Range Of Glomerular Filtration Rate Research Articles

Feasibility and Impact of the Measurement of Extracellular Fluid Volume Simultaneous with GFR by 125I-Iothalamate

The feasibility, validity, and possible applications of the assessment of extracellular fluid volume (ECFV) simultaneous with glomerular filtration rate (GFR) were assessed in a series of validation studies using the constant infusion method of (125)I-iothalamate (IOT). In 48 subjects with a broad range of GFR, distribution volume (V(d)) of IOT corresponded well with V(d) bromide (16.71 +/- 3.0 and 16.73 +/- 3.2 l, respectively, not significant), with a strong correlation (r = 0.933, P < 0.01) and without systematic deviations. Reproducibility assessment in 25 healthy male subjects showed coefficients of variation of 8.6% of duplicate measurement of V(d) IOT during strictly standardized (50 mmol Na(+)/d) sodium intake. An increase in dietary sodium intake (200 mmol Na(+)/d) induced a corresponding rise in V(d) IOT of 1.11 +/- 1.5 l (P < 0.01). In 158 healthy prospective kidney donors, the impact of indexing of GFR to ECFV was analyzed. Age, gender, height, and body surface area (BSA) were determinants of GFR. Whereas GFR, GFR/BSA, and GFR/height were gender-dependent, GFR/ECFV was gender-independent and not related to height or BSA. This supports the potential of normalizing GFR by ECFV. Thus, ECFV can be simultaneously assessed with GFR by the constant infusion method using IOT. After appropriate validation, also other GFR tracers could be used for such a simultaneous estimation, providing a valuable resource of data on ECFV in renal studies and, moreover, allowing GFR to be indexed to the body fluid compartment it clears: the ECFV.

A Comparison of Aerobic Exercise and Resistance Training in Patients With and Without Chronic Kidney Disease

The morbidity and mortality associated with chronic kidney disease (CKD) are primarily caused by atherosclerosis and cardiovascular disease, which may be in part caused by inflammation and oxidative stress. Aerobic exercise and resistance training have been proposed as measures to combat obesity, inflammation, endothelial dysfunction, oxidative stress, insulin resistance, and progression of CKD. In non-CKD patients, aerobic exercise reduces inflammation, increases insulin sensitivity, decreases microalbuminuria, facilitates weight loss, decreases leptins, and protects against oxidative injury. In nondialysis CKD, aerobic exercise decreases microalbuminuria, protects from oxidative stress, and may increase the glomerular filtration rate (GFR). Aerobic exercise in hemodialysis patients has been reported to enhance insulin sensitivity, improve lipid profile, increase hemoglobin, increase strength, decrease blood pressure, and improve quality of life. Resistance training, in the general population, decreases C-reactive protein, increases insulin sensitivity, decreases body fat content, increases insulin-like growth factor-1 (IGF-1), and decreases microalbuminuria. In the nondialysis CKD population, resistance training has been reported to reduce inflammation, increase serum albumin, maintain body weight, increase muscle strength, increase IGF-1, and increase GFR. Resistance training in hemodialysis increases muscle strength, increases physical functionality, and improves IGF-1 status. Combined aerobic exercise and resistance training during dialysis improves muscle strength, work output, cardiac fitness, and possibly dialysis adequacy. There is a need for more investigation on the role of exercise in CKD. If the benefits of aerobic exercise and strength training in non-CKD populations can be shown to apply to CKD patients as well, renal rehabilitation will begin to play an important role in the approach to the treatment, prevention, and slowed progression of CKD.

Reliability of GFR formulas based on serum creatinine, with special reference to the MDRD Study equation

Estimation of glomerular filtration rate (GFR) is central to the diagnosis, evaluation and management of chronic kidney disease (CKD). This review summarizes data on the performance of equations using serum creatinine to estimate GFR, particularly the Modification of Diet in Renal Disease (MDRD) Study equation. The size of studies evaluating GFR estimation equations and their level of sophistication in estimating bias, precision, validity and sensitivity to the source population have improved over the past decade. We update our review from 2006, which included 7 studies with over 500 individuals and 12 studies with 50–499 individuals with measured GFR evaluating the MDRD Study and Cockcroft–Gault equations. More recent studies include an individual level pooling analysis of 5504 participants in 10 studies which showed that creatinine calibration to reference methods improved the performance of the MDRD Study equation but increased bias for the Cockcroft‐Gault equation. The MDRD Study equation had a bias of 3.0 %, interquartile range of 29.0 % and percentage of estimates within 30 % of the measured GFR value (P30) of 82 % for estimates below 60 mL/(min×1.73 m2). Above this value, the bias was greater (8.7 %) and estimates are less useful since 30 % error is a large absolute error in GFR. Results vary across studies but are generally similar with disappointing performance in the high GFR range, which is of particular interest in early diabetic nephropathy. New equations using serum creatinine can reduce the bias present in the high GFR range but are unlikely to dramatically improve precision, suggesting a need for additional markers. Finally, algorithms are needed to tailor clinical practice based on data from GFR estimates and other participant characteristics, including the source population and level of proteinuria.

Cystatin C Is Not Superior to Creatinine-Based Models in Estimating Glomerular Filtration Rate in Former Kidney Donors

The long-term renal consequences of kidney donation need to be accurately quantitated. Cystatin C is a freely filtered glycoprotein that may not have the limitations of creatinine as a measure of glomerular filtration rate (GFR). Whether cystatin C is superior to creatinine-based estimates of GFR in those who have donated a kidney in the past has not been tested. We assessed the performance of seven cystatin C and two creatinine-based GFR prediction equations in 187 former kidney donors against iohexol GFR for measuring GFR. We calculated bias, precision, and relative accuracy of these models. The majority of former donors had a GFR >60 mL/min/1.73 m(2). All cystatin C models, except the Rule model, overestimated GFR (range 5.3-31.4 mL/min/1.73 m(2)). Among the cystatin C models, the Hoek and Rule formulas were least biased at 5.3 and -3.8 mL/min/1.73 m(2), most precise at 0.41, and were within 30% of iohexol GFR, 89.3 and 96% of the time, respectively. The Modification of Diet in Renal Disease (MDRD) formula underestimated GFR by 7.2 mL/min/1.73 m(2), was most precise (R(2)=0.47) and fell within 30% of measured GFR at the highest frequency of 96%. When all models were given a rank based on their performance in the bias, precision and accuracy domains, the MDRD model was clearly superior. The MDRD equation is superior to cystatin C-based equations for estimating GFR in former kidney donors. Creatinine measurement is cheaper and the MDRD GFR is given out by most laboratories and therefore it should be the preferred model in this population.

Validation of Neutron Activation as a Novel Method to Determine Glomerular Filtration Rate

Background/Aims: Despite widespread interest in determining the glomerular filtration rate (GFR) of patients, current methods all have significant limitations. Therefore, a compelling need exists for new tests of GFR that are both accurate and easy to perform. We have previously reported that the technique of neutron activation (NA) accurately measures iohexol in vitro. In this study, we demonstrate that NA can be used to determine GFR by measuring the clearance of iohexol, and directly compare these results to a gold-standard method based on ^99mTc-DTPA. Methods: We studied 57 patients with mild to moderate chronic kidney disease and normal volunteers. Subjects were simultaneously injected with iohexol and ^99mTc-DTPA. Blood and urine samples were collected over 4 h to calculate GFR by the UV/P method. Results: The range of GFRs was 28–212 ml/min. GFRs obtained using iohexol and ^99mTc-DTPA correlated closely (R = 0.95). The bias between the 2 techniques was 0.96 ml/min, and precision (defined as the standard deviation of the mean of the difference between the 2 values for each patient) was 10.6 ml/min. Accuracy was such that 98% of subjects had NA GFRs within 20% of the reference ^99mTc-DTPA measurements. Conclusions: We conclude that NA is an excellent technique to measure GFR. NA has several advantages over current methods to directly measure GFR, including the ability to reassay samples, high throughput and the avoidance of patient and hospital radioactivity exposure. In the future, NA could be applied to GFR agents that do not contain iodine, such as Gd-DTPA, and to the simultaneous measurement of agents that reflect renal blood flow, such as iodohippurate. Therefore, NA holds great potential to improve the measurement of renal function in a safe, easily obtainable way.

New Predictive Equations Improve Monitoring of Kidney Function in Patients With Diabetes

The Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations poorly predict glomerular filtration rate (GFR) decline in diabetic patients. We sought to discover whether new equations based on serum creatinine (the Mayo Clinic Quadratic [MCQ] or reexpressed MDRD equations) or four cystatin C-based equations (glomerular filtration rate estimated via cystatin formula [Cys-eGFR]) were less biased and better predicted GFR changes. In 124 diabetic patients with a large range of isotopic GFR (iGFR) (56.1 +/- 35.3 ml/min per 1.73 m2 [range 5-164]), we compared the performances of the equations before and after categorization in GFR tertiles. A total of 20 patients had a second determination 2 years later. The Cockcroft-Gault equation was the least precise. The MDRD equation was the most precise but the most biased according to the Bland-Altman procedure. By contrast with the MDRD and, to a lesser extent, the MCQ, three of the four Cys-eGFRs were not biased. All equations overestimated the low GFRs, whereas only the MDRD and Rule's Cys-eGFR equations underestimated the high GFRs. For the subjects studied twice, iGFR changed by -8.5 +/- 17.9 ml/min per 1.73 m2. GFR changes estimated by the Cockcroft-Gault (-4.5 +/- 6.8) and MDRD (-5.7 +/- 6.2) equations did not correlate with the isotopic changes, whereas new equation-predicted changes did: MCQ: -8.7 +/- 9.4 (r = 0.44, P < 0.05) and all four Cys-eGFRs: -6.2 +/- 7.4 to -7.3 +/- 8.4 (r = 0.60 to 0.62, all P < 0.005), such as 100/cystatin-C (r = 0.61, P < 0.005). The new predictive equations better estimate GFR than the Cockcroft-Gault equation. Although the MDRD equation remains the most accurate, it poorly predicts GFR decline, as it overestimates low and underestimates high GFRs. This bias is lesser with the MCQ and Cys-eGFR equations, so they better predict GFR changes.

Understanding estimated glomerular filtration rate: implications for identifying chronic kidney disease

Glomerular filtration rate (GFR) can be estimated using serum markers such as serum creatinine (SCr) or cystatin C. This review presents new insights into estimated GFR based on theory, validation studies, SCr assay standardization, cystatin C, and longitudinal comparison with measured GFR. The estimation of GFR by SCr differs in health and in chronic kidney disease (CKD) due to differences in GFR range and in creatinine production between these two populations. Among populations with normal baseline GFR, there is a more rapid decline in measured GFR than in SCr-based estimated GFR. While elevated SCr is specific for CKD, other disease processes may lead to elevated cystatin C. Validation is improved by refitting equation coefficients to compare populations, recognizing the asymmetry between estimated GFR and measured GFR, and using residual plots instead of Bland-Altman plots to assess bias. As a screening test, SCr should be interpreted as a marker of CKD probability in the context of the patient's clinical presentation. Measured GFR or creatinine clearance may be helpful in high-risk patients with normal SCr levels. GFR estimating equations should be reserved for patients with identified CKD. Standardized SCr and cystatin C assays are needed.

Bias and precision of estimated glomerular filtration rate in children

Determining true glomerular filtration rate (GFR) using an exogenous marker is time-consuming and cumbersome. Therefore, creatinine-based estimates of GFR are used. Recent papers using new population-specific/local parameters in their prediction equations, standardizing creatinine determination or adding other endogenous surrogate markers of GFR, like cystatin C, could demonstrate an improvement of bias inherent in the results of the prediction equations. Precision, however, is still poor. Currently, we have to accept a precision (as defined in the so-called Bland-Altman plot) of +/-20% in adults and +/-30-40% in children. This problem of poor precision/uncertainty is especially bothering in the higher, near normal GFR range. Caution should be exercised when applying prediction equations in individuals in need of an accurate GFR determination. In that case, a real clearance procedure has to be performed. In the long run, the true clearance procedure should be simplified using new exogenous GFR markers and developing new devices, allowing GFR measurements to be performed, for example, transcutaneously. Such a procedure would be more acceptable for both patients and physicians.

Kidney function estimating equations: where do we stand?

Estimation of the glomerular filtration rate (GFR) is central to the diagnosis, evaluation and management of chronic kidney disease. This review summarizes recent data on the performance of equations using serum creatinine to estimate the GFR, particularly the Modification of Diet in Renal Disease (MDRD) Study equation. During 2005 GFR estimation has received substantial attention with a focus on comparing the MDRD Study equation with the Cockcroft-Gault equation. Several large studies (n>500) have appeared. Most studies discuss creatinine calibration but few were able to standardize measurements. Studies that did calibrate the creatinine had improved performance. Overall, the MDRD Study equation performed well in populations with a low range of GFR and often outperformed the Cockcroft-Gault equation. Both equations have lower precision in high GFR populations, and the MDRD equation under-estimated the GFR in a number of studies. Efforts are underway to develop improved prediction equations by pooling data across many study populations. Equations for estimating the GFR from serum creatinine are useful for systematic staging of chronic kidney disease. The MDRD Study equation and systematic creatinine assay calibration improve the level of precision and accuracy in many settings. GFR estimates are less useful in the normal range of GFR, however, and are sensitive to the population under study.

Development of an outpatient finger-prick glomerular filtration rate procedure suitable for epidemiological studies

Development of an outpatient finger-prick glomerular filtration rate (GFR) procedure suitable for epidemiological studies. In clinical practice, reference GFR procedures are rarely used; in large-scale research studies, a great deal of effort and experience is required to obtain them, which is a considerable disincentive to using GFR as an end point. The major problem for both clinical staff and the subject is the length of time that the procedure takes, requiring continuous attendance in the outpatient clinic or its vicinity. Using iohexol as a marker, we therefore propose an alternative approach, which addresses this fundamental deterrent to a more widespread use of GFR measurement. Eighty-two GFR measurements were performed in a mixture of healthy subjects and patients with differing degrees of renal impairment with a wide range of GFRs. Serum was obtained from blood samples to enable a reference GFR to be calculated. Blood spots were collected on filter paper at the same intervals (120, 180, and 240 min), allowed to dry, and then sent through the post. Serum and blood spots were analyzed simultaneously for each individual by automated reverse-phase high-pressure liquid chromatography. Standard linear regression analyses confirmed a good agreement (r2 = 0.953) between the iohexol serum GFR and iohexol blood spots GFR. Bland-Altman analysis confirmed that there was no concentration bias. Paired comparisons (Wilcoxon's paired signed rank test) showed no significant difference between the two measurements. Capillary sampling is simple, effective, and significantly reduces the time and costs of performing plasma clearance GFR measurements. This approach will make the GFR measurement more accessible for clinical practice and large-scale epidemiological studies may become feasible.

Prediction of glomerular filtration rate in renal transplant recipients: cystatin C or Modification of Diet in Renal Disease equation?

To overcome disadvantages of serum creatinine two strategies have been suggested to identify patients with reduced glomerular filtration rate (GFR). On the one hand, the Modification of Diet in Renal Disease (MDRD) equation is now recommended to classify the stage of chronic kidney disease. On the other hand, cystatin C (Cys C) has been investigated in numerous studies, finding a higher sensitivity than creatinine in detecting diminished GFR. To date, no comparison of both strategies in patients after renal transplantation has been performed. One hundred and five consecutive renal transplant recipients underwent (99m)Tc-DTPA-- clearance measurement. Simultaneously, MDRD estimates were calculated and Cys C serum levels were determined. ROC analyses were performed at different decision points from 20 to 70 mL/min/1.73 m(2). Although the area under the curve did not differ significantly between MDRD and Cys C within the tested GFR range, the AUC for Cys C tended to be higher when GFR exceeded 55 mL/min/1.73 m(2). A significantly higher diagnostic accuracy for Cys C compared with MDRD (p = 0.045 at 65 mL/min/1.73 m(2)) was found when investigating the subgroup of patients with well-functioning grafts (GFR>40 mL/min/1.73 m(2)). MDRD equation is equivalent to Cys C measurement in renal transplant recipients. As availability of MDRD is superior to Cys C, we recommend GFR estimation using the MDRD equation. Nevertheless, Cys C may serve as a confirmation test of high MDRD estimates in patients with well-functioning grafts because of superior accuracy in these patients.

Assessing Glomerular Filtration Rate by Estimation Equations in Kidney Transplant Recipients

Surveillance of glomerular filtration rate (GFR) is crucial in the management of kidney transplant recipients. With special emphasis on serum creatinine (SCr) calibration assay, we assessed the performance of estimation equations as compared to iothalamate GFR (iGFR) in 209 patients using the modification of diet in renal disease (MDRD), Nankivell and Cockcroft-Gault methods. Fifty-five percent of patients were treated with a calcineurin inhibitor (CNI) and all were taken trimethroprim-sulfametoxazole at the time of SCr measurement. The mean iGFR was 44 +/- 26 mL/min/1.73 m2. The MDRD equation showed a median difference of 0.9 mL/min/1.73 m2 with 53% of estimated GFR within 20% of iGFR. Median differences were 7.5 and 7.0 mL/min/1.73 m2 for Nankivell and Cockcroft-Gault formulas, respectively. The accuracy of the Nankivell and Cockcroft-Gault formulas was such that only 38% and 37% of estimations, respectively, fell within 20% of iGFR. The performance of all equations was not uniform throughout the whole range of GFR, with some deterioration at the extremes of GFR levels. In addition, good performance of the MDRD equation was seen in subjects taking CNI. In conclusion, the overall performance of the MDRD equation was superior to the Nankivell and Cockcroft-Gault formulas in renal transplant recipients including subjects treated with CNI.

Glomerular filtration rate is a predictor of mortality after endovascular abdominal aortic aneurysm repair

Clinically evident renal disease is a risk factor for mortality after aneurysm repair. Serum creatinine is widely used as a measure of renal function in the preoperative evaluation of patients. Unfortunately, serum creatinine concentration is influenced by muscle mass, hydration status, and glomerular filtration rate (GFR). Calculated GFR, which takes predictors of muscle mass such as age, gender, and weight into account, is a more sensitive determinant of renal function than serum creatinine. We hypothesized that GFR would more accurately predict mortality after EVAR than serum creatinine. We retrospectively evaluated our database of 398 patients who underwent EVAR with the AneuRx device between October 1999 and October 2004. There were 340 men and 58 women with a mean age of 73. GFR was calculated using the Cockcroft-Gault equation. The patients were divided into four quartiles by preoperative GFR: I (7 to 45), II (45 to 60), III (61 to 79), and IV (> or =80). Survival was estimated with the Kaplan-Meier method, and heterogeneity of mortality across strata was evaluated using the log-rank test. The GFR quartiles were compared with clinically accepted criteria for abnormal renal function (serum creatinine level > or =1.7). Actuarial survival at 48 months was 61.5%, 70.5%, 86.0%, and 85.7% for GFR quartiles I to IV, respectively (P < .003). Thirty-day mortality was 2.2% in quartile I, 3.2% in quartile II, and 0 in quartiles III and IV (P = .03 for q1 + q2 vs q3 + q4, P < .02 for q2 vs q3 + q4). Survival curves for quartiles II to IV were statistically indistinguishable, with quartile II running tangential to the two higher quartiles after the perioperative period. Quartile I fared significantly worse than the other three quartiles for the entire follow-up period (P < .005). According to American Kidney Foundation criteria (GFR <90), 83.3% of patients had abnormal renal function compared with 16.1% with abnormal serum creatinine (>1.7) (P < .0002). The risk of perioperative and long-term mortality in patients undergoing EVAR is more accurately stratified by using calculated GFR than serum creatinine alone. A GFR <45 is associated with decreased survival after EVAR. Perioperative mortality at a GFR of 45 to 60 is comparable with that of the lower quartile (GFR <45), but late survival is comparable with that of patients with GFR >60. The finding of increased risk of early mortality in patients in the 45 to 60 GFR range, with survivors enjoying good long-term outcome, suggests that these patients may most benefit from the use of alternative contrast agents and periprocedural renal protection techniques.

Do Healthy Potential Kidney Donors in India Have an Average Glomerular Filtration Rate of 81.4 ml/min?

Background: Until now, a normal reference range for glomerular filtration rate (GFR) in adult Indian potential kidney donors has not been determined and values from a western population are being used as reference. Aim: To determine the reference range of GFR in healthy adult Indian potential kidney donors. Basic Procedures: GFR was measured in 610 (250 male, 360 female, average age 35.16 years) healthy potential kidney donors using the ^99mTc-DTPA (diethylenetriamine pentaacetic acid) two-plasma sample method of Russell. Results: The mean body surface area (BSA)-normalized GFR value of a young healthy Indian adult potential kidney donor was calculated as 81.4 ± 19.4 ml/min/1.73 m² BSA – for males it was 82.3 ± 21.3 ml/min/1.73 m² BSA and for females 80.8 ± 18.1 ml/min/1.73 m² BSA. There was no significant difference between derived mean GFR values in males and females with a p value of 0.37. Conclusions: The normal GFR value for the healthy Indian adult potential kidney donor appears to be much lower than the accepted value for a western population. The mean GFR value of a young healthy Indian adult potential kidney donor is 81.4 ± 19.4 ml/min/1.73 m² BSA, which is significantly different from the normal value of 109–125 ml/min derived from a western population. These findings might be useful in deciding on a suitable kidney donor in an Indian context.

Accurate measurement of individual glomerular filtration rate in cancer patients: an ongoing challenge

A narrow therapeutic index is a characteristic feature of cytotoxic agents. Some of these agents are almost entirely eliminated renally in unchanged active form. As a consequence, assessment of the individual glomerular filtration rate (GFR) may help to predict the pharmacokinetic behaviour of cytotoxic agents in plasma more precisely. In addition, GFR-adapted individualization of cancer chemotherapy may have an enormous impact on the severity of side effects. Several methods are available to determine GFR or creatinine clearance (CrCl). GFR-measurement based on experimental methods with radiolabelled isotopes, contrast media or inulin helps to reflect the real situation very closely. In addition, 24-h urine collection is a convenient and feasible method to measure creatinine clearance. Finally, several mathematical equations exist to estimate GFR or CrCl based on serum creatinine and other parameters. Only a few of these equations have been developed in oncologic patients. However, some of these equations are routinely used in clinical practice, because they allow a rapid estimation of GFR. Based on the fact that clinically relevant differences have been assessed between calculated values and the real situation, mathematical calculation of GFR or CrCl does not seem to be appropriate to assess individual renal function precisely enough over a broad range of individual GFR or CrCl. Whether the measurement of low-molecular-weight proteins, such as cystatin C and ss-trace protein, may help to reflect the real situation more precisely is a matter of controversial debate.

Determination of the production rate and non‐renal clearance of cystatin C and estimation of the glomerular filtration rate from the serum concentration of cystatin C in humans

Cystatin C has been proposed as an endogenous marker for measuring glomerular filtration rate (GFR) and is regarded as being equivalent to or better than creatinine. However, there are no published data on the production rate (Cyspr) or on the non‐renal clearance of cystatin C (CLnr) in humans, which are essential parameters for GFR calculation. GFR was determined by measuring the plasma clearance of iohexol. Cystatin C, creatinine, urea and albumin were determined on the same serum samples as iohexol; 381 patients with a GFR range of 12–151 ml/min/1.73 m2, and 70 patients on haemodialysis were evaluated. Renal clearance of cystatin C (CLr) equals GFR * S (the sieving coefficient). Plasma clearance (CL) = CLr+CLnr. The relationship between Cyspr and the elimination rate (CL * serum‐cystatin C) can be expressed as Cyspr = (S * GFR+CLnr) * serum‐cystatin C. Assuming that the unknown values of Cyspr and CLnr are independent of GFR, the equation can be solved from GFR (iohexol clearance) and serum cystatin C (s‐Cys) patient data. For S = 1, we found Cyspr = 0.124±0.023 mg/min/1.73 m2 and Clnr = 22.3 ml/min/1.73 m2. For S = 0.94, found in rats, the values will be Cyspr = 0.117 mg/min/1.73 m2 and Clnr = 21 ml/min/1.73 m2 and S‐Cys in 70 patients on chronic haemodialysis was found to be 5.74±1.15 mg/l, in agreement with a calculated value of 5.56 mg/l (s‐Cys = 124/22.3) for GFR = zero. The mean value of the calculated Clnr for the 70 patients was 22.7±6.6 ml/min/1.73 m2, which confirms the calculated level and indicates its biological variation. We thus propose the following formula for calculating GFR using the values found for CLnr and Cyspr in this study: GFR = 124/s‐Cys−22.3 ml/min/1.73 m2, where serum cystatin C concentration is given as mg/l.

Cystatin C: An emerging glomerular filtration rate marker

In this issue of SJCLI (pp. 111-124), Per Sjostrom and co-workers present a study on the ''Determination of the production rate and non-renal clearance of cystatin C and estimation of the glomerular filtration rate from the serum concentration of cystatin C in humans''. They have studied the non-renal clearance of cystatin C, which is of particular importance when using cystatin C for monitoring patients with severely decreased glomerular filtration rate (GFR), as non-renal clearance will have a relatively greater impact on the total clearance as the glomerular filtration decreases. They show that cystatin C has a significant non-renal clearance and they calculated this clearance. They have used the non-renal clearance to develop a new cystatin C formula that takes into account the non- renal clearance. The study shows that the production rate of cystatin C is independent of gender, age, lean body mass and GFR, which allows the use of simpler formulas for calculation of GFR. Lean body mass, weight and length are parameters that are often difficult to obtain for the laboratory. The study also presents data on the biological variability of production rate and extrarenal clearance. These are important contributions to our understanding of cystatin C as a GFR marker. Iohexol is usually considered the gold standard for GFR monitoring in Sweden. How iohexol GFR is analysed varies between laboratories. With decreasing GFR, the slope of the iohexol elimination curve becomes less pronounced. To my knowledge, no laboratory has a defined value for the slope of the elimination curve for rejecting a test result. Most laboratories thus probably compromise in the low GFR range with the assay quality rather than reporting that the test has to be repeated with longer time intervals between the injection and sampling time. There are also a number of methods for calculating the clearance and no external quality assurance programme, which would add to the total CV within the country. One could thus question how shiny the ''gold standard'' really is. Cystatin C has a low total CV and increases three to four times when GFR decreases from 50 ml/min to close to 0 ml/min. To me, these are important factors for a good test. In my opinion the present analytical characteristics favour cystatin C in the low GFR range while the fact that cystatin C is an endogenous substance favours iohexol as the best test. At

Factors associated with lipoprotein(a) in chronic kidney disease

It is unclear whether lipoprotein(a) (Lp[a]) levels in patients with chronic kidney disease (CKD) are elevated as a result of reduced glomerular filtration rate (GFR) or other factors associated with CKD. The goal of this study is to describe the association of Lp(a) level with GFR in the context of apoprotein(a) (apo[a]) isoform size, race, and other kidney disease-related factors, such as proteinuria, serum albumin level, C-reactive protein (CRP) level, and serum lipid levels. Lp(a) and apo(a) isoforms were measured in serum samples obtained at baseline from 804 participants in the Modification of Diet in Renal Disease study (GFR range, 13 to 55 mL/min/1.73 m2). The cross-sectional association between Lp(a) level and GFR, apo(a) isoform size, race, and other variables was analyzed in univariate and multivariate linear regression. Median Lp(a) level was greater in blacks than whites (97.5 versus 28.1 nmol/L; P < 0.001). Those with a low-molecular-weight apo(a) isoform size had greater Lp(a) levels than those with a high-molecular-weight apo(a) isoform size (57.5 versus 21.3 nmol/L; P < 0.001). Lp(a) level was not associated with GFR. Low-molecular-weight apo(a), black race, and greater levels of proteinuria, CRP, and triglycerides were independently associated with greater Lp(a) levels. In this population with CKD stages 3 to 4, GFR was not associated with Lp(a) level, whereas other factors related to CKD, such as proteinuria, CRP level, and triglyceride level, as well as genetic factors such as apo(a) isoform size and race, were associated with Lp(a) level.

Evaluation of renal function in intensive care: plasma cystatin C vs. creatinine and derived glomerular filtration rate estimates

Plasma cystatin C, a new marker of glomerular filtration rate (GFR), was prospectively evaluated in surgical intensive care. Cystatin C was measured (immunonephelometry, Dade-Behring) in 10 patients selected to cover a full range of GFR (phase I) and in 28 unselected consecutive patients followed for 5 days post-admission (phase II). Results were compared with (51)Cr-EDTA clearance (phase I only), plasma creatinine (kinetic Jaffe, Roche), 24-h or estimated by Cockcroft and Gault (CG) creatinine clearance (CrCl), and modified diet in renal disease (MDRD)-estimated GFR. In phase I, the highest correlation with(51)Cr-EDTA clearance (22-198 mL/min) was noted for CG CrCl (r(2): 0.883, p<0.001). During phase II follow-up, 24-h CrCl could not be calculated in 25% of daily evaluations. Cystatin C correlated with creatinine (0.856, p<0.0001) and CG CrCl with MDRD GFR (0.926, p<0.0001) in renal failure (10-78 mL/min, n=60). There was a +40% (p<0.001) median difference between cystatin C and creatinine (as a % of upper normal cut-off). Sensitivity/specificity to detect a <80 mL/min CG CrCl was 88/97% for cystatin C vs. 48/100% for creatinine (laboratory cut-off). In patients with normal and stable renal function (n=14), day-to-day intra-individual variation was 7.4% for cystatin C (vs. 10.6% for creatinine). In intensive care unit surgical adult patients, CG CrCl provides an easy and cost-effective estimate of GFR. Superior to creatinine, plasma cystatin C can be measured in selected patients where CG CrCl is known to be inaccurate.

In reply

The main focus of our article was to validate the Modification of Diet in Renal Disease (MDRD) formula in a Norwegian population, and we found that recalibration of the serum creatinine assay reduced the negative bias of this formula in the normal and near-normal glomerular filtration rate (GFR) range.1 Dr. Lhotta suggests that tubular secretion of creatinine might also contribute to negative bias in the near-normal GFR range. All formulae tested in our article showed this bias, and when exploring the data of the original MDRD article the same bias occurs,2 so this is a general problem.