The gold standard quantitative index of kidney function is a mGFR. A variety of methods may be used to measure and estimate kidney function in the acute care and ambulatory settings. Measurement of GFR is important for early recognition and monitoring of patients with CKD and as a guide for drug-dose adjustment.
It is important to recognize conditions that may alter renal function independent of underlying renal pathology. For example, protein intake, such as oral protein loading or an infusion of amino acid solution, may increase GFR.13 As a result, inter- and intrasubject variability must be considered when it is used as a longitudinal marker of renal function. Dietary protein intake has been demonstrated to correlate with GFR in healthy subjects. Brändle et al.77 evaluated renal function in four groups of healthy volunteers, each ingesting a diet controlled for protein over a 4-month period. The GFR was nonlinearly related to the urine nitrogen excretion, with an observed maximum of 181.7 mL/min (3.03 mL/s) at a urinary nitrogen excretion rate of 20 g/day (1.43 mol/day), or 125 g/day protein intake. Subjects who are vegetarian have a lower GFR because of their reduced dietary protein intake relative to individuals who consume a similar caloric but normal-protein-content diet. When challenged with a protein load, the vegetarian subjects are able to increase their GFR to the “normal” range.13 Findings from the Nurses’ Health Study78 indicate that longitudinal changes in GFR are independent of the source of protein (nondairy animal, dairy, or vegetable) in women with normal renal function. However, women with mild renal insufficiency (GFR 71 ± 7 mL/min [1.18 ± 0.12 mL/s]) who consumed the highest amount of protein (93 g/day) had a threefold greater risk of a more than or equal to 5 mL/min (≥0.08 mL/s) decline in GFR compared to the lowest protein group (60 g/day); rates of decline were highest in those consuming nondairy animal protein. The increased GFR following a protein load is the result of renal vasodilation accompanied by an increased renal plasma flow. The exact mechanism of the renal response to protein is unknown, but may be related to extrarenal factors such as glucagon, prostaglandins, and angiotensin II, or intrarenal mechanisms, such as alterations in tubular transport and tubuloglomerular feedback.79,80 Despite the evidence of a “renal reserve,” standardized evaluation techniques have not been developed. Therefore, assessment of a mGFR must consider the dietary protein status of the patient at the time of the study.
Measurement of Glomerular Filtration Rate
A mGFR remains the single best index of kidney function. As renal mass declines in the presence of age-related loss of nephrons or disease states such as hypertension or diabetes, there is a progressive decline in GFR. The rate of decline in GFR can be used to predict the time to onset of stage 5 CKD, as well as the risk of complications of CKD. Accurate measurement of GFR in clinical practice is a critical variable for the individualization of the dosage regimens of renally excreted medications so that one can maximize their therapeutic efficacy and avoid potential toxicity.
The GFR is expressed as the volume of plasma filtered across the glomerulus per unit time, based on total renal blood flow and capillary hemodynamics. The normal values for GFR are 127 ± 20 mL/min/1.73 m2 (1.22 ± 0.19 mL/s/m2) and 118 ± 20 mL/min/1.73 m2 (1.14 ± 0.19 mL/s/m2) in healthy men and women, respectively. These measured values closely approximate what one would predict if the normal renal blood flow were approximately 1.0 L/min/1.73 m2 (0.01 mL/s/m2), plasma volume was 60% of blood volume, and filtration fraction across the glomerulus was 20%. In that situation the normal GFR would be expected to be approximately 120 mL/min/1.73 m2 (1.16 mL/s/m2).
Optimal clinical measurement of GFR involves determining the renal clearance of a substance that is freely filtered without additional clearance because of tubular secretion or reduction as the result of reabsorption. Additionally, the substance should not be susceptible to metabolism within renal tissues and should not alter renal function. Given these conditions, the mGFR is equivalent to the renal clearance of the solute marker:
GFR = renal CL = (Ae)/AUC0–t
where renal CL is renal clearance of the marker, Ae is the amount of marker excreted in the urine in a specified period of time, t, and AUC0-t is the area under the plasma-concentration-versus-time curve of the marker.
Under steady-state conditions, for example during a continuous infusion of the marker, the expression simplifies to
GFR = renal CL = (Ae)/[(Css) × t]
where Css is the steady-state plasma concentration of the marker achieved during continuous infusion. The continuous infusion method can also be employed without urine collection, where plasma clearance is calculated as CL = infusion rate/Css. This method is dependent on the attainment of steady-state plasma concentrations and accurate measurement of infusate concentrations. Plasma clearance can also be determined following a single-dose IV injection with the collection of multiple blood samples to estimate area under the curve (AUC0-∞). Here, clearance is calculated as CL = dose/AUC. These plasma clearance methods commonly yield clearance values 10% to 15% higher than GFR measured by urine collection methods.81,82
Several markers have been used for the measurement of GFR and include both exogenous and endogenous compounds. Those administered as exogenous agents, such as inulin, sinistrin, iothalamate, iohexol, and radioisotopes, require specialized administration techniques and detection methods for the quantification of concentrations in serum and urine, but generally provide an accurate measure of GFR. Methods that employ endogenous compounds, such as creatinine or cysC, require less technical expertise, but produce results with greater variability. The GFR marker of choice depends on the purpose and cost of the compound which ranges from $2,000 per vial for radioactive for 125I-iothalamate (Glofil-125, QOL Medical) to $6 per vial for nonradiolabeled iothalamate (Conray-60, Mallincrodt) or iohexol (Omnipaque-300, GE Medical) (Table e42-5).
TABLE e42-5Sensitivity and Clinical Utility of Renal Function Tests |Favorite Table|Download (.pdf) TABLE e42-5 Sensitivity and Clinical Utility of Renal Function Tests
| ||Accuracy ||Clinical Utility ||Cost |
|Inulin clearance ||++++ ||+ || |
|Radiolabeled markers ||+++ ||+ ||$$$ |
|Nonisotopic contrast agents ||+++ ||++ ||$$$ |
|Creatinine clearance ||++ ||+++ ||$$ |
|Serum cystatin C ||+ ||+++ ||$$ |
|Serum creatinine ||+ ||++++ ||$ |
Inulin and Sinistrin Clearance
Inulin is a large fructose polysaccharide (5,200 Da), obtained from the Jerusalem artichoke, dahlia, and chicory plants. It is not bound to plasma proteins, is freely filtered at the glomerulus, is not secreted or reabsorbed, and is not metabolized by the kidney. The volume of distribution of inulin approximates extracellular volume, or 20% of ideal body weight. Because it is eliminated by glomerular filtration, its elimination half-life is dependent on renal function and is approximately 1.3 hours in subjects with normal renal function. Measurement of plasma and urine inulin concentrations can be performed using high-performance liquid chromatography.83 Sinistrin, another polyfructosan, has similar characteristics to inulin; it is filtered at the glomerulus and not secreted or reabsorbed to any significant extent. It is a naturally occurring substance derived from the root of the North African vegetable red squill, Urginea maritime, which has a much higher degree of water solubility than inulin. Assay methods for sinistrin have been described using enzymatic procedures, as well as high-performance liquid chromatography with electrochemical detection.84 Alternatives have been sought for inulin as a marker for GFR because of the problems of availability, high cost, sample preparation, and assay variability.
Iothalamate is an iodine-containing radiocontrast agent that is available in both radiolabeled (125I) and nonradiolabeled forms. This agent is handled in a manner similar to that of inulin; it is freely filtered at the glomerulus and does not undergo substantial tubular secretion or reabsorption. The nonradiolabeled form is most widely used to measure GFR in ambulatory and research settings, and can safely be administered by IV bolus, continuous infusion, or subcutaneous injection.82 Plasma and urine iothalamate concentrations can be measured using high-performance liquid chromatography.85,86 Plasma clearance methods that do not require urine collections have been shown to be highly correlated with renal clearance, making them particularly well-suited for longitudinal evaluations of renal function.82,87 These plasma clearance methods require two-compartment modeling approaches because accuracy is dependent on duration of sampling. For example, Agarwal et al.87 demonstrated that short sampling intervals can overestimate GFR, particularly in patients with severely reduced GFR. In individuals with GFR more than 30 mL/min/1.73 m2 (greater than 0.29 mL/s/m2), a 2-hour sampling strategy yielded GFR values that were 54% higher compared with 10-hour sampling, whereas the 5-hour sampling was 17% higher. In individuals with GFR less than 30 mL/min/1.73 m2 (less than 0.29 mL/s/m2), the 5-hour GFR was 36% higher and 2-hour GFR was 126% higher than the 10-hour measurement. The authors proposed a 5- to 7-hour sampling time period with eight plasma samples to be the most appropriate and feasible approach for most GFR evaluations.
Iohexol, a nonionic, low osmolar, iodinated contrast agent, has also been used for the determination of GFR. It is eliminated almost entirely by glomerular filtration, and plasma and renal clearance values are similar to observations with other marker agents: Strong correlations of 0.90 or greater and significant relationships with iothalamate have been reported.88,89,90 These data support iohexol as a suitable alternative marker for the measurement of GFR. A reported advantage of this agent is that a limited number of plasma samples (as few as two collected at 120 and 300 minutes after injection) can be used to quantify iohexol plasma clearance.91 For patients with a reduced GFR more time must be allotted—more than 24 hours if the eGFR is less than 20 mL/min (0.33 mL/s).
The GFR has also been quantified using radiolabeled markers, such as 125I-iothalamate (614 Da, radioactive half-life of 60 days), 99mTc-DPTA (393 Da, radioactive half-life of 6.03 hours), and 51Cr-ethylenediaminetetraacetic acid (51Cr-EDTA; 292 Da, radioactive half-life of 27 days).92 These relatively small molecules are minimally bound to plasma proteins and do not undergo tubular secretion or reabsorption to any significant degree. 125I-iothalamate and 99mTc-DPTA are used in the United States, whereas 51Cr-EDTA is used extensively in Europe. The use of radiolabeled markers allows one to determine the individual contribution of each kidney to total renal function.93 Various protocols exist for the administration of these markers and subsequent measurement of GFR using either plasma or renal clearance calculation methods. The nonrenal clearance of these agents appears to be low (3-8 mL/min [0.05-0.13 mL/s]), suggesting that plasma clearance is an acceptable technique except in patients with severe renal insufficiency (GFR less than 30 mL/min [less than 0.50 mL/s]). Indeed, highly significant correlations between renal clearance among radiolabeled markers has been demonstrated.94 Although total radioactive exposure to patients is usually minimal, use of one of these agents does require compliance with radiation safety committees and appropriate biohazard waste disposal.
Optical Real-Time Glomerular Filtration Rate Markers
A clinically applicable technique to rapidly measure GFR, particularly in critically ill patients with unstable kidney function, is highly desirable. The currently available GFR measurement approaches, as outlined above, are technically demanding, time-consuming, and often cost-prohibitive. Research is underway to develop rapid, accurate, safe, and inexpensive techniques to address this need.95,96 For example, small, nontoxic, exogenously administered fluorescent tracers are being investigated for “real-time” GFR measurement, and at least two have entered early phase clinical trials. Both methods involve administration of optically active compounds, with continuous detection of the fluorescence signal using fiber optic or photonics technologies. A system involving injection of fluorescent dextran molecules with blood sampling and rapid (bedside) detection over 120 minutes is being developed by FAST BioMedical (Indianapolis, IN), and an NIH-funded clinical trial in healthy volunteers and patients with AKI/CKD was completed in 2014 (NCT01978314, ClinicalTrials.gov). Another method being developed by MediBeacon, LLC (St. Louis, MO), involves injection of a hydrophilic pegylated pyrazine dye (MB-102), with continuous detection using a transdermal photonics system. The results of preclinical safety and early Phase 1 testing indicate that the lead compound (MB-102) yields comparable estimates of GFR to those obtained with iohexol administration in healthy subjects.97 The current challenge of these approaches will be to translate fluorescent signals into quantitative in vivo measurements of GFR.
Measured Creatinine Clearance
Although the measured (24-hour) CLcr has been used as an approximation of GFR for decades, it has limited clinical utility for a multiplicity of reasons. Short-duration witnessed mCLcr correlates well with mGFR based on iothalamate clearance performed using the single-injection technique. In a multicenter study98 of 136 patients with type 1 diabetic nephropathy, the correlations of simultaneous mCLcr, and 24-hour CLcr (compared to CLiothalamate) were 0.81 and 0.49, respectively, indicating increased variability with the 24-hour clearance determination. In a selected group of 110 patients, measurement of a 4-hour CLcr during water diuresis provided the best estimate of the GFR as determined by the CLiothalamate. Furthermore, the ratio of CLcr to CLiothalamate did not appear to increase as the GFR decreased. These data suggest that a short collection period with a water diuresis may be the best CLcr method for estimation of GFR.
A limitation of using creatinine as a filtration marker is that it undergoes tubular secretion. Tubular secretion augments the filtered creatinine by approximately 10% in subjects with normal kidney function. If the nonspecific Jaffe reaction is used, which overestimates the Scr by approximately 10% because of the noncreatinine chromogens, then the measurement of CLcr is a very good measure of GFR in patients with normal kidney function. Tubular secretion, however, increases to as much as 100% in patients with kidney disease, resulting in mCLcr values that markedly overestimate GFR. For example, Bauer et al.31 reported that the CLcr-to-CLinulin ratio in subjects with mild impairment was 1.20; for those with moderate impairment, it was 1.87; and in those with severe impairment, it was 2.32. Thus, a mCLcr is a poor indicator of GFR in patients with moderate to severe renal insufficiency, that is, stages 3 to 5 CKD.
Because cimetidine blocks the tubular secretion of creatinine the potential role of several oral cimetidine regimens to improve the accuracy and precision of mCLcr as an indicator of GFR has been evaluated. The CLcr-to-CLDPTA ratio declined from 1.33 with placebo to 1.07 when 400 mg of cimetidine was administered four times a day for 2 days prior to and during the clearance determination.99 Similar results were observed when a single 800-mg dose of cimetidine was given 1 hour prior to the simultaneous determination of CLcr and CLiothalamate; the ratio of CLcr to CLiothalamate was reduced from a mean of 1.53 to 1.12.100 Thus a single oral dose of 800 mg of cimetidine should provide adequate blockade of creatinine secretion to improve the accuracy of a CLcr measurement as an estimate GFR in patients with stages 3 to 5 CKD.
To minimize the impact of diurnal variations in Scr on CLcr, the test is usually performed over a 24-hour period with the plasma creatinine obtained in the morning, as long as the patient has stable kidney function. Collection of urine remains a limiting factor in the 24-hour CLcr because of incomplete collections, and interconversion between creatinine and creatine that can occur if the urine is not maintained at a pH less than 6.
Estimation of Glomerular Filtration Rate
Because of the invasive nature and technical difficulties of directly measuring GFR in clinical settings, many equations for estimating GFR have been proposed over the past 10 years (Table e42-6). A series of related GFR estimating equations have been developed for the primary purpose of identifying and classifying CKD in many patient populations.101,102,103,104,105,106,107,108 The initial equation was derived from multiple regression analysis of data obtained from the 1,628 patients enrolled in the Modification of Diet in Renal Disease Study (MDRD) where GFR was measured using the renal clearance of 125I-iothalamate methodology. A four-variable version of the original MDRD equation (MDRD4), based on plasma creatinine, age, sex, and race, was shown to provide a similar estimate of GFR results when compared to a six-variable equation predecessor.102 However, this equation was shown to be inaccurate at GFR more than 60 mL/min/1.73m2 (less than 0.58 mL/s/m2), for reasons not associated with standardization of Scr (IDMS) assay results.103 The MDRD4–IDMS equation is still included in the recommendations of the National Kidney Foundation (NKF) and the National Kidney Disease Education Program (NKDEP) for calculating the eGFR in patients with a history of CKD risk factors and a GFR less than 60 mL/min/1.73 m2 (less than 0.58 mL/s/m2). A recent study conducted by the FDA compared the eGFR estimated by the MDRD4 equation to the CLcr estimated by the Cockcroft-Gault (CG) equation in 973 subjects enrolled in pharmacokinetic studies conducted for new chemical entities submitted to the FDA from 1998 to 2010.107 The MDRD4 eGFR results consistently overestimated the CLcr calculated by the CG method. The FDA investigators concluded that “For patients with advanced age, low weight, and modestly elevated serum creatinine concentration values, further work is needed before the MDRD equations can replace the CG equation for dose adjustment in approved product information labeling.”
TABLE e42-6Equations for the Estimation of Glomerular Filtration Rate in Adults with Stable Renal Function |Favorite Table|Download (.pdf) TABLE e42-6 Equations for the Estimation of Glomerular Filtration Rate in Adults with Stable Renal Function
|Levey et al.102 (MDRD4) ||eGFR = 186 × (Scr)–1.154 × (age)–0.203 × (0.742 if patient is female) × (1.210 if patient is black) |
|Levey et al.103 (MDRD4-IDMS) ||eGFR = 175 × (Scr)–1.154 × (age)–0.203 × (0.742 if patient is female) × (1.210 if patient is black) |
|Levey et al.109 (CKD-EPI) ||eGFR = 141 × min(Scr/ κ, 1)α × max(Scr/,κ, 1)–1.209 × 0.993age × 1.018 [if female] × 1.159 [if black] |
|Schaeffner et al.111 (BIS1) ||eGFR = 3736 × (Scr)–0.87 × (age)–0.95 × (0.82 if patient is female) |
|Schaeffner et al.111 (BIS2) ||eGFR = 767 × (cysC)–0.61 × (Scr)–0.40 × (age)–0.57 × (0.87 if patient is female) |
|Larsson et al.117 ||eGFR = 77.24 × (cysC in mg/L)–1.2623 |
|Macdonald et al.116 || |
eGFR = 127.7 × (cysC in mg/L)–1.17 × (age in years)–0.13 × 0.91 (if female) × 1.06 (if black)
*eGFR = 127.7 × (–0.105 + 1.13 × standardized ScysC)–1.17 × age–0.13 × (0.91 if female) × (1.06 if black)
eGFR (mL/min/1.73 m2) = 76.7 × (cysC in mg/L)–1.19
*eGFR (mL/min/1.73 m2) = 76.7 × (–0.105 + 1.13 × cysC in mg/L)–1.19
eGFR (mL/min/1.73 m2) = 177.6 × (Scr in mg/dL)–0.65 × (cysC in mg/L)–0.57 × (age in years)–0.20 × 0.82 [if female] × 1.11 [if black]
*eGFR (mL/min/1.73 m2) = 177.6 × (Scr in mg/dL)–0.65 × (–0.105 + 1.13 × cysC in mg/L)–0.57 × (age in years)–0.20 × 0.82 [if female] × 1.11 [if black]
Although widely adopted and incorporated into many EMR systems throughout the United States, the four-variable MDRD study equation has been shown to be inaccurate and inferior to other eGFR equations as well as the CG equation. Replacement of MDRD4 with updated versions, such as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), in automated eGFR reporting systems is intended, although the timeline for the transition is not consistent across all clinical settings.
A single eGFR equation may not be best suited for all populations, and choice of equation has been shown to impact CKD prevalence estimates.108 This has led to a revitalized interest in the development of new equations to estimate GFR. The newest equations to be proposed for the estimation of GFR have been derived from wider CKD populations than the MDRD study, and include the CKD-EPI109,110 and the Berlin Initiative Study (BIS).111 The CKD-EPI equation was developed from pooled study data involving 5,500 patients (including the original MDRD population), with mean GFR values of 68 ± 40 mL/min/1.73 m2 (0.65 ± 0.39 mL/s/m2) (range 2-190 mL/min/1.73 m2 [0.02-1.83 mL/s/m2]). It has been reported that the CKD-EPI equation is less biased (2.5 vs 5.5 mL/min/1.73 m2 [0.024 vs 0.053 mL/s/m2]) but similarly imprecise compared to MDRD4.110
Chronic Kidney Disease–EPI Equation
The CKD-EPI study equation was compared to the MDRD equation using pooled data from patients enrolled in research or clinical outcomes studies, where GFR was measured by any exogenous tracer.110 The results of the study indicated that the bias of CKD-EPI equation was 61% to 75% lower than the MDRD equation for patients with eGFR of 60 to 119 mL/min/1.73 m2 (0.58-1.15 mL/s/m2). Based on these findings, the CKD-EPI equation is most appropriate for estimating GFR in individuals with eGFR values more than 60 mL/min/1.73 m2 (greater than 0.58 mL/s/m2). Both the KDOQI and the Australasian Creatinine Consensus Working Groups now recommend that clinical laboratories switch from the MDRD4 to CKD-EPI for routine automated reporting.23,112 If one’s clinical lab does not automatically calculate eGFR using the CKD-EPI, it becomes a bit of a challenge since the equation requires a more complex algorithm than the MDRD equation.
Limitations of the pooled analysis approach used to develop the MDRD and CKD-EPI equations include the use of different GFR markers between studies (iothalamate, 51CR-EDTA, 99mTc-DTPA), different methods of administration of the GFR markers (subcutaneous and IV), and different clearance calculations (renal clearance vs plasma disappearance). These limitations may partly explain the reduced accuracy observed with the MDRD4 equation at GFR values more than 60 mL/min/1.73 m2 (greater than 0.58 mL/s/m2). Additionally, a recent inspection of the MDRD GFR study data showed that large intrasubject variability in GFR measures was a likely contributor to the inaccuracy of the gold standard method ([125I] iothalamate urinary clearance) that was used to create the MDRD equation.113
Numerous studies have reported that the MDRD4 and CKD-EPI eGFR equation derived values overestimate CG equation values for eCLcr.114,115 For example, Wargo et al.114 evaluated 409 patients with CKD admitted to a tertiary care clinic. The CKD-EPI equation values significantly overestimated the CG equation derived eCLcr determinations (39.9 mL/min vs 34.8 mL/min [0.67 mL/s vs 0.58 mL/s], respectively; p less than 0.001), with 95% of cases ranging from –5.1 mL/min to +15.3 mL/min (–0.09 mL/s to +0.26 mL/s). In the largest retrospective study comparing the eCLcr by CG and eGFR by MDRD4, Melloni et al.115 reported that eGFR (expressed in mL/min) resulted in a failure to make manufacturer-recommended dose reductions for enoxaparin and the glycoprotein IIb/IIIa inhibitor (GPI) eptifibatide in up to 50% of their cohort of more than 49,000 patients. The excessive eGFR-derived doses were also correlated with major bleeding episodes (odds ratio 1.57 [95% CI 1.35-1.84]). Thus, the MDRD4 equation for eGFR should not be used in lieu of eCLcr by CG for renal dose adjustments for these drugs. The results of these studies highlight the need to understand that eGFR equations such as MDRD4 and CKD-EPI were developed for the purpose of identifying and stratifying CKD based on large multicenter epidemiologic studies. Extension of their use for individualized drug dosing has not been fully evaluated and automatic substitution of MDRD4 or CKD-EPI in place of estimated or mCLcr for drug dose calculations should be avoided (Fig. e42-5).
Algorithm for estimating kidney function using eGFR and/or eCLcr approaches. Creatinine clearance is converted from mL/min to mL/s by multiplying by 0.0167. (BMI, body mass index; CG, Cockcroft-Gault; CKD, chronic kidney disease; eCLcr, estimated creatinine clearance; eGFR, estimated glomerular filtration rate.)
Cystatin C-Based Equations
Addition of serum cysC as a covariate in equations to estimate GFR has been employed as a means to improve creatinine-based estimations of GFR that historically were limited to the following variables; lean body mass (LM), age, sex, race, and Scr.116,117,118,119,120,121
A significant limitation of serum cysC as a renal biomarker is the influence of body mass on serum concentrations. MacDonald et al.116 and Vupputuri et al.119 reported that fat-free mass is a significant covariate in GFR determination using cysC. Using GFR measured as plasma inulin clearance, LM accounted for at least 16.3% of the variance in GFR values obtained using serum cysC (p less than 0.001). When using a serum cysC-based estimate of GFR, which incorporates the serum cysC, age, race, and sex, a higher prevalence of CKD was reported in obese patients when compared to the MDRD4 equation.119 In a recent retrospective analysis of over 1,000 elderly individuals (mean age 85 years) enrolled in the Cardiovascular Health Study, GFR was estimated using the CKD-EPI and CKD-EPI-cysC equation, specifically equation 9 in Table e42-6.121 In this population, all-cause mortality rates were significantly different between equations. The CKD-EPI equation yielded a U-shaped association, whereas the CKD-EPI-cysC equation yielded a linear relationship at eGFR values less than 60 mL/min/1.73 m2 (less than 0.58 mL/s/m2), suggesting that cysC does not accurately predict mortality risk in patients with low Scr, reduced muscle mass, and malnutrition. The combined use of serum cysC and creatinine in modified CKD-EPI equations has recently been reported. The CKD-EPIcreatinine_cystatin C, equation 10 in Table e42-6 is now recommended for use in patients where unreliable serum creatinine values are anticipated, such as extremes in body mass, diet, or creatinine assay interferences.120
The BIS, another eGFR equation includes cysC for CKD classification.111 An analysis conducted in a cross-sectional cohort of 570 Caucasians average ages 78.5 years and mGFR 60 mL/min/1.73m2 (range: 17-116 mL/min/1.73m2 [mGFR 0.58 mL/s/m2 and range of 0.16-1.12 mL/s/m2]) by iohexol plasma clearance compared the eGFR calculated by BIS1 (creatinine) and BIS2 (creatinine + cysC), to eCLcr by CG with eGFR by multiple CKD-EPI equations. The BIS2 equation yielded the smallest bias followed by the BIS1 and Cockcroft–Gault equations. The total error rate for misclassification of subjects with GFR less than 60 mL/min/1.73m2 (less than 0.58 mL/s/m2) was smallest for the BIS2 equation (11.6%), followed by the CKD-EPIcystatin C equation (15.1%). Among the creatinine-based equations, BIS1 had the smallest misclassification rate (17.2%), followed by the CKD-EPI (20.4%). Further evaluation of the BIS equations in patients with varying ethnicities, chronic diseases, and GFR values is warranted before its use can be broadly recommended.
Additional research on the utility of these new eGFR equations in diverse ethnic groups has resulted in modifications or “correction factors,” such as those for Japanese124 and Chinese125 populations. Studies to determine the impact of adding cysC into these equations are yet to be reported.
A variety of online resources provide eGFR calculators such as the NKDEP Web site,126 which provides eGFR calculators based on the MDRD4–IDMS, CKD-EPI, and CKD-EPIcreatine_cystatin C equations. The NKDEP continues to recommend that laboratories report eGFR values greater than or equal to 60 as “greater than 60 mL/min/1.73 m2 (greater than 0.58 mL/s/m2), not as an exact number,” due to inaccuracies of eGFR equations at higher levels of GFR. It should be noted that one must verify that a given equation is appropriate for the institutional creatinine reporting method.
Estimation of Creatinine Clearance
Many equations describing the mathematical relationships between various patient factors and mCLcr, the most widely recognized surrogate for GFR in clinical settings. Most equations incorporate factors such as age, gender, weight, and Scr, without the need for urine collection. The most widely used of these estimators is the CG equation,127 which identified age and body mass as factors, which significantly contribute to the estimate of CLcr. This relationship was based on observations from 249 male patients with stable kidney function in whom the creatinine production rates were estimated. Estimated creatinine clearance (eCLcr), using the CG equation, is one of the methods endorsed by the FDA for stratifying patients in drug development pharmacokinetic studies, and has been reported most often in FDA-approved package inserts for new drug entities since the 1990s.4,105
One of the key considerations with the use of this equation is whether or not a modified weight index should replace actual body weight. Several modified weight indices have been proposed and this remains a controversial issue. For obese individuals, defined as those with a body mass index (BMI) greater than or equal to 30 kg/m2 but less than 40 kg/m,2 it is generally recommended that total or actual body weight be used. This is based on a recent analysis by the FDA indicating that the CG equation had less than 10% bias in nearly 600 normal weight, overweight, and obese individuals enrolled in drug pharmacokinetic studies.128 In morbidly obese individuals (BMI ≥40 kg/m,2 obesity class III) an alternate measure of body weight such as lean body weight (LBW) was shown to significantly reduce bias in the CG equation, where LBW is calculated as:
and BMI is calculated as:
BMI (kg/m2) = weight (kg)/height (m)2
Regardless of the approach used to estimate renal function in obese patients, it is imperative that drug therapy outcomes be monitored closely in this population.
The use of ideal or adjusted body weight for estimating CLcr in obese patients is controversial. Some clinicians recommend using a weight adjustment in patients who are more than 30% above ideal body weight (IBW), where an adjusted body weight is employed. However, recent studies by the FDA indicate that use of IBW or adjusted body weight should be avoided in those with BMI more than 40. Further research evaluating weight-based adjustments and drug pharmacokinetic outcomes is needed.
Luke et al.129 evaluated the ability of the CG method and four other methods to determine eCLcr, with inulin clearance being considered the standard measure of GFR. The simultaneously determined inulin and measured creatinine clearances correlated best, r2 = 0.85, and the mCLcr overestimated CLinulin by approximately 15% due to tubular secretion of creatinine. Of the five eCLcr, the ones calculated by the CG and Mawer et al. methods130 correlated the best with GFR. Other methods, such as Jelliffe131 and Hull et al.132 consistently underestimated the mCLcr (Table e42-7).
TABLE e42-7Equations for the Estimation of Creatinine Clearance in Adults with Stable Renal Function |Favorite Table|Download (.pdf) TABLE e42-7 Equations for the Estimation of Creatinine Clearance in Adults with Stable Renal Function
|Cockroft and Gault127 || |
Men: CLcr = (140 – age)ABW/(Scr × 72)
Women: CLcr × 0.85
|Jelliffe131 || |
Men: CLcr = (100/Scr) – 12
Women: CLcr = (80/Scr) – 7
|Jelliffe131 || |
Men: CLcr = 98 – [0.8 (age – 20)]/Scr
Women: CLcr × 0.9
|Mawer et al.130 || |
Men: ABW [29.3 – (0.203 × age)] [1 – (0.03 × Scr)]/(14.4 × Scr)
Women: ABW [25.3 – (0.175 × age)] [1 – (0.03 × Scr)]/(14.4 × Scr)
|Hull et al.132 || |
Men: CLcr = [(145 – age)/Scr] – 3
Women: Clcr × 0.85
Patients undergoing screening for participation in the African American Study of Kidney Disease (AASK) were evaluated for kidney function based on eCLcr, simultaneous 125I-iothalamate and measured 24-hour CLcr.133 The simultaneous mCLcr provided the best estimate of GFR. The CG method was the preferred method for eGFR, based on performance and ease of use. This method was noted to underestimate the GFR by 9%, perhaps because of the increased excretion rate of creatinine by black patients.134
Administration of cimetidine has also resulted in improved performance of the CG equation as means to calculate eGFR. Ixkes et al.135 gave patients three 800-mg doses of cimetidine in 24 hours, and measured creatinine plasma levels from 3 to 7 hours following the final dose. During this 4-hour period, the CLiothalamate was determined as the measure of GFR. The CG calculations were performed with the plasma creatinine measurement 3 hours after the last dose of cimetidine. The ratio of the CG eCLcr-to-CLiothalamate decreased from 1.28 ± 0.21 to 0.98 ± 0.11 in the presence of cimetidine. This cimetidine dosing schedule also improved the accuracy of CG eCLcr relative to GFR in renal transplant patients with GFR values ranging from 20 to 80 mL/min/1.73 m2 (0.19-0.77 mL/s/m2).136,137
Evaluation of renal hemodynamics is particularly complicated in patients with liver disease and cirrhosis, where filtration fraction is associated with the degree of ascites, renal artery vasoconstriction, and vascular resistance.138 The estimation of CLcr or GFR can be problematic in patients with preexisting liver disease and renal impairment. Lower-than-expected Scr values may result from reduced muscle mass, protein-poor diet, diminished hepatic synthesis of creatine (a precursor of creatinine), and fluid overload can lead to significant overestimation of CLcr. Orlando et al.139 evaluated 10 healthy subjects, 10 patients with mild liver disease, and 10 with severe liver disease, and observed a mCLcr-to-CLinulin ratio of 1.05, 1.03, and 1.04 for each group, respectively. When the CLcr of patients with severe liver disease was estimated using the CG equation, the resultant ratio (eCLcr-to-CLinulin) was 1.23. Lam et al.140 likewise noted an overestimation by CG of the mCLcr in patients with severe disease, by 40% to 100%.
Studies of renal function in patients with severe hepatic disease confirm the earlier observations of Hull et al.132 and Caregaro et al.141 who reported that mCLcr overestimated GFR by up to 50% in hepatic patients with a GFR of 56 ± 19 mL/min/1.73 m2 (0.54 ± 0.18 mL/s/m2) because of increased tubular secretion of creatinine. The effect of cimetidine administration on mCLcr was evaluated in a small study by Sansoe et al.142 In 12 patients with compensated cirrhosis, Scr values increased from 0.68 ± 0.11 to 0.94 ± 0.14 mg/dL (60 ± 10 μmol/L-83 ± 12 μmol/L) during coadministration of cimetidine (1,000 mg given as 400 mg × 1 then 200 mg every 3 hours) during a 9-hour clearance period. The mCLcr declined from 138 ± 20 prior to cimetidine administration to 89 ± 13 mL/min (2.30 ± 0.33-1.49 ± 0.22 mL/s), with no change in mGFR.
Evaluations of new eGFR equations for use in patients with liver disease have yielded mixed results. In cirrhotic patients being evaluated for liver transplant (mGFR 58 ± 5.1 mL/min/1.73 m2 [0.56 ± 0.049 mL/s/m2]) the eGFR by the MDRD4 and the eCLcr by CG significantly overestimated mGFR by 30% to 50%, and both were considered unacceptable methods for kidney function assessment in liver transplant patients.143,144 Gerhart et al.145 evaluated the performance of the CKD-EPI and MDRD4–IDMS equations in patients with liver disease following transplantation (group 1, n = 59) and those with cirrhosis (group 2; n = 44). When compared to mGFR, both equations yielded slightly positively biased estimates of GFR (4-9 mL/min/1.73 m2 [0.04-0.09 mL/s/m2]) in transplanted patients. However, in patients with hepatic cirrhosis, both equations were significantly positively biased (40-42 mL/min/1.73 m2 [0.39-0.40 mL/s/m2]), with low precision (21-26 mL/min/1.73 m2 [0.20-0.25 mL/s/m2]) and low accuracy with only 7% of patients having eGFR values within 30% of the mGFR. Incorporation of cysC into eGFR equations has recently shown promise in patients with liver disease. In 72 cirrhotic patients, Mindikoglu et al.146 reported that the CKD-EPIcreatinine-cystatin C equation was significantly more precise than the CG, CKD-EPI, or CKD-EPIcystatin C when compared to iothalamate-mGFR. The accuracy of the CKD-EPIcreatinine-cystatin C equation, measured as percentage of eGFR that differed by more than 30% with respect to mGFR, was significantly less than mCLcr (p = 0.024), CG (p = 0.0001), MDRD (p = 0.027), and CKD-EPIcreatinine (p = 0.012) equations. In summary, renal function assessment in patients with hepatic disease should be performed by measuring glomerular filtration, and GFR estimation equations that combine creatinine and cysC are preferred.
Other Special Populations
Davis and Chandler147 confirmed the accuracy of the CG eCLcr method in trauma patients with stable kidney function, and Thakur et al.43 demonstrated its acceptable performance in 42 paraplegic patients. Kidney transplant recipients are frequently monitored for renal function, as numerous complications may occur during the life of the allograft. Ruiz-Esteban et al.148 evaluated the bias and precision of the MDRD4 and CKD-EPI relative to CG in 153 postrenal transplant patients. Here, the mean bias for MDRD4 was –10.6 ± 12.7 compared to –9.8 ± 11.3 mL/min/1.73 m2 (–0.10 ± 0.12 compared to –0.09 ± 0.11 mL/s/m2) for CKD-EPI (p = 0.006), with the CKD-EPI having a higher percentage of patients within 30% of the CG value than the MDRD equation (86.9% vs 81.7%, p less than 0.001). Huang et al.149 reported the inability of several CLcr equations to predict renal function in hospitalized patients with advanced HIV disease. All of the prediction methods overestimated the measured 24-hour CLcr. The reasons for the poor predictability of these methods are unclear, although 24-hour collection methods result in increased variability, often because of inadequate collection of urine. Another recently discovered problem with estimating CLcr in HIV patients relates to drug-creatinine interactions. Nucleoside reverse transcriptase inhibitors (dolutegravir, rilpivirina) and cobicistat can block OCT2 and MATE1-mediated tubular secretion of creatinine, leading to elevations in serum creatinine (0.1-0.2 mg/dL[0.9-1.8 μmol/L]) and reductions in CLcr by up to 5 to 15 mL/min (0.08-0.25 mL/s).42,150
Kidney function assessment during pregnancy is usually performed using a 24-hour CLcr determination, and estimation equations have been shown to perform poorly particularly in the preeclampsia population. For example, Alper et al.151 recently evaluated the CG, MDRD4 and CKD-EPI equations in 543 women, aged 16 to 49 years, with preeclampsia after the 20th week of gestation. When compared to 24-hour mCLcr (mean 133 ± 43 mL/min [2.22 ± 0.72 mL/s]), the CG equation was positively biased (36 ± 2 mL/min [0.60 ± 0.03 mL/s]) whereas both the MDRD4 and CKD-EPI were negatively biased (–20 ± 1.5 mL/min [–0.33 ± 0.025 mL/s]).Thus, kidney function estimating equations should not be used during pregnancy.
Patients with unstable kidney function or AKI present a unique situation because Scr values are changing, and steady state cannot be assumed, which is one of the assumptions of all the above-mentioned eCLcr methods. It is now widely accepted that a change in the Scr of more than 50% over a period of 7 days, or an increase in Scr by at least 0.3 mg/dL (≥27 μmol/L) over a 24- to 48-hour period indicates the presence of AKI.152 Methods to measure GFR in this population, such as 125I-iothalamate clearance, are cumbersome and costly especially in the acute care setting. Although several equations have been proposed the calculate eCLcr in AKI patients or those with rapidly progressive renal disease,153,154,155 a rigorous evaluation of the accuracy and precision of each of these proposed methods is lacking and none of them is currently recommended for clinical use. Use of semiquantitative approaches is preferred for the purpose of estimating severity of disease using RIFLE or AKIN criteria (see Chapter 43 for more details).
Use of abbreviated CLcr measurements (less than 24 h) may be valuable for detecting early evidence of AKI in critically ill patients. Pickering et al.156 recently reported that 4-hour CLcr measurements were significantly better at predicting AKI events than Scr alone in 484 patients. However, the lack of true mGFR in these patients prevented assessment of the accuracy and precision of the CLcr values. Hoste et al.157 used 1-hour CLcr measurements to evaluate the CG and MDRD equations in critically ill patients within 1 week of ICU admission. Both equations were poorly correlated with CLcr and were similarly imprecise with Bland-Altman 95% confidence intervals ranging from –77 to 64 mL/min (–1.29 to 1.07 mL/s) for CG and –77 to 58 mL/min/1.73 m2 (–0.74 to 0.56 mL/s/m2) for MDRD.
It is thus, ultimately, most important to recognize that renal function in patients with AKI is generally markedly lower than one would estimate using steady-state methods, and dose adjustments should be made if necessary to avoid drug toxicity (see Chapters 28 and 33).
Kidney Function in Children
Kidney function in the neonate is difficult to assess because of difficulty in urine and blood collection, the frequent presence of a non–steady-state Scr, and apparent disparity between development of glomerular and tubular function. Preterm infants demonstrate significantly reduced GFR prior to 34 weeks, which rapidly increases and becomes similar to term infants within the first week of life.158 Evaluation of GFR in preterm infants on day 3 of life, using an inulin infusion, failed to identify a relationship between patient weight and GFR. Gestational age, which ranged from 23.4 to 36.9 weeks (mean: 30.2 weeks), however, correlated with both GFR and reciprocal of Scr. The inulin clearance increased from 0.67 to 0.85 mL/min (0.011-0.014 mL/s) in those with gestational age less than 28 weeks versus those of 32 to 37 weeks of age, while Scr decreased from 1.05 to 0.73 mg/dL (93-65 μmol/L), respectively. Creatinine was measured using a specific enzymatic method to avoid interference from bilirubin or drugs.159 CLcr has also been evaluated in infants younger than 1 week, and values of 17.8 mL/min/1.73 m2 (0.171 mL/s/m2) on day 1 increased to 36.4 mL/min/1.73 m2 (0.351 mL/s/m2) by day 6.160 In light of these rapid changes in GFR, estimation of GFR is not recommended for infants younger than 1 week. Kidney function expressed as GFR standardized to body surface area (BSA) increases with age and stabilizes at approximately 1 year. In older children, GFR is best assessed using standard measurement techniques for GFR. Subcutaneous administration of 125I-iothalamate has been effectively used to measure GFR in children ranging in age from 1 to 20 years.161 The original equation to estimate GFR as described by Schwartz et al.162 is dependent on the child’s age and length:
GFR = [length (cm) × k]/(Scr in mg/dL)
where k is defined by age group: infant (1-52 weeks) = 0.45; child (1-13 years) = 0.55; adolescent male = 0.7; and adolescent female = 0.55. Serum creatinine in μmol/L can be converted to mg/dL by multiplication using 0.0113 as the conversion factor.
A newer version of the Schwartz equation163 was developed from a population of 349 children (1-19 years) with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. This simple equation is commonly referred to as the Schwartz “Bedside” formula:
GFR = 0.41 * [length (cm)/Scr in mg/dL]
Lee et al.164 recently reported that this new Bedside Schwartz equation performed better than the original Schwartz equation for patients with mild-moderate CKD, but was less accurate in patients with mild CKD. Thus, the appropriate use of the Bedside Schwartz equation and accuracy in subpopulations of CKD is yet to be fully determined.
Equations derived from adult populations have also been evaluated in pediatric patients. Peirrat et al.165 compared the MDRD, Schwartz, and CG equations in children 3 to 19 years. In children younger than 12 years, the Schwartz and MDRD equations were significantly more biased than CG, and CG provided the best prediction of GFR in children older than 12 years. The results of these investigations suggest that further studies will be needed to clarify the value of any of these predictive methods in children. Most recently, an equation for GFR based on beta-trace protein was shown to yield similar values of GFR compared to the Schwartz equation in 387 pediatric patients (10.7 ± 7.1 years) who underwent a 99mTC-DTPA GFR scan.74 The most recent GFR equation evaluated in pediatrics includes use of cysC, BUN, Scr (in mg/dL) and demographic data derived from over 600 pediatric patients enrolled in the CKiD study166:
This equation had the lowest root-mean square error (0.147), highest R2 (0.863) and frequency of values within 30% of iohexol-mGFR (91.3%) when compared to seven other GFR equations.
Kidney Function in the Elderly
Cross-sectional studies have historically shown that GFR declines as a function of age.167,168 The largest prospective study conducted in healthy elderly individuals is the Baltimore Longitudinal Study on Aging (BLSA).168 In an initial analysis of 254 BLSA participants without kidney disease, it was reported that mCLcr decreases at the rate of approximately 0.75 mL/min/1.73 m2/y (0.0072 mL/s/m2/y) beginning at the fourth decade of life. These subjects were then evaluated prospectively for up to 23 years. Interestingly, approximately one-third of the subjects showed no change in renal function from their baseline value, and a small number showed an increased clearance. These changes may be a result of normal physiologic changes or of subclinical insults to the kidneys initiating the events leading to chronic progressive loss of renal function. Fliser et al.169 studied renal functional reserve in healthy young (23-32 years) and elderly (61-82 years) volunteers using an amino acid infusion technique. mGFR increased by 16% in young and 17% in elderly subjects following the infusion. Renal functional reserve thus appears to be maintained in healthy elderly individuals.
Interpretation of the Scr alone is difficult in the elderly patient primarily because of the decreased muscle mass and resultant lower production rate of creatinine. Thus, the Scr often remains within the normal range despite a reduction in the number of functional nephrons. As renal function declines, the kidneys excrete a larger fraction of creatinine. This perpetuates the “normal” Scr. Recent recommendations such as the adoption of standardized creatinine assays by clinical laboratories and reporting of Scr values to two decimal places will likely improve the accuracy of renal function estimation in the elderly population.35
Estimation of CLcr in elderly with low serum creatinine values is controversial. Some clinicians advocate for replacing serum creatinine with an arbitrary value of 1.0 mg/dL (88 μmol/L) to account for reduced muscle mass. This practice should be avoided, and has been shown to significantly underestimate kidney function in elderly populations. Furthermore, the impact of this practice on GFR estimates such as CKD-EPI and other equations has yet to be evaluated in this population.
The CG formula127 continues to provide a valid estimate of the CLcr in elderly populations. Smythe et al.170 estimated CLcr in 23 patients older than 60 years using seven different methods, and compared the results to a measured 24-hour CLcr determination. Estimations were performed with the actual Scr and also with the Scr corrected, or rounded, up to 1.0 mg/dL (88 μmol/L) if the actual value was less than 1.0 mg/dL (less than 88 μmol/L). Changing the Scr to 1.0 mg/dL (88 μmol/L) resulted in a significantly lower eCLcr (–28.8 mL/min [–0.481 mL/s]) compared to the unadjusted Scr (+2.3 mL/min [+0.038 mL/s]). In patients older than 60 years with Scr less than 1.0 mg/dL (less than 88 μmol/L), rounding the Scr value up to 1.0 mg/dL (88 μmol/L) resulted in dose estimates for gentamicin that were significantly lower (–90 ± 67 mg/day) than doses calculated based on the actual Scr value.171 In an analysis of the BLSA dataset, Dowling et al.172 evaluated 269 elderly individuals: age 81 ± 6 (mean + SD) years, Scr 1.1 ± 0.4 mg/dL (97 ± 35 μmol/L), and 24-hour mCLcr of 53 ± 13 mL/min (0.88 ± 0.22 mL/s). The CG equation yielded the least biased estimate of mClcr, whereas the MDRD4 and CKD-EPI equations significantly overestimated the CG and mClcr values by 30% to 47%. Rounding low serum creatinine values up to an arbitrary value of 1.0 mg/dL (88 μmol/L) resulted in CG values that significantly underestimated mClcr (44 vs 56 mL/minute [0.73 vs 0.93 mL/s], p less than 0.001) and uncorrected CG (p less than 0.001). Taken together, these results strongly suggest that the commonly accepted practice of fixing or rounding Scr to an arbitrary value in elderly patients should be avoided.
An alternative to the estimation of GFR or a 24-hour mCLcr is a 4-hour mCLcr performed during water diuresis. This approach correlated with the inulin clearance as well as with an observed inpatient 24-hour mCLcr.93 However, one must be aware of the potential risk of hyponatremia in the geriatric patient who is unable to tolerate an oral water load, as well as the need for complete bladder emptying to ensure accurate results. O’Connell et al.173 assessed the accuracy of 2- and 8-hour urine collections compared with 24-hour CLcr determinations in 45 hospitalized patients older than 65 years with indwelling urethral catheters. The 8-hour timed urine collection for CLcr showed minimal bias (2.2 mL/min [0.037 mL/s]) as compared with the 24-hour value, whereas the 2-hour determination was both positively biased (11 mL/min [0.18 mL/s]) and less precise (25 mL/min [0.42 mL/s]).
Impact on Drug Dosing Recommendations
The automated reporting of eGFR in the clinical setting has led some practitioners to consider substituting eGFR in place of eCLcr for renal dose adjustments as recommended in regulatory agency approved product labelling. The prime concern with this approach, particularly in the elderly, is that substitution of eGFR values in CLcr-based dosage adjustment algorithms may result in dosing errors and toxicity especially for drugs with narrow therapeutic indices since eGFR tends to overestimate eCLcr.172,174,175,176,177,178,179,180,181Roberts et al.174 reported that the MDRD eGFR values overestimated gentamicin clearance by 29% (p less than 0.001), whereas the Cockcroft and Gault yielded only 10% overestimation (p less than 0.01), and MDRD overestimated renal function more as age increased. Retrospective studies in more than 1,200 patients with renal disease have shown that overestimation of renal function using the MDRD4 with or without IDMS eGFR equation results in up to 30% to 60% higher doses for digoxin, amantadine, and various antimicrobials compared to doses calculated using eCLcr.176,177,178,179,180,181 In contrast Stevens et al.182 reported that use of an eGFR (MDRD4 equation in mL/min based on a calculated BSA), yields dosage regimens for a subset of drugs that are similar to those calculated using mGFR. The authors of this study concluded that the MDRD4 equation could be used for renal dose adjustments. However, this practice was not widely adopted. Modifications to the CKD-EPI equation, including use of cysC, are now being evaluated in drug pharmacokinetic studies, and may be particularly useful for patients with apparently normal renal function. For example, Frazee et al.183 retrospectively evaluated vancomycin use in critically ill patients (n = 170) and found that the CKD-EPIcreatinine-cystatin C equation (converted to mL/min) yielded a 2.5-fold improvement in achieving target trough values, when compared to eCLcr–. Of note, the predicted trough values were improved among those with normal GFR (greater than 120 mL/min [greater than 2 mL/s]), where under dosing is often problematic. A more detailed discussion of the utilization of kidney function estimates and renal dosing approaches is provided in Chapter 48.
Drug-dose individualization is often required in patients with CKD. Approved drug labeling typically includes dose-adjustment information based on the patient’s CLcr using the CG method. Automated eGFR reporting by many hospital laboratories has now raised the question if any other GFR estimation equations should be used as a guide for drug-dose adjustments.