Measurement of Kidney Function

Transcription

1 Med Clin N Am 89 (2005) Measurement of Kidney Function Lesley A. Stevens, MD, FRCPC*, Andrew S. Levey, MD Division of Nephrology, Tufts University School of Medicine, Tufts New England Medical Center, 750 Washington Street, Box 391, Boston, MA 02111, USA Accurate estimation of kidney function is central to the detection, evaluation, and treatment of chronic kidney disease (CKD). Glomerular filtration rate (GFR) is widely accepted as the best overall measure of kidney function. For this reason, CKD is defined based on the level of GFR (Box 1), and clinical recommendations for individuals at increased risk of CKD and for patients at each stage of CKD include assessment of GFR (Table 1). This article reviews the physiologic basis of GFR, the methods for measurement of GFR, and new recommendations for GFR estimation in clinical practice. In particular, it emphasizes the strengths and limitations of different methods and describes the current recommendations based on this discussion. Determinants and measurement of glomerular filtration rate Determinants of glomerular filtration rate The GFR is the product of the filtration rate in single nephrons and the number of nephrons in both kidneys. Reductions in GFR can be caused by either a decline in nephron number (as in CKD) or by a decline in single nephron GFR, which can be caused by physiologic or pharmacologic factors causing hemodynamic alterations in glomerular filtration (Box 2). An increase in single nephron GFR caused by increased glomerular capillary pressure or glomerular hypertrophy can compensate for a decrease in nephron number, and the level of GFR may not reflect the loss of nephrons. There may be substantial kidney damage before GFR declines. * Corresponding author. 35 Kneeland Street, 6th Floor, Boston, MA address: Lstevens1@tufts-nemc.org (L.A. Stevens) /05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi: /j.mcna medical.theclinics.com

2 458 STEVENS & LEVEY Box 1. National Kidney Foundation Kidney Disease Outcomes Quality Initiative definition of/criteria for chronic kidney disease Kidney damage for 3 months or more, as defined by structural or function abnormalities of the kidney, with or without decreased GFR, manifest by either pathologic abnormalities; or markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests. GFR < 60 ml/min/1.73 m 2 for 3 months or more, with or without kidney damage. Data from Kidney Disease Outcome Quality Initiative. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 2):S Given this, detection of early stages of CKD requires testing for markers of kidney damage in addition to estimation of GFR. Normal range for glomerular filtration rate The normal level of GFR varies according to age, sex, and body size, and is affected by normal physiologic states that affect single nephron GFR, such as pregnancy or protein intake. Within an individual, GFR is remarkably constant over time [1], but varies considerably among people, even after adjustment for the known variables of age, sex, and body size [2]. Normal GFR in young adults is approximately 120 to 130 ml/min/1.73 m 2 and declines with age [3,4]. More than 25% of individuals of age greater than or equal to 70 years have GFR less than 60 ml/min/1.73 m 2, which may be caused by normal aging or the high prevalence of systemic diseases that cause kidney disease [5]. Regardless as to whether the cause of the reduced GFR is from normal aging or from pathologic processes, the level of GFR for the definition of CKD does not vary by age. GFR less than 60 ml/min/1.73 m 2 in the elderly is an independent predictor of adverse outcomes, such as death and cardiovascular disease [6], and also requires adjustment in drug dosages, as in younger patients with CKD. Urinary clearance The GFR cannot be measured directly. Instead, it is estimated from the urinary clearance of a filtration marker. The clearance of a substance is defined as the rate at which it is cleared from the plasma per unit

3 KIDNEY FUNCTION MEASUREMENT 459 Table 1 Uses of glomerular filtration rate according to stage of chronic kidney disease CKD stage Description GFR (ml/min/1.73 m 2 ) Importance of GFR a At high, increased risk Detection of CKD GFR \ 60 ml/min/1.73 m 2 for 3 mo defines CKD 1 Kidney damage with normal or high GFR > 90 Initiate treatment and monitor response to treatment 2 Kidney damage with mild, Quantify progression low GFR 3 Moderate, low GFR Selection of appropriate treatment strategies Measure response to treatment Association of comorbid conditions Drug dosing 4 Severe, low GFR Referral to nephrologist 5 Kidney failure \ 15 Interpretation of symptoms Initiate kidney replacement therapy a The importance of GFR is cumulative in that recommended care at each stage of disease includes care for less severe stages. CKD definition and stages from Kidney Disease Outcome Quality Initiative. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 2):S concentration. For substances that are cleared from the plasma by excretion in the urine, C x ¼ U x V=P x ð1þ where C x is the clearance of the marker X, U x is the urinary concentration of X, V is the urine flow rate, and P x is the average plasma concentration of X Box 2. Factors affecting glomerular filtration rate Kidney disease Pregnancy Reduced kidney perfusion Marked increase or deficit of extracellular fluid volume Nonsteroidal anti-inflammatory drug use Acute protein load and habitual protein intake Blood glucose control (in patients with diabetes) Level of arterial blood pressure and class of antihypertensive agents used

4 460 STEVENS & LEVEY during the time interval of urine collection. If substance X is freely filtered across the capillary wall, unhindered by its size, charge, or binding to plasma proteins, and neither secreted nor reabsorbed then GFR P x ¼ U x V ð2þ GFR ¼ C x ð3þ A substance that meets these requirements is defined as an ideal filtration marker because its clearance can be used to estimate GFR. For markers that exhibit tubular secretion (TS x ) in addition to glomerular filtration, clearance exceeds GFR, and for markers that exhibit tubular reabsorption (TR x )in addition to glomerular filtration, clearance is less than GFR. GFR ¼ðU x V ÿ TS x þ TR x Þ=P x ð4þ GFR ¼ C x ÿ TS x =P x þ TR x =P x ð5þ Estimation of glomerular filtration rate using exogenous filtration markers In addition to the properties of an ideal marker described previously, an exogenous marker used for the estimation of GFR must be physiologically inert, not alter kidney function or be altered during its passage through the nephron, and be accurately and reproducibly measured. Inulin, a 5200-d uncharged polymer of fructose, is freely filtered, is inert, does not alter kidney function, is neither secreted nor reabsorbed, and is the gold standard filtration marker. The clearance method originally described includes a continuous intravenous infusion; bladder catheterization; and performance under standard conditions (water loading, morning measurement, fasting [7]). Inulin is not readily available, however, and is difficult to assay. Recently, a number of alternative filtration markers have been validated, including iohexol, chromium-51 ethylenediaminetetraacetic acid, technetium-99m diethylenetriamine pentaacetic acid, and iodine-125 iothalamate. Alternative clearance methods, including bolus subcutaneous infusion, spontaneous bladder emptying, and plasma disappearance (rather than urinary clearance), have also been validated. These measurement protocols are still too complicated, however, for routine clinical practice in most centers. Estimation of glomerular filtration rate using endogenous filtration markers Because of the complexities of the measurement of the clearance of exogenous markers for routine clinical practice, the discovery and

5 KIDNEY FUNCTION MEASUREMENT 461 evaluation of endogenous filtration markers has been an area of continuous investigation. GFR can be estimated either from urinary clearance or plasma (serum) levels during the steady state. Examples of endogenous markers are urea, creatinine, and cystatin C. All have some use as markers for GFR, but none meets all criteria required of an ideal filtration marker. Before considering individual endogenous markers, it is important to review some general considerations. Estimation of glomerular filtration rate from urinary clearance For substances that are excreted in the urine, clearance measurements are usually obtained from a 24-hour urine collection to measure excretion rate and a single measurement of serum concentration (usually equivalent to plasma). Twenty-four hour urine collections are inconvenient, however, and their accuracy and reliability are limited because of frequent errors in timing and collection. Current guidelines recommend 24-hour urine collections only in special circumstances (discussed later). More importantly, all of the endogenous markers are either reabsorbed or secreted in the tubules, and the measurement of their urinary clearance induces a systemic bias in the estimation of GFR. Estimation of glomerular filtration rate from serum levels If a substance X is in steady state, its plasma level can be used to estimate GFR. A steady state is achieved when the rate of generation and release into body fluids of X is constant and is equal to the rate of elimination of X from body fluids (either from excretion or metabolism). In the steady sate, the plasma concentration of substance X is stable. In addition, if substance X is excreted solely in the urine, the rate of generation can be assessed by the urinary excretion rate. U x V ¼ G x ð6þ And substituting back into equation 4, GFR ¼ðG x ÿ TS x þ TR x Þ=P x ð7þ If extrarenal elimination (E x ) is present, then U x V ¼ G x ÿ E x ð8þ GFR ¼ðG x ÿ E x ÿ TS x þ TR x Þ=P x ð9þ

6 462 STEVENS & LEVEY By rearranging equation 9, the plasma level can be related to generation, extrarenal elimination, tubular secretion, and tubular reabsorption, and to the level of GFR. P x ¼ðG x ÿ E x ÿ TS x þ TR x Þ=GFR ð10þ Although values for G, E, TS, TR, and GFR may differ among individuals and within individuals over time, this physiologic relationship is invariant across settings and over time. Understanding equation 10 allows for explicit articulation of the physiologic factors that influence the plasma level of any substance excreted by the kidney. All of these factors should be considered when interpreting a plasma level for estimation of GFR. Unfortunately, other than the level of GFR, whose reciprocal relationship with the serum level has been well-described, these factors are rarely considered and often not known. Estimation of glomerular filtration rate from equations based on serum levels of endogenous markers The physiologic factors influencing the plasma level of a substance, as described in equation 10, are usually not measured. Many of these factors, however, especially those related to the generation of the endogenous serum marker, are related to demographic or clinical variables (eg, age, sex, and race) that are easily observed. Estimating equations for GFR using the serum marker in combination with observed surrogates for these unmeasured physiologic factors can provide more accurate estimates of GFR than plasma levels alone. The relationships between the observed surrogates and the unmeasured physiologic factors are likely to vary among different populations and clinical settings, and an estimating equation developed in one setting may perform poorly in a different setting. In addition, the relationship between the observed surrogates and the unmeasured physiologic determinants may differ over time. An estimating equation developed based on a crosssectional analysis may be suboptimal for estimation of longitudinal changes in GFR, even in the same data set or same population [8]. For these reasons, the value of any estimating equation lies in the rigor of its development and the variety of settings and validation in populations other than the study population in which it was developed [9]. Urea as a filtration marker The excretion of urea was recognized as an estimate of kidney function even before the elaboration of the concept of the GFR. The factors influencing both the excretion of urea by the kidney and its generation are complex and vary widely among individuals and over time. As a result,

7 KIDNEY FUNCTION MEASUREMENT 463 neither the urea clearance nor the serum urea level (for historical reasons, usually referred to as the blood urea nitrogen) are used today as an index of kidney function. Urea is a 60-d end product of protein catabolism. It is freely filtered by the glomerulus, passively reabsorbed in both the proximal and distal nephron [10], and excreted in high concentration in the urine. Because of tubular reabsorption, urea clearance underestimates GFR. Extracellular fluid volume depletion and states of antidiuresis are associated with increased urea reabsorption, leading to a greater decrease in urea clearance than the concomitant decrease in GFR. Under these conditions, the ratio of blood urea nitrogen in milligrams per deciliter to serum creatinine concentration in milligrams per deciliter exceeds the usual value of 10:1. Conversely, extracellular volume expansion and states of diuresis increase urea clearance more than GFR and can be associated with a blood urea nitrogen to creatinine ratio less than 10:1. Urea is synthesized primarily by the liver, with dietary protein intake as the principal determinant of urea generation. Variation in urea generation can cause alterations in the blood urea nitrogen in addition to those caused by variation in urea clearance. Causes of increased urea generation include administration of corticosteroids, diuretics, or tetracyclines; absorption of blood from the gut; infection; acute kidney failure; trauma; congestive heart failure; and sodium depletion. Decreases in urea generation may occur in severe malnutrition and liver disease. Creatinine as a filtration marker Creatinine is a 113-d end product of muscle catabolism and the serum creatinine concentration is the most commonly used index of kidney function. Advantages for the use of serum creatinine concentration are that it is easy to measure, inexpensive, and widely available. There is a wide body of literature that supports the reciprocal relationship between the steady state plasma level of creatinine with GFR [11]. There are important limitations, however, to its use. Understanding these limitations is essential to interpretation of GFR estimates using serum creatinine. Urinary clearance Creatinine is freely filtered at the glomerulus, actively secreted by cation transporters in the proximal nephron, and excreted in the urine. Approximately 5% to 10% of urinary creatinine excretion is caused by creatinine secretion at normal levels of GFR, and creatinine clearance overestimates GFR by approximately 10 to 20 ml/min/1.73 m 2. The rate of creatinine secretion varies among individuals and over time and the GFR cannot be precisely predicted from level of creatinine clearance. As GFR declines, the relative proportion of creatinine secretion versus filtration rises.

8 464 STEVENS & LEVEY Consequently, creatinine secretion has a greater effect on the serum creatinine concentration at lower levels of GFR. Polycystic kidney disease and tubulointerstitial disease seem to be associated with lower mean levels of creatinine secretion than other diseases [12]. Higher protein intake can cause increased creatinine secretion. Several medications, such as cimetidine, trimethoprim, and fenofibrate, can inhibit tubular secretion of creatinine. Some have advocated administration of cimetidine to block creatinine secretion during 24-hour urine collections for creatinine clearance, thereby allowing for a more accurate measurement of GFR, especially in patients with moderate to severe reductions in GFR. Cimetidine causes only a partial blockade of tubular secretion, however, and does so variably, making it difficult to compare across individuals or even within the same individual over time. Creatinine metabolism Creatinine generation is related to the muscle metabolism and dietary meat intake. Creatinine is generated in muscle from the nonenzymatic conversion of creatinine and phosphocreatine [13]. Approximately 98% of the creatinine pool is maintained in muscle [14], and approximately 1.6% to 1.7% per day is converted to creatinine [15], which is rapidly excreted by the kidney. Creatinine generation is directly proportional to muscle mass, which in turn varies according to age, sex, and race and is affected by conditions causing muscle wasting. Creatinine generation is also affected by dietary meat intake, because meat includes creatine, which can be converted to creatinine by cooking [16,17]. Increased meat intake can cause a long-term increase in serum creatinine because of an increase in the creatinine pool, and a transient increase in serum creatinine caused by gastrointestinal absorption of creatinine. Extrarenal elimination of creatinine can occur in the gastrointestinal tract by bacterial degradation of creatinine contained in intestinal secretions. Extrarenal elimination is not detectable in normal individuals, but may account for up to 68% of daily creatinine generation in patients with severely reduced GFR [18,19] because of increased concentration of creatinine in gastrointestinal secretions and bacterial overgrowth of the upper gastrointestinal tract. In principle, antibiotics could cause an increase in serum creatinine in patients with CKD because of eradication of bacterial overgrowth and decrease in extrarenal elimination of creatinine. This may be a relevant consideration in patients with CKD who develop superimposed acute renal failure. Table 2 summarizes the impact of these and others factors on serum creatinine levels. The implications of variation in these physiologic determinants among individuals and within individuals over time are that for the same level of GFR, different people or even the same person at two points in time can have different levels of serum creatinine. Fig. 1A shows

9 KIDNEY FUNCTION MEASUREMENT 465 Table 2 Factors affecting serum creatinine concentration Factor Affect on serum creatinine Mechanism and comment Age Decrease Reduction in creatinine generation because of age-related decline in muscle mass Sex Female Decrease Reduced creatinine generation because of reduced muscle mass Race African American Increase Higher creatinine generation rate because of higher average muscle mass in African Americans; not known how muscle mass in other races compares to that of African Americans or whites Diet Vegetarian diet Decrease Decrease in creatinine generation Ingestion of cooked meats Increase Transient increase in creatinine generation; however this may be blunted by transient increase in GFR Body habitus Muscular Increase Increased muscle generation because of increased muscle mass increased protein intake Malnutrition, muscle wasting, amputation Decrease Reduced creatinine generation because of reduced muscle mass reduced protein intake Obesity No change Excess mass is fat, not muscle mass and does not contribute to increased creatinine generation Medications Trimethoprim, cimetidine, fibric acid derivatives other than gemfibrozol Increase Reduced tubular secretion of creatinine Keto acids, some cephalosporins Increase Interference with alkaline picrate assay for creatinine Data from Levey AS. Assessing the effectiveness of therapy to prevent the progression of renal disease. Am J Kidney Dis 1993;22: the variability in serum creatinine (shown as the inverse) for the same level of GFR. The lines indicate that for a GFR of 60 ml/min/1.73 m 2, the serum creatinine concentration can vary between 0.8 and 1.7 mg/dl. Creatinine assay Accurate measurement of serum creatinine is critical to accurate and consistent estimates of GFR. The most commonly used assay for serum

10 Fig. 1. GFR measured as urinary clearance of iodine-125 iothalamate and adjusted for body surface area in 1628 patients. Estimates include (A) reciprocal serum creatinine (100/P cr )(R 2 = 80.4%), (B) Cockcroft-Gault equation standardized for body surface area (R 2 = 84.2%), and (C) MDRD Study equation 7 (R 2 = 90.3%). 466 STEVENS & LEVEY

11 KIDNEY FUNCTION MEASUREMENT 467 creatinine, the alkaline picrate ( Jaffe ) assay, detects a color change when creatinine interacts with picrate under alkaline conditions. This reaction is subject to interference from substances other than creatinine (noncreatinine chromogens), which in normal serum can account for up to 20% of the color reaction. Calibration of assays to adjust for this interference is not standardized across laboratories. In one study, there was a 13% average overestimation of serum creatinine compared with the reference standard [20]. In contrast, the average coefficient of variation (reproducibility) of serum creatinine measures within laboratories was 8%, which is much better than for many other analytes [20]. In this same study, differences in calibration of serum creatinine assays to the reference standard accounted for 85% of the difference between laboratories. The wide range of normal values for serum creatinine among clinical laboratories seems to be caused by lack of standardization of calibration, rather than imprecision of measurement. Differences can also occur within laboratories over time. For example, Fig. 2 shows results over time in serum creatinine results in quality control procedures conducted by the College of American Pathology at the central laboratories for the Modification of Diet in Renal Disease (MDRD) Study (Cleveland Clinic Laboratory) and NHANES III (White Sands clinical Laboratory) [21]. Current efforts are underway to standardize serum Fig. 2. Serum creatinine values in MDRD Study and NHANES III clinical laboratories over time. Serum creatinine values in the Cleveland Clinic (MDRD Study) and White Sands (NHANES III) laboratories minus the mean serum creatinine level in all laboratories participating in the College of American Pathology survey for that quarter. The same five samples are analyzed in all participating laboratories in each quarter. Lines indicate the average of the difference for each quarter at Cleveland Clinic and White Sands during 1992 to 2000.

12 468 STEVENS & LEVEY creatinine testing among clinical laboratories and to trace results to a gold standard at the National Institute for Standards and Technology. The concentration of noncreatinine chromogens does not increase as GFR declines; therefore, the overestimation of serum creatinine is proportionately greater at low serum creatinine values (higher GFR). Other substances can interfere with the alkaline picrate assay, such as keto acids and some cephalosporins (see Table 2). Of note, noncreatinine chromogens do not interfere with measurements of urine creatinine. Estimating equations for glomerular filtration rate using serum creatinine Estimating equations overcome some of the limitations of using serum measurements alone and avoid the inconvenience of 24-hour urine collections. The most often used one is the Cockcroft-Gault equation [22], which estimates creatinine clearance (C cr based on serum creatinine, age, sex, and body weight). C cr ¼ð140 ÿ ageþweight ð 0:85 if femaleþ=ð72 P x Þ ð11þ Where C cr is expressed in ml/min, age in years, weight in kg, and P x in mg/dl. The equation was developed in 249 men with creatinine in steady state, with the adjustment factor for women based on a theoretical 15% lower muscle mass. Because of the inclusion of weight in the numerator, as a measure of muscle mass, the equation overestimates creatinine clearance in patients who are edematous, overweight, or obese. Comparison with normal values for creatinine clearance requires measurement of height, computation of body surface area, and adjustment to 1.73 m 2. As expected, the Cockcroft-Gault equation systematically overestimates GFR because it was developed to estimate creatinine clearance, not GFR (Fig. 1B). A more recent equation for the estimation of GFR adjusted for 1.73 m 2 has been rigorously developed using data from 1628 patients enrolled in the baseline period of the MDRD Study (Fig. 1C) [23,24]. The MDRD Study equation is more accurate than the Cockcroft-Gault equation and measured creatinine clearance, with 91% of the estimated values falling within 30% of the measured values. The four-variable equation is as follows: GFR ¼ 186 ðp cr Þ ÿ1:154 ðageþ ÿ0:203 ð 0:742 if femaleþ ð 1:210 if African AmericanÞ (12) GFR is expressed in ml/min/1.73 m 2, P cr in mg/dl, age in years, and race as African American or not.

13 KIDNEY FUNCTION MEASUREMENT 469 The MDRD Study equation was developed in patients with CKD (mean GFR 40 = ml/min/1.73 m 2 ) who were predominantly white and did not have diabetic kidney disease or kidney transplants. The equation has now been validated in African Americans with nondiabetic kidney disease, in diabetic kidney disease, and in kidney transplant recipients [25], but not in individuals at the extremes of body size; with high levels of dietary meat intake; overweight or obesity; amputation; conditions associated with muscle-wasting; children; pregnant women; the elderly (age>70 years); other racial or ethnic subgroups; in individuals at increased risk for CKD; or in normal individuals. The Cockcroft-Gault and MDRD Study equations improve on the use of serum creatinine alone by incorporating known demographic and clinical variables as observed surrogates for the unmeasured physiologic factors other than GFR that affect serum creatinine concentration (see equation 10). For example, terms for age, sex, and race reflect differences in the creatinine generation related to changes in muscle mass with aging and between sexes and races. It is likely, however, that neither equation is accurate in individuals who were not included in the study population in which the equation was developed. In these populations, the most appropriate estimate of kidney function is creatinine clearance measured in a 24-hour urine collection. Box 3 lists indications for collecting a 24-hour urine specimen for the measurement of creatinine clearance to estimate GFR. Estimating equations based on serum creatinine also requires attention to calibration of the serum creatinine assay [21]. The use of the MDRD Study equation, or any other equation, without recalibration of serum creatinine assay to the assay used in the laboratory in which the equation was developed can introduce a systematic error into GFR estimates because of variability in measurement of serum creatinine between the two laboratories Box 3. A 24-hour urine collection may be required to estimate glomerular filtration rate in the following conditions Extremes of age and body size Severe malnutrition or obesity Disease of skeletal muscle Paraplegia or quadriplegia Vegetarian diet Rapidly changing kidney function Pregnancy Before dosing drugs with significant toxicity that are excreted by the kidneys

14 470 STEVENS & LEVEY [21]. This error is significantly reduced at lower levels of GFR because of relative decrease in noncreatinine chromogens relative to the level of creatinine. The effect of calibration on Cockcroft-Gault cannot be similarly tested because the methods in the laboratory where this equation was developed have not been maintained. Despite the limitations of the MDRD Study equation, it represents a significant advance over using serum creatinine alone or measured creatinine clearance to estimate GFR. Advantages include that it is more accurate than other equations previously developed; it can be easily implemented with measurement of creatinine and knowledge of age, sex, and race; it does not require urine collection or measurement of height and weight; and it predicts GFR rather than creatinine clearance. The MDRD Study equation has now been recommended for routine clinical use by the National Kidney Foundation, American Society of Nephrology, and the National Kidney Disease Education Program of the National Institutes of Health. Appreciation of the limitations of the equation and of serum creatinine helps interpretation of the value for an individual patient. Cystatin C as a filtration marker At this time, cystatin C is the only endogenous filtration marker being considered as a potential replacement for serum creatinine [26 30]. Cystatin is a 13-kd nonglycosylated basic protein. Indirect evidence suggests that cystatin C is produced at a constant rate by all tissues; its generation may be invariant across populations and over time. Its small size and limited direct measurements in the rat suggest that cystatin C is freely filtered by the glomerulus. After filtration, cystatin C is reabsorbed and catabolized by the tubular epithelial cells, with only small amounts excreted in the urine [27,30]. Consequently, urinary clearance of cystatin C cannot be measured. Advantages of using cystatin C as a filtration marker are the laboratory assay is becoming standardized across the industry, and its generation is thought to be constant over time and not related to muscle mass. There is some preliminary evidence, however, that serum levels of cystatin C may be associated with age, gender, weight and height, smoking status, and level of C-reactive protein even after adjustment for creatinine clearance [31]. The major disadvantage of cystatin C as a filtration marker is the absence of excretion in the urine, which precludes simple investigations to understand better factors that may affect its generation and extrarenal elimination. Several studies have compared creatinine with cystatin C with conflicting results [26]. Most studies are small, however, and the populations included are limited in range of age and level of GFR. In general, it seems that cystatin C may have an advantage in detecting mildly decreased GFR, whereas serum creatinine may be better at lower levels of GFR.

15 KIDNEY FUNCTION MEASUREMENT 471 Clinical applications Accurate estimation of GFR is critical to care of patients with CKD. The current staging system for CKD is built primarily on the level of GFR in that as GFR declines, the stage increases (see Table 1). Decreasing levels of GFR (or higher CKD stage) are associated with a higher prevalence of a wide range of symptoms and complications including hypertension, anemia, malnutrition, bone disease, and neuropathy. At each stage, accurate assessment of GFR is required for evaluation and treatment. Recommendations for evaluation or care of CKD at each stage are cumulative, with care at each stage of disease including care for less severe stages (see Table 1). Although the type of kidney disease (diagnosis), level of proteinuria, and other factors are important in determining rate of progression, CKD progression is often defined as the decline in GFR. Current guidelines recommend using estimated GFR from serum creatinine as the primary method of reporting kidney function, because of inadequacies in serum creatinine alone. Currently, the most accurate method for estimation of GFR seems to be the MDRD Study equation. The MDRD Study equation is mathematically more complex than the Cockcroft-Gault equation, and cannot be used at the bedside. The MDRD Study equation has been programmed into medical decision support software for PDAs and is available on websites, such as With the increasing use of technology for physician education support, the complexity of an equation should not be a barrier to its use. Current guidelines also recommend that clinical laboratories automatically report estimated GFR whenever a serum creatinine is ordered. Until there is a national program for standardization of the creatinine assay, clinical laboratories that wish to report estimated GFR using the MDRD Study equation could calibrate the serum creatinine assay to the Central Laboratory of the MDRD Study. If the assay cannot be calibrated, laboratory reports could provide a specific number for patients with estimated GFR less than 60 ml/min/1.73 m 2, and greater than 60 ml/min/ 1.73 m 2 for other patients. Recognition of the limitations in all estimating equations and in all filtration markers discussed in this article should assist in clinical interpretation of GFR estimates. Estimation of GFR from the MDRD Study equation is not appropriate for all patients (see Table 2 and Box 3). In these patients, a clearance measurement (either a 24-hour urine collection for creatinine clearance or an exogenous filtration) can be used. In assessing a change in GFR over time for an individual patient, recognition of the potential role of changes in creatinine generation (ie, muscle loss or gain, meat intake) is important to proper interpretation in differences between the two estimates of GFR. As with all diagnostic tests used in medical practice,

16 472 STEVENS & LEVEY understanding of the strengths and limitations is a prerequisite for excellent medical care. In the future, if equations are improved or new filtration markers, such as cystatin C, ultimately replace creatinine as a filtration marker, then clinical laboratories can easily adjust the formulas or change analytes without significant interruption in the workflow or ability to report GFR estimates. Some laboratories have begun automatic GFR reporting. It is expected that this will increase in frequency with the recognition of the importance of GFR estimates to the proper evaluation and treatment of patients with CKD. References [1] Smith HW. The kidney: structure and function in health and disease. New York: Oxford University Press; [2] Wesson LG. Physiology of the human kidney. New York: Grune & Stratton; [3] Davies D, Shock N. Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 1950;29: [4] Lindeman R, Tobin J, Shock N. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33: [5] Kidney Disease Outcome Quality Initiative. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39(2 Suppl 2):S [6] Manjunath G, Tighiouart H, Coresh J, et al. Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 2003;63: [7] Smith HW, Chasis W, Goldrig W, et al. Glomerular dynamics in the normal human kidney. J Clin Invest 1940;19:751. [8] Diggle P, Liang K, Zeger S. Analysis of longitudinal data. Oxford: Clarendon Press; [9] Stevens LA, Levey AS. Clinical implications for estimating equations for GFR. Ann Int Med 2004;141: [10] Forster FP. Urea and the early history of renal clearance studies. In: Schmidt-Nielson B, editor. Urea and the kidney. Amsterdam: Excerpta Medica; p [11] Kassirer JP. Clinical evaluation of kidney function: glomerular function. N Engl J Med 1971; 285:385. [12] Effects of diet and antihypertensive therapy on creatinine clearance and serum creatinine concentration in the Modification of Diet in Renal Disease Study. J Am Soc Nephrol 1996;7: [13] Borsook H, Dubnoff JW. The hydrolysis of phosphocreatine and the origin of urinary creatinine. J Biol Chem 1974;168: [14] Hunter A. The physiology of creatine and creatinine. Physiol Rev 1922;2: [15] Heymsfield SB, Arteaga C, McManus C, et al. Measurement of muscle mass in humans: validity of the 24-hour urinary creatinine method. Am J Clin Nutr 1983;37: [16] Jacobsen FK, Christensen CK, Mogensen CE, et al. Pronounced increase in serum creatinine concentration after eating cooked meat. BMJ 1979;1: [17] Mayersohn M, Conrad KA, Achari R. The influence of a cooked meat meal on creatinine plasma concentration and creatinine clearance. Br J Clin Pharmacol 1983;15: [18] Jones JD, Burnett PC. Creatinine metabolism in humans with decreased renal function: creatinine deficit. Clin Chem 1974;20:1204. [19] Hankins DA, Babb AL, Uvelli DA, et al. Creatinine degradation I: the kinetics of creatinine removal in patients with chronic kidney disease. Int J Artif Organs 1981;4:35 9. [20] Ross J, Miller W, Myers G, et al. The accuracy of laboratory measurements in clinical chemistry: a study of 11 routine chemistry analytes in the College of American Pathologists

17 KIDNEY FUNCTION MEASUREMENT 473 Chemistry Survey with fresh frozen serum, definitive methods, and reference methods. Arch Pathol Lab Med 1998;122: [21] Coresh J, Astor BC, McQuillan G, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 2002;39: [22] Cockcroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: [23] Levey A, Bosch J, Lewis J, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130: [24] Levey A, Greene T, Kusek J, et al. A simplified equation to predict glomerular filtration rate from serum creatinine [abstract]. J Am Soc Nephrol 2000;11:155A. [25] Lewis AL, Cheek D, Greene T, et al. Comparison of cross-sectional renal function measurements in African-Americans with hypertensive nephrosclerosis and of primary formulas to estimate glomerular filtration rate. Am J Kidney Dis 2001;38: [26] Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002;40: [27] Laterza OF, Price CP, Scott MG. Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 2002;48: [28] Newman DJ, Thakkar H, Edwards RG, et al. Serum cystatin C: a replacement for creatinine as a biochemical marker of GFR. Kidney Int Suppl 1994;47:S20 1. [29] Randers E, Erlandsen EJ. Serum cystatin C as an endogenous marker of the renal function: a review. Clin Chem Lab Med 1999;37: [30] Grubb AO. Cystatin C: properties and use as diagnostic marker. Adv Clin Chem 2000;35: [31] Knight E, Verhave J, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004;65: