Assessment of kidney function

INTRODUCTION — Patients with kidney disease may have a variety of different clinical presentations. Some have symptoms that are directly referable to the kidney (gross hematuria, flank pain) or to extrarenal symptoms (edema, hypertension, signs of uremia). Many patients, however, are asymptomatic and are noted on routine examination to have an elevated serum creatinine concentration or an abnormal urinalysis.

Once kidney disease is discovered, the presence or degree of kidney function impairment, kidney damage, and rapidity of progression are assessed, and the underlying disorder is diagnosed. Although the history and physical examination can be helpful, the most useful information is initially obtained from estimation of the glomerular filtration rate (GFR), assessment of albuminuria (or proteinuria), and examination of the urinary sediment.

The kidney performs many functions, including elimination of nitrogenous wastes; regulation of fluid, electrolyte, acid-base, and mineral balance; control of blood pressure; and synthesis and secretion of erythropoietin and other hormones. The GFR is considered the best overall measure of the kidney's ability to carry out these various functions, and therefore estimation of the GFR is used clinically to assess the degree of kidney impairment and to follow the course of the disease. However, the GFR provides no information on the cause of the kidney disease. This is achieved by the urinalysis, measurement of urinary protein excretion, kidney imaging, and, if necessary, kidney biopsy.

This topic will provide an overview of the issues concerning assessment of the GFR in the patient with chronic kidney disease (CKD). The utility of the urinalysis, radiologic studies, and kidney biopsy are discussed separately, as is the general approach to the patient with kidney disease:

●(See "Urinalysis in the diagnosis of kidney disease".)

●(See "Radiologic assessment of kidney disease".)

●(See "The kidney biopsy".)

●(See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)

OVERVIEW OF KIDNEY FUNCTION — Prior to discussing the evaluation of glomerular filtration rate (GFR), it is helpful to first briefly review normal kidney physiology. The kidney performs a number of essential processes:

●It participates in the maintenance of the constant extracellular environment that is required for adequate functioning of the cells. This is achieved by excretion of some of the waste products of metabolism (such as urea, creatinine, and uric acid) and by specifically adjusting the urinary excretion of water and electrolytes to match net intake and endogenous production (table 1 and table 2). The kidney is able to regulate individually the excretion of water and solutes such as sodium, potassium, and hydrogen, largely by changes in tubular reabsorption or secretion.

●It secretes hormones that participate in the regulation of systemic and renal hemodynamics (renin, prostaglandins, and bradykinin), red blood cell production (erythropoietin), and calcium, phosphorus, and bone metabolism (1,25-dihydroxyvitamin D3 or calcitriol).

In the patient with kidney disease, some or all of these functions may be diminished or entirely absent. As an example, patients with nephrogenic diabetes insipidus have a decreased urinary concentrating ability, but other functions are entirely normal. By comparison, all kidney functions may be significantly impaired in the patient with end-stage kidney disease, thereby resulting in the retention of uremic toxins, marked abnormalities in fluid and electrolyte balance, and anemia and bone disease.

GLOMERULAR FILTRATION RATE

Normal GFR — The glomerular filtration rate (GFR) is equal to the sum of the filtration rates in all of the functioning nephrons. The filtering units of the kidney, the glomeruli, filter approximately 180 liters per day (125 mL/min) of plasma. The normal value for GFR depends upon age, sex, and body size, and is approximately 140 to 173 liters per day/1.73 m² (90 to 120 mL/min/1.73 m² ), with considerable variation even among healthy individuals [1-5].

Significance of a declining GFR — In patients with kidney disease, a fall in glomerular filtration rate (GFR) implies either progression of the underlying disease or the development of a superimposed and often reversible problem, such as decreased kidney perfusion due to volume depletion. In addition, the level of GFR has prognostic implications in patients with chronic kidney disease (CKD), and such patients are staged, in part, according to GFR. These issues are discussed in detail separately. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Definition and staging of chronic kidney disease in adults".)

There is not an exact correlation between the loss of kidney mass (ie, nephron loss) and the loss of GFR. The kidney adapts to the loss of some nephrons by compensatory hyperfiltration in the remaining, normal nephrons. Thus, an individual who has lost one-half of total kidney mass will not necessarily have one-half the normal amount of GFR.

These concepts have important consequences:

●A stable GFR does not necessarily imply stable disease. Signs of disease progression other than a change in GFR must be investigated, including increased activity of the urine sediment, a rise in protein excretion, or an elevation in blood pressure.

●Similarly, an increase in GFR may indicate improvement in the kidney disease or may imply a counterproductive increase in filtration (hyperfiltration) due to hemodynamic factors. (See "Secondary factors and progression of chronic kidney disease".)

●Some patients who have true underlying kidney disease may go unrecognized because they have a normal GFR.

ASSESSMENT OF GFR — The true glomerular filtration rate (GFR) cannot be measured directly in humans. Rather, it is determined from clearance measurements or serum levels of filtration markers, which are exogenous or endogenous solutes that are mainly eliminated by glomerular filtration.

Urinary clearance equals the rate of urinary excretion of the marker divided by its plasma concentration. Plasma clearance is the amount of marker eliminated from plasma per unit time factored by its plasma concentration. The gold standard method, which is recommended in selected circumstances, is urinary or plasma clearance of an exogenous filtration marker. (See 'Measurement of GFR (selected settings)' below.)

However, in most clinical settings, blood levels of endogenous filtration markers are used to estimate GFR (eGFR). Creatinine, which is widely available and frequently measured, is the most commonly used endogenous marker (algorithm 1). (See 'eGFR from creatinine (primary approach)' below.)

Cystatin C is another endogenous filtration marker. It is less commonly available compared with creatinine and is recommended as a confirmatory test. (See 'eGFR from cystatin C' below.)

Blood concentrations of endogenous filtration markers, like creatinine and cystatin C, are determined by GFR and other non-GFR physiologic determinants that cannot be easily measured, including generation rate of the marker, tubular secretion and reabsorption of the marker, or extrarenal elimination. GFR estimating equations incorporate known demographic and clinical variables as observed surrogates for these unmeasured non-GFR determinants. Estimation equations also appear to be reasonably accurate for following changes in GFR over long periods of time [2,6]. These equations do not provide accurate estimates of GFR in settings where the serum creatinine or cystatin C concentrations are changing rapidly (eg, acute kidney injury).

There are limitations to GFR estimating equations. Surrogates are only able to capture average relationships between the marker and its non-GFR determinants. Understanding the limitations is helpful for optimal assessment of GFR across the range of individuals and clinical scenarios [7].

We advise that, in some situations, eGFR calculated based upon the creatinine concentration be confirmed by performing other tests (algorithm 1) [8]. For confirmation, we usually obtain an eGFR based on plasma concentrations of both creatinine and cystatin C. If there is concern about the accuracy of cystatin C based estimates, we measure the GFR using either an exogenous filtration marker or measure the creatinine clearance with a timed urine collection. (See 'Confirmation of eGFR (when needed)' below.)

Estimation of GFR

eGFR from creatinine (primary approach) — For estimating GFR (eGFR) in most clinical situations, we and others recommend using the 2021 chronic kidney disease epidemiology (CKD-EPI) creatinine equation (calculator 1) rather than other creatinine-based estimating equations, such as the 2009 CKD-EPI equation, the Modification of Diet in Renal Disease (MDRD) study equation, or the Cockcroft-Gault equation (algorithm 1). Importantly, the 2021 CKD-EPI equation does not include a term for race.

Our recommendations are consistent with those made by the American Society of Nephrology (ASN) and National Kidney Foundation (NKF) [9]. Estimation of GFR in children is presented separately. (See "Chronic kidney disease in children: Definition, epidemiology, etiology, and course", section on 'Glomerular filtration rate'.)

Creatinine is derived from the metabolism of creatine in skeletal muscle and from dietary intake of cooked meat. It is released into the circulation at a relatively constant rate. Mean serum creatinine values differ between males and females (due to differences in muscle mass and, therefore, creatinine generation) as well as other factors [10-12]. Such factors are non-GFR determinants of the serum creatinine.  

Estimated GFR calculated with any creatinine-based equation will therefore be less accurate in people with more prominent non-GFR determinants of the serum creatinine (eg, high or low muscle mass or creatine/creatinine intake, children, patients with cirrhosis, serious chronic illness such as chronic heart failure, amputations or neuromuscular disease, or those with a high-protein or vegetarian diet) [7]. (See 'Limitations of creatinine-based eGFR' below.)

The 2009 CKD-EPI equation was developed to provide an accurate estimate of GFR among individuals with normal or only mildly reduced GFR (ie, above 60 mL/min per 1.73 m²) [13]. This equation was developed using data pooled from 10 studies and validated against data derived from 16 additional studies, in which the gold standard was direct measurement of GFR using external filtration markers (eg, iothalamate). The study population included people with and without kidney disease who had a wide range of GFRs. In the validation dataset, the 2009 CKD-EPI equation was as accurate as the MDRD study equation among individuals with eGFR less than 60 mL/min per 1.73 m² and somewhat more accurate in those with higher GFRs (figure 1).

These older equations include a term for race that, for any given creatinine value, results in a higher eGFR for Black individuals as compared with other individuals [14]. The rationale for using a race term in eGFR equations was based upon the empirical observation that the association between creatinine and GFR differs in self-reported Black people compared with others. This difference was thought to reflect biologic variations in non-GFR determinants such as muscle mass or creatinine handling. Inclusion of the race term led to unbiased estimates in both race groups.

The ongoing use of a race term in these equations is thought to no longer be appropriate [15-19]. First, race is a social construct, and including the coefficient for race ignores the substantial diversity within self-identified Black or African American patients. Second, there are observations that the race term does not improve accuracy of eGFR based upon creatinine when applied in all populations, such as African populations [20,21].

As a result of these concerns, the CKD-EPI group developed the 2021 CKD-EPI equation for estimating GFR from serum creatinine without a term for race (calculator 1). The equation was developed in the same dataset used for development of the 2009 CKD-EPI creatinine equation and was validated in a new dataset composed of 4050 participants in 12 studies [22]. Compared with the 2009 CKD-EPI creatinine equation, the 2021 equation is slightly less accurate [22,23], but it is acceptable for clinical use in many circumstances.

In the overall dataset, the 2021 equation underestimated measured GFR (mGFR) in Black individuals by 3.6 mL/min per 1.73 m² but overestimated mGFR in other individuals by approximately the same amount (3.9 mL/min per 1.73 m²) (figure 2) [22]. Although differences between mGFR and eGFR for this population were negligible, individual-level differences between the mGFR and the eGFR can be clinically relevant. In addition, differences between eGFR and mGFR can be large enough to affect chronic kidney disease (CKD) staging.

As an example, in an analysis of 3223 participants from four prospective cohorts in the United States, although the median difference between mGFR and eGFR was only 0.6 mL/min per 1.73 m², individual-level differences were often large (figure 3) [24]. At an eGFR of 60 mL/min per 1.73 m², 50 percent of mGFRs ranged from 52 to 67, 80 percent from 45 to 76, and 95 percent from 36 to 87 mL/min per 1.73 m². At an eGFR of 30 mL/min per 1.73 m², 50 percent of mGFRs ranged from 27 to 38, 80 percent from 23 to 44, and 95 percent from 17 to 54 mL/min per 1.73 m². Among patients with eGFR of 45 to 59 mL/min per 1.73 m², 36 percent had mGFR greater than 60 whereas 20 percent had mGFR less than 45 mL/min per 1.73 m²; among those with eGFR of 15 to 29 mL/min per 1.73 m², 30 percent had mGFR greater than 30 and 5 percent had mGFR less than 15 mL/min per 1.73 m². The eGFR based on cystatin C did not provide substantial improvement.

The ASN and NKF task force recommended the immediate adoption of the 2021 CKD-EPI creatinine equation which estimates kidney function without a race variable. The task force also recommended increased use of cystatin C combined with serum creatinine to confirm GFR [9]. (See 'Confirmation of eGFR (when needed)' below.)

One consequence of the 2021 CKD-EPI creatinine equation, when applied to the population, is a higher estimated prevalence of chronic kidney disease (CKD) among Black individuals (by 2 percent) and a lower estimated prevalence of CKD among other individuals (by 1.5 percent) (figure 2). The magnitude of the change is lower at lower levels of GFR. As an example, the estimated prevalence of stage 4 CKD (eGFR 15 to 29 mL/min/1.73 m²) only increased by 0.1 percent in Black individuals and decreased by only 0.38 percent in other individuals.

Another consequence is a minimization of the racial differences in risk of end-stage kidney disease (ESKD, also called kidney failure) at specific levels of creatinine-based eGFR. When eGFR was calculated using equations that included a race term, Black individuals had a substantially higher risk of ESKD at any given baseline eGFR [25]. Conversely, when the 2021 CKD-EPI creatinine equation was used to estimate eGFR among individuals with CKD (ie, eGFR <60 mL/min/1.73 m²), there was no significant difference in ESKD risk by race (figure 4) [26]. However, when the 2021 CKD-EPI using both creatinine and cystatin C was used, which is known to be more accurate than the creatinine-based equation, the racial differences persisted.

Other equations have emerged using standardized serum creatinine assays, such as the revised Lund-Malmö equation, which was developed in predominantly White populations, and the European Kidney Function Consortium (EKFC) equation, which, although also developed in predominantly White populations, uses a race-specific Q value [27-31]. In one study, the European Kidney Function Consortium creatinine equation was slightly more accurate than the 2021 CKD-EPI creatinine equation in both White and Black populations [32]. However, we use equations that do not take race into account.

There are also outstanding questions about calculating creatinine-based eGFR in Eastern Asian populations [33]. In Japan, for example, a modified CKD-EPI equation is used that applies a correction factor of 0.813, thereby decreasing the eGFR for a given creatinine value in this population. Such calibration factors are not generalizable across countries, which may also reflect population differences in non-GFR determinants or differences in methods to measure GFR or assay creatinine. Cystatin C-based eGFR appears to be more accurate than creatinine-based eGFR in some, but not all, Eastern Asian countries and does not require a calibration factor [33-35]. We do not use these correction factors for people from the Eastern Asian countries who are currently living in the United States. We would more readily consider confirmatory tests if the clinical situation requires a more accurate value.

Limitations of creatinine-based eGFR — There are several key limitations of using creatinine to estimate GFR (eGFR). These include variations in creatinine production, variations in creatinine secretion, extrarenal creatinine excretion, and issues associated with creatinine measurement.

A rise in serum creatinine from a previously stable baseline almost always represents a reduction in GFR (figure 5). However, certain drugs can interfere with either creatinine secretion or the assay used to measure the serum creatinine, and dietary changes or dietary supplements can alter creatinine production. In these settings, there will be a change in eGFR, but no change in measured GFR, no change in cystatin C-based eGFR (eGFRcys), and no concurrent elevation in the (blood urea nitrogen) BUN. (See "Drugs that elevate the serum creatinine concentration".)

●Variation in creatinine production – The production of creatinine differs among and within people over time. As examples, individuals with significant variations in dietary intake (vegetarian diet, creatine supplements) or reduction in muscle mass (amputation, malnutrition, muscle wasting) produce different amounts of creatinine than the general population. There is a great deal of variation in the effect of all of these among individuals. The accuracy of estimation equations appears to be affected to a greater extent among lower extremity amputees, given the much greater reduction in muscle mass, compared with upper extremity amputations.

There are certain settings in which there may be an acute increase in creatinine load. One example is a recent meal of cooked meat. In addition, it has been suggested that the serum creatinine rises more rapidly with rhabdomyolysis (up to 2.5 mg/dL or 220 micromol/L per day) than with other causes of acute kidney injury [36]. Release of preformed creatinine from injured muscle and/or release of creatine phosphate that is then converted into creatinine in the extracellular fluid have been proposed as explanations for this finding. However, neither of these mechanisms appears to account for most of the increase in the serum creatinine concentration [37]. An alternative explanation is that rhabdomyolysis often affects healthier individuals with higher muscle mass, while other forms of acute kidney injury frequently affect patients who are chronically ill and have lower muscle mass.

●Variation in creatinine secretion – The accuracy of GFR estimation with both the creatinine clearance and creatinine-based estimation equations is limited by the fact that as the GFR falls, the rise in the serum creatinine is partially opposed by enhanced proximal tubular creatinine secretion [38-42]. In early kidney disease when the GFR is still near normal, an initial decline in GFR may lead to only a slight increase (0.1 to 0.2 mg/dL [9 to 18 micromol/L]) in the serum creatinine. The net effect is that patients with a true GFR as low as 60 to 80 mL/min (as measured by the clearance of a true filtration marker such as inulin or radioisotopic iothalamate or diethylenetriaminepentaacetic acid [DTPA] [38,43,44]) may still have a serum creatinine that is ≤1 mg/dL (88 micromol/L) [45]. Thus, a relatively stable serum creatinine in the normal or near-normal range does not necessarily imply that the disease is stable.

However, once the serum creatinine exceeds 1.5 to 2 mg/dL (132 to 176 micromol/L), the secretory process is effectively saturated. After this, a stable value usually represents a stable GFR [45].

Apart from the increase in creatinine secretion with a decline in true GFR, creatinine secretion can vary over time and can also be affected by certain disorders and medications [38,46,47]:

•Tubular creatinine secretion is significantly increased in patients with the nephrotic syndrome. In one study, in which GFR was determined by inulin clearance, decreased serum albumin levels were associated with a marked increase in tubular creatinine secretion (36 mL/min per 1.73 m² for nephrotic patients with serum albumin levels less than 2.6 g/dL versus 11 mL/min per 1.73 m² for normal controls) [46]. Patients with sickle cell disease may also have an increase in creatinine secretion. Thus, patients with nephrotic syndrome and sickle cell disease may have a GFR that is substantially lower than what can be estimated from the serum creatinine.

•The presence of certain drugs may increase the level of the serum creatinine by as much as 0.4 to 0.5 mg/dL (35 to 44 micromol/L) by decreasing creatinine secretion. These drugs are discussed separately. (See "Drugs that elevate the serum creatinine concentration".)

●Extrarenal creatinine excretion – Extrarenal creatinine elimination is increased in advanced kidney failure (eg, eGFR <15 mL/min per 1.73 m²). In this setting, there are intestinal bacterial overgrowth and increased bacterial creatininase activity [48]. As a result, the serum creatinine concentration is lower than would be expected from the GFR.

●Requirement for stable serum creatinine – Endogenous filtration markers (eg, creatinine, cystatin C) can only be used to estimate GFR in individuals with stable serum creatinine [49]. Early in the course of acute kidney injury, for example, the GFR is markedly reduced, but there has not yet been time for the filtration marker to accumulate and, therefore, for the filtration marker to reflect the degree of kidney disease severity. An equation has been developed that estimates the true GFR given the rate of change in creatinine [50].

●Measurement issues – Serum creatinine is most often measured by the alkaline picrate method. Certain substances may interfere with the assay, thereby artifactually increasing the serum creatinine concentration. This colorimetric assay can recognize other compounds as creatinine chromogens, particularly acetoacetate in diabetic ketoacidosis, or bilirubin [51-55]. In the setting of diabetic ketoacidosis, the serum creatinine can rise by 0.5 to >2 mg/dL (44 to 176 micromol/L), a change that is rapidly reversed with insulin therapy [54,56]. Cefoxitin and flucytosine are drugs that can produce a similar effect. (See "Drugs that elevate the serum creatinine concentration".)

Differences in method and equipment used to determine the creatinine values can lead to variation in reported serum creatinine values [52,57]. This variation has been substantially reduced by the national program established by the National Kidney Disease Education Program to standardize creatinine assays so that they are all traceable to reference materials. Most manufacturers now use such calibrators, and therefore most clinical laboratories in the United States have assays traceable to these reference materials [58].

The variation in serum creatinine measurement methods leads to variation in creatinine-based GFR estimation [59]. This difference can result in substantial variations in GFR estimation when the serum creatinine concentration is relatively normal.

eGFR from cystatin C — Cystatin C is increasingly being used in in clinical practice. If cystatin C is used to estimate GFR (eGFR), we recommend the 2021 CKD-EPI creatinine-cystatin C equation (which employs both markers) or the 2012 CKD-EPI cystatin C equation. Of these, the equation that uses both creatinine and cystatin C is more accurate. Equations that estimate GFR based upon cystatin C can be found [60-68].

Cystatin C is a low-molecular-weight protein that is a member of the cystatin superfamily of cysteine protease inhibitors. Cystatin C is filtered at the glomerulus and not reabsorbed. However, it is metabolized in the tubules, which prevents use of cystatin C to directly measure clearance.

There are several non-GFR determinants of serum cystatin C; higher cystatin C levels are, for example, associated with male sex, greater height and weight, higher lean body mass, higher fat mass, diabetes, higher levels of inflammatory markers (eg, C-reactive protein), hyper- and hypothyroidism, and glucocorticoid use [34,49,69-76]. In addition, cystatin C levels increase with age [69] and vary by race (figure 6) [77] although, for both, the effect is less than observed for creatinine. Thus, like creatinine, non-GFR determinants of cystatin C also need to be considered in interpreting estimates of GFR that include cystatin C. The most accurate GFR estimates come from equations that contain both markers.

The 2012 CKD-EPI cystatin C and creatinine-cystatin C equation was developed using data pooled from 10 studies and validated against data derived from 16 additional studies in which the gold standard was direct measurement of GFR using external filtration markers (eg, iothalamate). The study population included people with and without kidney disease who had a wide range of GFRs. In the validation dataset, the 2012 CKD-EPI creatinine-cystatin C equation was more accurate than either the CKD-EPI creatinine or cystatin C equation.

Like the 2021 CKD-EPI creatinine equation, the 2021 CKD-EPI creatinine-cystatin C equation was developed without a term for race. The equation was generated using the same dataset used for development of the 2012 CKD-EPI creatinine-cystatin C equation and was validated in a new dataset composed of 4050 participants in 12 studies [16]. As noted above, the 2021 CKD-EPI creatinine equation is modestly less accurate than the 2012 CKD-EPI creatinine equation (underestimating GFR in Black individuals and overestimating eGFR in other individuals) (figure 7). However, such differences among race groups are attenuated with the 2021 CKD-EPI creatinine-cystatin C equation.

Confirmation of eGFR (when needed) — As noted above, confirmation of creatinine-based estimated GFR (eGFR) is appropriate in the following settings (algorithm 1):

●Individuals with prominent non-GFR determinants of serum creatinine:

•High muscle mass

•Creatine supplements

•Low muscle mass (eg, children, chronic heart failure, amputations, neuromuscular disease)

•High animal protein diet

•Vegetarian diet

•Liver disease

•Extreme frailty

●For confirmation of the diagnosis of CKD when the creatinine-based eGFR is 45 to 60 mL/min per 1.73 m² and there are no other features of CKD (such as albuminuria or radiologic abnormalities).

●Kidney donor evaluation – In the United States, performance of a clearance measurement (24-hour urine for creatinine clearance or urinary or plasma clearance of exogenous filtration markers) is required for GFR evaluation. Given errors in these measurements, it is helpful to interpret clearance measurements in light of the eGFR results [78,79]. An online tool for performing this evaluation is available. Very high posttest probabilities for creatinine-based eGFR (eGFRcr) or creatinine- and cystatin C-based eGFR (eGFRcrcys) provide reassurance that measured GFR is above the threshold, while very low posttest probabilities provide reassurance that measured GFR is below the threshold. (See 'Measurement of GFR (selected settings)' below and "Calculation of the creatinine clearance".)

With the exception of evaluating a potential kidney donor that requires clearance measurement in the United States, we first use the 2021 CKD-EPI creatinine-cystatin C equation to confirm eGFR in these settings.

If the eGFRcr and eGFRcrcys are in close agreement, one can be more certain of the level of eGFR, and, in most cases, there is no need to progress to clearance methods. However, if the two estimates differ, or if there are concerns that both creatinine and cystatin C may be unreliable markers of GFR, then we proceed to alternative methods.

These include measurement of GFR (using plasma or urinary clearance of an exogenous marker) or calculation of the creatinine clearance from a 24-hour urine collection, as is done to evaluate potential kidney donors. However, these methods are more cumbersome and can be reserved for when there remain additional questions about the accuracy of GFR estimation based upon serum markers. (See "Calculation of the creatinine clearance".)

As with the 2021 CKD-EPI creatinine equation, there can be important individual-level differences between eGFR (using the 2021 CKD-EPI creatinine-cystatin C equation) and measured GFR [22,24].

Methods of estimation we do not use — As noted above, we use the 2021 CKD-EPI creatinine equation to estimate GFR. If confirmation is needed, we use the 2021 CKD-EPI creatinine-cystatin C equation, calculate the creatinine clearance on a 24-hour urine collection, or measure GFR using an exogenous filtration marker. (See 'Confirmation of eGFR (when needed)' above.)

We do not recommend the use of the following methods to estimate GFR:

●The Modification of Diet in Renal Disease (MDRD) equation – The first modern-era GFR estimating equation was derived from data on adult patients with predominantly nondiabetic CKD who were enrolled in the MDRD study and who had GFR measured at baseline using urinary clearance of iothalamate (calculator 2) [80].

●The Cockcroft-Gault equation – The Cockcroft-Gault equation estimates creatinine clearance from the serum creatinine in a patient with a stable serum creatinine [81]. This formula takes into account assumptions that creatinine production decreases with advancing age and is greater in individuals with greater weight. However, this equation was developed at a point in history when obesity was far less common. In the current era, higher weight may mean greater fat mass and not greater muscle mass. For females, the formula requires multiplication by 0.85 to account for smaller muscle mass compared with males (calculator 3), but this is based on a hypothetic assumption [82,83].

The equation is not adjusted for body surface area. Thus, to compare with normal values, the result should be adjusted for body surface area. Normalization for body surface increases the accuracy of this equation, particularly among those with decreased kidney function [84].

The Cockcroft-Gault equation was developed prior to the use of standardized creatinine assays and has not been revised for use with creatinine values traceable to standardized reference materials. Thus, using the Cockcroft-Gault equation with creatinine values measured by most laboratories in the United States today will result in a 10 to 40 percent overestimate of creatinine clearance.

●Serum creatinine – Creatinine is freely filtered across the glomerulus and is neither reabsorbed nor metabolized by the kidney. However, approximately 10 to 40 percent of urinary creatinine is derived from tubular secretion by the organic cation secretory pathways in the proximal tubule. Thus, if GFR, creatinine secretion by the renal tubules, creatine intake (ie, diet), and the creatinine pool size (ie, muscle mass) all remain constant, then the serum creatinine concentration should remain constant.

The serum creatinine concentration varies inversely with the GFR. If, for example, the GFR falls by 50 percent, creatinine excretion will initially be reduced. Assuming that tubular creatinine secretion, diet, and muscle mass do not change, this reduction in GFR will lead to creatinine retention and a rise in the serum creatinine until it has doubled (figure 5); at this point, the filtered load will again be equal to excretion. The shape of the curve relating the GFR to serum creatinine has an important clinical implication (figure 5): in patients with normal or slightly reduced GFR, a small rise in serum creatinine usually reflects a marked fall in GFR, whereas a marked rise in serum creatinine in patients with advanced disease reflects a small absolute reduction in GFR.

However, this curve depicts a hypothetical relationship; in reality, a reduction in GFR results in increased tubular creatinine secretion that blunts the rise in serum creatinine. Thus, a 50 percent reduction in GFR does not produce a doubling of serum creatinine but rather a smaller rise than would have occurred if the decrease in GFR had occurred without an increase in secretion.

●Blood urea nitrogen (BUN) – Although the BUN, like serum creatinine, also varies inversely with the GFR, it is generally less useful than the serum creatinine because the BUN can change independently of the GFR [38,85]. The rate of urea production is not constant, increasing with a high-protein diet and with enhanced tissue breakdown due to hemorrhage, trauma, or glucocorticoid therapy; conversely, a low-protein diet or liver disease can lower the BUN without change in GFR [86,87].

Approximately 40 to 50 percent of the filtered urea is passively reabsorbed, mostly in the proximal tubule. Thus, when volume depletion is associated with enhanced proximal sodium and water reabsorption, there is a parallel increase in urea reabsorption. As a result, the BUN will rise out of proportion to any change in GFR and therefore to any change in the serum creatinine. This elevation in the BUN-to-creatinine ratio is one of the suggestive clinical signs of decreased kidney perfusion (prerenal disease) as the cause for kidney failure. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults".)

The measurement of the clearance of urea is useful in one setting. Among patients with severe kidney disease, the urea clearance significantly underestimates the GFR. Since the creatinine clearance significantly overestimates this function, one method to estimate the GFR in patients with advanced kidney disease is to average both the creatinine and urea clearances [88,89]. (See "Calculation of the creatinine clearance".)

Measurement of GFR (selected settings) — Measurement of glomerular filtration rate (GFR) is complex, time consuming, and cumbersome to do in clinical practice. As such, GFR is usually estimated from serum markers. (See 'Measurement of GFR with plasma clearance' below.)

However, in some clinical situations, it is important to have more precise knowledge of the GFR than can be provided by estimates. (See 'Confirmation of eGFR (when needed)' above.)

Measurement of GFR with urinary clearance — Although glomerular filtration rate (GFR) cannot be measured directly, the best method for determining GFR is measurement of the urinary clearance of an ideal filtration marker. Using a filtration marker (x), the equation to calculate the clearance of x (Cx) is:

Where Px is the serum concentration of the marker, Ux is the urinary concentration of x, and V is the urine flow rate.  

An ideal filtration marker is defined as a solute that is freely filtered at the glomerulus, nontoxic, neither secreted nor reabsorbed by the renal tubules, and not changed during its excretion by the kidney. If these criteria are met, the filtered load is equal to the rate of urinary excretion:

Where GFR x Px is the filtered load, and Ux x V is the urinary excretion rate. By substitution into Equation 1:

Various filtration markers are available:

●Inulin – The gold standard of exogenous filtration markers is inulin. Inulin is a physiologically inert fructose polymer that is freely filtered at the glomerulus and is neither secreted, reabsorbed, synthesized, nor metabolized by the kidney [90]. Thus, the amount of inulin filtered at the glomerulus is equal to the amount excreted in the urine, which can be measured. Inulin, however, is in short supply (and is no longer available in the United States), expensive, and difficult to assay. In addition, the classic protocol for measuring inulin clearance requires a continuous intravenous infusion to achieve a steady state plasma concentration, multiple blood samples, and bladder catheterization for accurate collection of a timed urine specimen.

●Alternative exogenous filtration markers – Because measurement of inulin clearance is impractical, radioactive or nonradioactive iothalamate, iohexol, DTPA, and ethylenediaminetetraacetic acid (EDTA) have been used to measure GFR [38,90-92]. The marker is administered by intravenous bolus or bolus subcutaneous injection. Subcutaneous injection allows for a slower release of the marker into the circulation and more constant plasma levels. Multiple (two to four) 20- to 30-minute urine collections are then obtained, and clearance is computed for each urine collection period to obtain an average value. Administration of water before and during the protocol is necessary to stimulate urine flow. Sources of error include differences in properties of the exogenous filtration marker used to replace inulin, errors in determining the concentration of the marker [6,93], or random errors due to the complex procedure. A meta-analysis of studies comparing one marker to another or to inulin concluded that renal clearances of ⁵¹Cr-EDTA or iothalamate and plasma clearances of ⁵¹Cr-EDTA or iohexol are the most accurate methods [94].

Measurement of GFR with plasma clearance — Plasma clearance is an alternative to urinary clearance for measurement of glomerular filtration rate (GFR). It is performed by timed plasma measurements after administering a bolus intravenous injection of an exogenous filtration marker; the clearance equation is:

Where Ax is the amount of the marker administered, and Px is the plasma concentration computed from the entire area under the disappearance curve.

As noted above, plasma clearances of ⁵¹Cr-EDTA or iohexol are the most accurate methods [94]. Measurement of GFR using plasma clearance takes longer than measurement using urinary clearance (ie, 5 to 10 hours may be required to establish the disappearance curve, depending on the severity of kidney function impairment). In addition, GFR may be overestimated when measured by plasma clearance if a shorter protocol is used and among patients with edema (because of a larger volume of distribution of the filtration marker).

GLOMERULAR FILTRATION RATE FOR DRUG DOSING — Drug dosing guidelines have historically been developed using the Cockcroft-Gault equation to estimate kidney function. This practice had been consistent with the original recommendation of the US Food and Drug Administration (FDA) to pharmaceutical industries to use an estimating equation, rather than serum creatinine alone, in pharmacokinetic studies to determine drug dosing in kidney disease. Most pharmacokinetic studies for drug dosing in kidney disease were performed using the Cockcroft-Gault equation since this equation was suggested by the FDA prior to publication of the Modification of Diet in Renal Disease (MDRD) study equation [95].

Standardization of creatinine assays created a problem with drug dosing because many pharmacokinetic studies were performed using nonstandardized serum creatinine values, and therefore the results of these studies cannot necessarily be translated reliably into current clinical practice [96]. Use of the Cockroft-Gault equation could lead to inaccuracies in drug dosing in patients with kidney disease. After creatinine values were standardized, pharmacokinetic studies have been done using a variety of methods.

The Kidney Disease Improving Global Outcomes 2011 clinical update on drug dosing in patients with acute and chronic kidney diseases recommended using the most accurate method for glomerular filtration rate (GFR) evaluation for each patient (rather than limiting the evaluation to the Cockcroft-Gault formula) and specifically including estimated GFR (eGFR) as it is reported by clinical laboratories or measured GFR if creatinine-based estimates are not accurate for individual patients [97].

If eGFR is used for drug dosing in very large or small patients, the reported eGFR (which is normalized to body surface area) should be multiplied by the estimated body surface area and then divided by 1.73 to obtain an eGFR in units of mL/min (ie, not normalized to body surface area).

As noted above, for patients at the extremes of muscle mass, with unusual diets, or with conditions associated with changes in creatinine secretion, all estimation equations that use the serum creatinine are limited. In such cases, dosing decisions should be made based upon GFR estimated with cystatin- or creatinine-cystatin-based equations, with measured creatinine clearance, or with measured GFR using exogenous filtration markers, particularly if prescribing drugs with a narrow therapeutic window. (See 'Measurement of GFR (selected settings)' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults" and "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Glomerular filtration rate (GFR) – The GFR is equal to the sum of the filtration rates in all of the functioning nephrons. The normal value for GFR depends upon age, sex, and body size, and is approximately 140 to 173 liters per day/1.73 m² (100 to 120 mL/min/1.73 m²), with considerable variation even among healthy individuals. A fall in GFR typically indicates a chronic or acute kidney injury. In addition, the level of GFR has prognostic implications in patients with chronic kidney disease (CKD). (See 'Glomerular filtration rate' above.)

●Assessment of GFR in clinical practice – In most clinical settings, blood levels of endogenous filtration markers are used to estimate GFR (eGFR). Creatinine, which is widely available and frequently measured, is the most commonly used endogenous marker (algorithm 1). Cystatin C is another endogenous filtration marker. It is less commonly available compared with creatinine and is recommended as a confirmatory test. (See 'Assessment of GFR' above.)

●Estimating GFR (primary approach) – For estimating GFR in most clinical situations, we and others recommend using the 2021 chronic kidney disease epidemiology (CKD-EPI) creatinine equation (calculator 1) rather than other creatinine-based estimating equations (algorithm 1), such as the 2009 CKD-EPI equation, the Modification of Diet in Renal Disease (MDRD) study equation, or the Cockcroft-Gault equation. Importantly, the 2021 CKD-EPI equation does not include a term for race. Compared with the 2009 CKD-EPI creatinine equation, the 2021 equation is slightly less accurate; it underestimates measured GFR in Black individuals and overestimates measured GFR in other individuals; however, the overall accuracy is reasonable for both groups (figure 2). There are several key limitations of using creatinine to estimate GFR. These include variations in creatinine production, variations in creatinine secretion, extrarenal creatinine excretion, and issues associated with creatinine measurement. (See 'eGFR from creatinine (primary approach)' above and 'Limitations of creatinine-based eGFR' above.)

●Confirmation of eGFR (when needed) – Confirmation of creatinine-based eGFR is appropriate in the following individuals: those with prominent non-GFR determinants of serum creatinine (eg, high or low muscle mass, a high protein diet, creatine supplements, vegetarian diet, liver disease, extreme frailty); when confirmation of a CKD diagnosis is required in someone with a creatinine-based eGFR is 45 to 60 mL/min per 1.73 m² and no other features of CKD (such as albuminuria or radiologic abnormalities); and in potential kidney donors. To confirm eGFR in most patients, we measure cystatin C and use the 2021 CKD-EPI creatinine-cystatin C equation. If the creatinine-based eGFR and the creatinine-cystatin C-based eGFR differ, or if there are concerns that both creatinine and cystatin C may be unreliable markers of GFR, then we proceed to alternative methods (measurement of GFR or calculation of creatinine clearance from a 24-hour urine). (See 'Confirmation of eGFR (when needed)' above.)

●Measurement of GFR in selected settings – Measurement of GFR is complex, time consuming, and cumbersome to do in clinical practice. However, when necessary, GFR can be measured using urinary clearance of an ideal filtration marker (eg, inulin, iothalamate, iohexol) or using plasma clearance (of ⁵¹Cr-EDTA or iohexol). (See 'Measurement of GFR (selected settings)' above.)

●GFR assessment for drug dosing – Drug dosing guidelines have historically been developed using the Cockcroft-Gault equation to estimate kidney function. However, for various reasons, use of the Cockroft-Gault equation could lead to inaccuracies in drug dosing in patients with kidney disease. We recommended using eGFR (or measured GFR if there are concerns about eGFR accuracy). If eGFR is used for drug dosing in very large or small patients, the reported eGFR (which is normalized to body surface area) should be multiplied by the estimated body surface area and then divided by 1.73 to obtain an eGFR in units of mL/min. (See 'Glomerular filtration rate for drug dosing' above.)