glomerular capillary pressure) or surface area (e.g., glomerular hypertrophy) can compensate for decreases in nephron number; therefore the level of GFR may not reflect the loss of nephrons. As a result, there may be substantial kidney damage before GFR decreases.
Glomerular filtration rate cannot be measured directly in humans; thus “true” GFR cannot be known with certainty. However, GFR can be assessed from clearance measurements (measured GFR [mGFR]) or serum levels of endogenous filtration markers (estimated GFR [eGFR]).
Measurement of the Glomerular Filtration Rate
Classically, “measured” GFR is determined from the urinary clearance of an “ideal” filtration marker (inulin). Urinary clearance is calculated as the product of the urinary flow rate (V) and the urinary concentration (U x ) divided by the average plasma concentration (P x ) during the clearance period. Urinary excretion of a substance depends on filtration, tubular secretion, and tubular reabsorption. Substances that are filtered but neither secreted nor reabsorbed by the tubules are ideal filtration markers because their urinary clearance equals GFR. Alternative exogenous filtration markers include iothalamate, iohexol, ethylenediaminetetraacetic acid, and diethylenetriaminepentaacetic acid, which are often chelated to radioisotopes for ease of detection but may differ in their renal handling from inulin. Urinary clearance requires a timed urine collection for measurement of urine volume, and special care must be taken to avoid incomplete urine collections, which will limit the accuracy of the clearance calculation. Plasma clearance is an alternative method to measure GFR and has the advantage of avoiding the need for a timed urine collection but is also affected by extrarenal elimination. All these considerations mean that measured GFR may differ from true GFR.
Estimation of the Glomerular Filtration Rate
Because of the difficulties in measuring GFR, GFR is often estimated with serum level endogenous filtration markers. For markers that are freely filtered, the plasma level is related to the reciprocal of the level of GFR, but the plasma level of many filtration markers is also influenced by generation, tubular secretion and reabsorption, and extrarenal elimination; these are collectively termed non-GFR determinants of the plasma concentration ( Fig. 3.1 ). In the steady state, a constant plasma level is maintained because generation is equal to urinary excretion and extrarenal elimination. Estimating equations incorporate demographic and clinical variables as surrogates for the non-GFR determinants and provide a more accurate estimate of GFR than the reciprocal of the plasma concentration alone. Estimated GFR may differ from measured GFR if it is in the nonsteady state or if there is a discrepancy between the true and average value for the relationship of the surrogate to the non-GFR determinants of the filtration marker. Other sources of error include measurement error in the endogenous filtration marker (including failure to calibrate the assay for the filtration marker to the assay used in the development of the equation) or measurement error in GFR in developing the equation. In principle, the magnitude of all these errors is likely greater at higher measured GFR, although such errors may be more clinically significant at lower measured GFR.
Creatinine is the most commonly used endogenous filtration marker in clinical practice, and cystatin C shows promise. In the past, urea was widely used. The concepts discussed later are relevant for children and adults; however, the specifics of the following discussion focus on estimating GFR in adults. Table 3.1 includes the two most commonly used GFR estimating equations for children.
| Creatinine-Based Equations | ||||
| Cockcroft-Gault Formula | ||||
| C cr (mL/min) = (140 – age) × weight/72 × Scr × 0.85 [if female] | ||||
| MDRD Study Equation for Use With Standardized Serum Creatinine (Four-Variable Equation) | ||||
| GFR (mL/min per 1.73 m 2 ) = 175 × S Cr −1.154 × age −0.203 × 0.742 [if female] × 1.210 [if black] | ||||
| CKD-EPI Equation for Use With Standardized Serum Creatinine | ||||
| GFR (mL/min per 1.73 m 2 ) = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1) 1.209 × 0.993 Age × 1.018 [if female] × 1.157 [if black] where 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 Scr/ κ or 1, and max indicates the maximum of Scr/ κ or 1. | ||||
| Female | ≤0.7 → | GFR = 144 × (Scr/0.7) −0.329 | × (0.993) Age | × 1.157 [if black] |
| >0.7 → | GFR = 144 × (Scr/0.7) −1.209 | |||
| Male | ≤0.9 → | GFR = 141 × (Scr/0.9) −0.411 | ||
| >0.9 → | GFR = 141 × (Scr/0.9) −1.209 | |||
| Schwartz Formula (Younger Than 18 Years of Age) | ||||
| GFR = 0.413 × ht/Scr GFR = 40.7 × [HT/Scr] 0.640 × [30/BUN] 0.202 | ||||
| Cystatin C-Based Equations | ||
|---|---|---|
| CKD-EPI Cystatin C Eq. 2012 | ||
| 133 × min(Scys/0.8, 1) −0.499 × max(Scys/0.8, 1) −1.328 × 0.996 Age × 0.932 [if female] where Scys is serum cystatin C, min indicates the minimum of Scr/ κ or 1, and max indicates the maximum of Scr/ κ or 1. | ||
| Female | ≤0.8 | GFR = 133 × (Scys/0.8) −0.499 × 0.996 Age × 0.932 |
| >0.8 | GFR = 133 × (Scys/0.8) −1.328 × 0.996 Age × 0.932 | |
| Male | ≤0.8 | GFR = 133 × (Scys/0.8) −0.499 × 0.996 Age |
| >0.8 | GFR = 133 × (Scys/0.8) −1.328 × 0.996 Age | |
| Creatinine-Cystatin C-Based Equations | |||
|---|---|---|---|
| CKD-EPI Creatinine-Cystatin C Eq. 2012 | |||
| 135 × min(Scr/κ, 1)α × max(Scr/κ, 1) −0.601 × min(Scys/0.8, 1) −0.375 × max(Scys/0.8, 1) −0.711 × 0.995 Age × 0.969 [if female] × 1.08 [if black] where Scr is serum creatinine, Scys is serum cystatin C, κ is 0.7 for females and 0.9 for males, α is −0.248 for females and −0.207 for males, min indicates the minimum of Scr/ κ or 1, and max indicates the maximum of Scr/ κ or 1. | |||
| Female | ≤0.7 | ≤0.8 | GFR = 130 × (Scr/0.7) −0.248 × (Scys/0.8) −0.375 × 0.995 Age × 1.08 [if black] |
| >0.8 | GFR = 130 × (Scr/0.7) −0.248 × (Scys/0.8) −0.711 × 0.995 Age × 1.08 [if black] | ||
| >0.7 | ≤0.8 | GFR = 130 × (Scr/0.7) −0.601 × (Scys/0.8) −0.375 × 0.995 Age × 1.08 [if black] | |
| >0.8 | GFR = 130 × (Scr/0.7) −0.601 × (Scys/0.8) −0.711 × 0.995 Age × 1.08 [if black] | ||
| Male | ≤0.9 | ≤0.8 | GFR = 135 × (Scr/0.9) −0.207 × (Scys/0.8) −0.375 × 0.995 Age × 1.08 [if black] |
| >0.8 | GFR = 135 × (Scr/0.9) −0.207 × (Scys/0.8) −0.711 × 0.995 Age × 1.08 [if black] | ||
| >0.9 | ≤0.8 | GFR = 135 × (Scr/0.9) −0.601 × (Scys/0.8) −0.375 × 0.995 Age × 1.08 [if black] | |
| >0.8 | GFR = 135 × (Scr/0.9) −0.601 × (Scys/0.8) −0.711 × 0.995 Age × 1.08 [if black] | ||
| Schwartz Formula (Less Than 18 Years of Age) | |||
| 39.1 × (HT/Scr) 0.516 × (1.8/cysC) 0.294 × (30/BUN) 0.169 × (HT/1.4) 0.188 × 1.099 [if male] | |||
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