GFR-estimating Equations Research Articles

Measuring the Glomerular Filtration Rate in Obese Individuals without Overt Kidney Disease

Background: Identifying methods to accurately measure the glomerular filtration rate (GFR) in obese individuals without kidney overt kidney disease is necessary to understanding the pathophysiology and natural history of obesity-related kidney disease. Methods: Using a cross-sectional design, iohexol clearance and disposition was measured, an optimal sampling schedule was identified, and the reliability of GFR-estimating methods was described in 29 obese individuals with normal serum creatinine levels. Iohexol disposition was measured using population pharmacokinetics. The agreement with GFR-estimating equations was assessed by intraclass coefficients. Results: Mean age was 44 ± 10 years, body mass index 45 ± 10, creatinine 0.7 ± 0.2 mg/dl (62 ± 18 µmol/l) , and cystatin C 0.83 ± 0.18 mg/dl (8.3 ± 1.8 mg/l). Iohexol disposition fit a two-compartment model and 5 sampling windows were identified over a 4-hour period to optimize model accuracy and minimize blood draws. Precision was not compromised with this sampling design. Neither creatinine nor cystatin C were linearly correlated with the measured GFR though cystatin C was independent of body composition. Agreement was fair to poor between the measured GFR and GFR-estimating equations. Conclusion: This study offers a rigorous method to study obesity-related kidney disease and improve upon suboptimal GFR-estimating methods.

Comparative Performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study Equations for Estimating GFR Levels Above 60 mL/min/1.73 m 2

The Modification of Diet in Renal Disease (MDRD) Study equation underestimates measured glomerular filtration rate (GFR) at levels>60 mL/min/1.73 m2, with variable accuracy among subgroups; consequently, estimated GFR (eGFR)>or=60 mL/min/1.73 m2 is not reported by clinical laboratories. Here, performance of a more accurate GFR-estimating equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, is reported by level of GFR and clinical characteristics. Test of diagnostic accuracy. Pooled data set of 3,896 people from 16 studies with measured GFR (not used for the development of either equation). Subgroups were defined by eGFR, age, sex, race, diabetes, prior solid-organ transplant, and body mass index. eGFR from the CKD-EPI and MDRD Study equations and standardized serum creatinine. Measured GFR using urinary or plasma clearance of exogenous filtration markers. Mean measured GFR was 68+/-36 (SD) mL/min/1.73 m2. For eGFR<30 mL/min/1.73 m2, both equations have similar bias (median difference compared with measured GFR). For eGFR of 30-59 mL/min/1.73 m2, bias was decreased from 4.9 to 2.1 mL/min/1.73 m2 (57% improvement). For eGFR of 60-89 mL/min/1.73 m2, bias was decreased from 11.9 to 4.2 mL/min/1.73 m2 (61% improvement). For eGFR of 90-119 mL/min/1.73 m2, bias was decreased from 10.0 to 1.9 mL/min/1.73 m2 (75% improvement). Similar or improved performance was noted for most subgroups with eGFR<90 mL/min/1.73 m2, other than body mass index<20 kg/m2, with greater variation noted for some subgroups with eGFR>or=90 mL/min/1.73 m2. Limited number of elderly people and racial and ethnic minorities with measured GFR. The CKD-EPI equation is more accurate than the MDRD Study equation overall and across most subgroups. In contrast to the MDRD Study equation, eGFR>or=60 mL/min/1.73 m2 can be reported using the CKD-EPI equation.

The CKD-EPI Equation for Estimating GFR from Serum Creatinine

The Cockcroft-Gault equation was published in 1976 and was widely adopted for estimation of creatinine clearance from serum creatinine levels (1). The equation was developed using two steps: First, urinary creatinine excretion per body weight (UV/kg) was estimated from age in hospitalized patients; creatinine clearance was then calculated by multiplying by weight and dividing by serum creatinine (P) using the standard “UV/P” clearance formula. Not surprising, the high-risk patients who were used to develop the Cockcroft-Gault equation had lower muscle mass (creatinine excretion) than healthier individuals in the general population (2). The lack of a standardized serum creatinine assay has also been considered a problem with the Cockcroft-Gault equation, but this is not the case. Serum creatinine assay calibration has no influence on the coefficients of the Cockcroft-Gault equation, because the regression did not involve serum creatinine. Because the Cockcroft-Gault equation was developed using only white men, however, the model was not optimized to account for gender and race differences in muscle mass. Nonetheless, the Cockcroft-Gault equation is still used widely, particularly for drug dosing, for which estimates in ml/min units are desired. Because the Cockcroft-Gault equation has been used to determine recommended dosages for various medications (3), there is a consistent approach when using this equation to adjust medication dosage. However, the clinician should keep in mind that many dosing recommendations were made prior to serum creatinine standardization. By contrast, the most widely used GFR-estimating equation today is the Modification of Diet in Renal Disease (MDRD) equation, which was published in 1999 and later simplified (4,5). This equation automatically estimates GFR from serum creatinine for most laboratories (6). This equation was developed using patients who who had CKD identified …

Evaluating cimetidine for GFR estimation in liver transplant recipients

Background. Serum creatinine (Scr)-based equations lack accuracy in predicting glomerular filtration rate (GFR) in patients with liver disease. Cimetidine has been shown to improve the performance of Scr-based GFR formulae. Methods. We evaluated the use of cimetidine on the performance of GFR-estimating equations in 39 liver transplant recipients. The patients received oral cimetidine (800 mg tid) during a 24-h urine collection. The next day, the patients underwent radionucleotide GFR (rGFR) determination and Scr was measured for creatinine clearance (CrCl) and GFR estimation using the Cockcroft-Gault, Nankivell and modified diet in renal disease (MDRD) equations. Data were analysed using the Pearson correlation statistic and Bland-Altman plots. Results. The mean rGFR was 65 +/- 26.4 mL/min. The use of cimetidine increased the bias between rGFR and the Nankivell and MDRD equations. The combined root mean square error for the CrCl, Cockcroft-Gault, Nankivell and MDRD equations without cimetidine were 20.2, 15.6, 17.0 and 15.5 and cimetidine-aided were 28.2, 23.2, 23.7 and 24.3, respectively. Conclusions. All the tested equations without using cimetidine predicted GFR with modest accuracy. The addition of cimetidine decreased the precision and increased the bias of all the GFR-estimating equations. In the absence of accurate GFR-estimating equations, rGFR should be used to monitor kidney function in liver transplant recipients.

Development and validation of GFR-estimating equations using diabetes, transplant and weight

We have reported a new equation (CKD-EPI equation) that reduces bias and improves accuracy for GFR estimation compared to the MDRD study equation while using the same four basic predictor variables: creatinine, age, sex and race. Here, we describe the development and validation of this equation as well as other equations that incorporate diabetes, transplant and weight as additional predictor variables. Linear regression was used to relate log-measured GFR (mGFR) to sex, race, diabetes, transplant, weight, various transformations of creatinine and age with and without interactions. Equations were developed in a pooled database of 10 studies [2/3 (N = 5504) for development and 1/3 (N = 2750) for internal validation], and final model selection occurred in 16 additional studies [external validation (N = 3896)]. The mean mGFR was 68, 67 and 68 ml/min/ 1.73 m(2) in the development, internal validation and external validation datasets, respectively. In external validation, an equation that included a linear age term and spline terms in creatinine to account for a reduction in the magnitude of the slope at low serum creatinine values exhibited the best performance (bias = 2.5, RMSE = 0.250) among models using the four basic predictor variables. Addition of terms for diabetes and transplant did not improve performance. Equations with weight showed a small improvement in the subgroup with BMI <20 kg/m(2). The CKD-EPI equation, based on creatinine, age, sex and race, has been validated and is more accurate than the MDRD study equation. The addition of weight, diabetes and transplant does not significantly improve equation performance.

Assessing glomerular filtration rate (GFR) in elderly Chinese patients with chronic kidney disease (CKD): A comparison of various predictive equations

The aim of this study was to evaluate the applicability of formulas based on serum creatinine (SC) levels in elderly Chinese patients with CKD. A total of 103 elderly CKD patients were investigated. The GFR was estimated with Cockcroft–Gault-equation, MDRD1-equation, abbreviated MDRD-equation, Jelliffe-1973-equation, Mawer-equation, Hull-equation, Jelliffe-1971-equation, SC-reciprocal-equation, Gate-equation and Bjornsson-equation. The accuracy of estimated GFR (eGFR) values was compared with the 99mTc-DTPA-GFR (standardized GFR = sGFR) in elderly CKD patients. Bland–Altman analysis demonstrated that Hull-equation, Cockcroft–Gault-equation and Bjornsson-equation were better than the other ones. However, the agreement limits of all the equations exceeded the prior acceptable tolerances defined as 60 ml/min/(1.73 m 2). Linear regressions showed that the slopes of Jelliffe-1973-equation, Cockcroft–Gault-equation and Bjornsson-equation were closer to the identical line. The median of difference of MDRD1-equation, abbreviated MDRD-equation and Gate-equation were smaller. Accuracy of Jelliffe-1973-equation, Cockcroft–Gault-equation and Hull-equation were better than those of the other equations. But 30% accuracy of all the equations were less than 70%. When compared the bias as well as accuracy of eGFR with sGFR values in different stages of CKD, GFR estimated by MDRD1-equation, Hull-equation, Cockcroft–Gault-equation and Jelliffe-1973-equation showed good results. These results suggested that when SC was checked with enzymatic method, GFR-estimation equations may show great bias in elderly Chinese CKD patients. Further improved formulas are needed to evaluate renal function in elderly Chinese patients with CKD.

Comparison of Drug Dosing Recommendations Based on Measured GFR and Kidney Function Estimating Equations

Kidney disease alters the pharmacokinetic disposition of many medications, requiring dosage adjustment to maintain therapeutic serum concentrations. The Cockcroft-Gault (CG) equation is used for pharmacokinetic studies and drug dosage adjustments, but the Modification of Diet in Renal Disease (MDRD) Study equation is more accurate and more often reported by clinical laboratories than the CG equation. Diagnostic test study. Pooled data set for 5,504 participants from 6 research studies and 4 clinical populations with measured glomerular filtration rate (GFR). Estimated kidney function using the MDRD Study and CG equations incorporating actual (CG) or ideal body weight (CG(IBW)) and standardized serum creatinine concentrations. Measured GFR assessed by using iodine-125-iothalamate urinary clearance. Concordance of assigned kidney function categories designated by the Food and Drug Administration (FDA) Guidance for Industry for pharmacokinetic studies and recommended dosages of 15 medications cleared by the kidneys. Concordance of kidney function estimates with measured GFR for FDA-assigned kidney function categories was 78% for the MDRD Study equation compared with 73% for the CG equation (P < 0.001) and 66% for the CG(IBW) equation (P < 0.001). Concordance between the MDRD Study equation and CG and CG(IBW) equations was 78% and 75%, respectively (P < 0.001). Concordance of kidney function estimates with measured GFR for recommended drug dosages was 88% for MDRD Study equation compared with 85% for the CG equation (P < 0.001) and 82% for the CG(IBW) equation (P < 0.001), with lower concordance when dosing recommendations for drugs included narrow GFR ranges. Concordance rates between the CG and CG(IBW) equations and MDRD Study equation were 89% and 88%, respectively (P < 0.05). Results based on simulation rather than pharmacokinetic studies. Outcome was drug dosage recommendations, rather than observed drug efficacy and safety. The MDRD Study equation can also be used for pharmacokinetic studies and drug dosage adjustments. As more accurate GFR-estimating equations are developed, they should be used for these purposes.

Appraisal of GFR-Estimating Equations Following Kidney Donation

It is not clear which serum creatinine-based glomerular filtration rate (GFR)-estimating model performs best in kidney donors. Study of diagnostic accuracy. From a population of 3,698 kidney donors, 255 donors underwent iohexol GFR measurement (mGFR). INDEX TEST (INTERVENTION): mGFR by means of plasma disappearance of iohexol. GFR was estimated (eGFR) by using the Cockcroft-Gault equation (eGFR(CG)), Mayo Clinic equation (eGFR(MC)), and Modification of Diet in Renal Disease (MDRD) Study equation (eGFR(MDRD)). Mean mGFR was 71.8 +/- 11.8 mL/min/1.73 m(2), and 85.5% had mGFR greater than 60 mL/min/1.73 m(2). eGFR(CG) underestimated mGFR by 3.96 +/- 13.3 mL/min/1.73 m(2) and was within 30% of mGFR 89.4% of the time. eGFR(MC) overestimated mGFR by 8.44 +/- 11.9 mL/min/1.73 m(2) and was within 30% of mGFR in 83.1% of cases. eGFR(MDRD) underestimated mGFR by only 0.43 +/- 11.7 mL/min/1.73 m(2), and the proportion within 30% of mGFR was greatest in the tested model; 94.1% of the time. However, eGFR(MC) was most accurate in classifying donors according to having eGFR less than 60 mL/min/1.73 m(2). Lack of ethnic diversity and response bias. The MDRD Study equation is least biased, and because it is routinely reported by most laboratories, it is the best readily available model for estimating GFR in kidney donors.

Revised Equations for Estimated GFR From Serum Creatinine in Japan

Estimation of glomerular filtration rate (GFR) is limited by differences in creatinine generation among ethnicities. Our previously reported GFR-estimating equations for Japanese had limitations because all participants had a GFR less than 90 mL/min/1.73 m2 and serum creatinine was assayed in different laboratories. Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory. Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study. Measured GFR (mGFR) computed from inulin clearance. Estimated GFR (eGFR) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4). Performance of equations was assessed by means of bias (eGFR - mGFR), accuracy (percentage of estimates within 15% or 30% of mGFR), root mean squared error, and correlation coefficient. In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS-MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR (mL/min/1.73 m2) = 194 x Serum creatinine(-1.094) x Age(-0.287) x 0.739 (if female). In the validation data set, bias was -1.3 +/- 19.4 versus -5.9 +/- 19.0 mL/min/1.73 m2 (P = 0.002), and accuracy within 30% of mGFR was 73% versus 72% (P = 0.6) for equation 3 versus equation 1 and -2.1 +/- 19.0 versus -7.9 +/- 18.7 mL/min/1.73 m(2) (P < 0.001) and 75% versus 73% (P = 0.06) for equation 4 versus equation 2 (P = 0.06), respectively. Most study participants had chronic kidney disease, and some may have had changing GFRs. The new Japanese coefficient for the modified IDMS-MDRD Study equation and the new Japanese equation are more accurate for the Japanese population than the previously reported equations.

Current Status and Future Perspectives for CKD Testing

Chronic kidney disease (CKD) is common in the United States. CKD usually is silent until its late stages; thus, many patients with CKD are not aware of their kidney disease. Often, they are found to have CKD only shortly before the onset of symptomatic kidney failure, when there are few opportunities to prevent adverse outcomes. Earlier detection allows more time for evaluation and treatment, but requires explicit testing strategies for asymptomatic individuals at increased risk. CKD is defined as kidney damage or glomerular filtration rate (GFR) less than 60 mL/min/1.73 m(2) for 3 months or longer. In the majority of patients, CKD can be detected by using 2 simple tests: a urine test for the detection of proteinuria and a blood test to estimate GFR. Understanding the strengths and limitations of CKD testing is critical for appropriate interpretation of the results. The major strength of CKD testing is its feasibility of implementation in public health activities and clinical practice, enabling the detection of CKD by using objective measures without knowledge of the cause of the kidney disease. The major limitation of testing for urine protein is that both total protein and albumin excretion can be increased transiently for a number of factors. The major limitation of current GFR-estimating equations is the inaccuracy of estimates at 60 mL/min/1.73 m(2) and greater, which is the threshold for the definition of CKD. Repeated testing for urine protein and interpretation of GFR estimates in the context of kidney damage and the clinical context of patient presentation can help overcome these limitations.

Estimating GFR Using Serum Cystatin C Alone and in Combination With Serum Creatinine: A Pooled Analysis of 3,418 Individuals With CKD

Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables. Test of diagnostic accuracy. Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438). Measured GFR (mGFR). Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study. GFR was measured by using urinary clearance of iodine-125-iothalamate in the US studies and chromium-51-EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used. Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m(2) (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables. Study population composed mainly of patients with CKD. Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.

Assessing Kidney Function — Measured and Estimated Glomerular Filtration Rate

In the coming years, estimates of the glomerular filtration rate (GFR) may replace the measurement of serum creatinine as the primary tool for the assessment of kidney function. Indeed, many clinical laboratories already report estimated GFR values whenever serum creatinine is measured. This review considers current methods of measuring GFR and GFR-estimating equations and their strengths and weaknesses as applied to chronic kidney disease.

The importance of metrological traceability on the validity of creatinine measurement as an index of renal function: International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)

The glomerular filtration rate (GFR) is currently considered the best overall index of kidney function. The possibility that laboratories might routinely report an estimated GFR has become practically feasible with the development of a formula, the "four-variable" Modification of Diet in Renal Disease study (MDRD) equation that uses age, sex, race, and serum creatinine parameters. However, a limitation of this equation for general implementation in healthcare is related to the use of differently calibrated creatinine measurement procedures among laboratories. The only way to achieve universal implementation of the GFR prediction equation, with the associated clinical benefits for patients, is, therefore, to promote worldwide standardization of methods to determine creatinine, together with the introduction of a revised GFR-estimating equation appropriate for use with standardized creatinine methods.

Application of GFR-estimating equations in Chinese patients with chronic kidney disease

To evaluate whether the Modification of Diet in Renal Disease (MDRD) equations could be applied accurately to Chinese patients with chronic kidney disease (CKD), glomerular filtration rates (GFRs) estimated by using MDRD equation 7 (7GFR), the abbreviated MDRD equation (aGFR), and the Cockcroft-Gault equation (cGFR) were compared in patients with different stages of CKD. The study enrolled patients with CKD diagnosed according to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative guidelines. All patients were older than 18 years and without acute renal function deterioration, edema, skeletal muscle atrophy, or amputation. Sex, age, body height, and body weight were recorded, and plasma creatinine levels were measured by means of Jaffe's kinetic method using a Hitachi 7600 analyzer (Hitachi, Tokyo, Japan; reagents from Roche Diagnostics, Mannheim, Germany). Creatinine, urea, and albumin were measured in a single clinical laboratory. Dual plasma sampling of technetium Tc 99m-labeled diethylene triamine pentaacetic acid plasma clearance was used as the reference standard GFR (sGFR) for comparison of 7GFRs, aGFRs, and cGFRs at different stages of CKD. The study enrolled 261 patients, including 146 men and 115 women. Causes of CKD included primary or secondary glomerular disease, obstructive kidney disease, chronic tubulointerstitial disease, and others. Values for 7GFR, aGFR, and cGFR were significantly greater than for sGFR in patients with CKD stages 4 to 5 (the lower the sGFR, the greater the difference); whereas 7GFR, aGFR, and cGFR were significantly lower than sGFR in patients with CKD stage 1. Our results show that in a Chinese population with CKD, MDRD equation 7 and the abbreviated MDRD equation overestimated GFR in patients with CKD stages 4 to 5 and underestimated GFR in those with CKD stage 1. These results indicate that careful modification of these equations may be necessary in Chinese populations with CKD.