Sten-Erik Bäck

Measuring GFR: A Systematic Review.

BACKGROUND No comprehensive systematic review of the accuracy of glomerular filtration rate (GFR) measurement methods using renal inulin clearance as reference has been published. STUDY DESIGN Systematic review with meta-analysis of cross-sectional diagnostic studies. SETTING & POPULATION Published original studies and systematic reviews in any population. SELECTION CRITERIA FOR STUDIES Index and reference measurements conducted within 48 hours; at least 15 participants studied; GFR markers measured in plasma or urine; plasma clearance calculation algorithm verified in another study; tubular secretion of creatinine had not been blocked by medicines. INDEX TESTS Endogenous creatinine clearance; renal or plasma clearance of chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA), diethylenetriaminepentaacetic acid (DTPA), iohexol, and iothalamate; and plasma clearance of inulin. REFERENCE TEST Renal inulin clearance measured under continuous inulin infusion and urine collection. RESULTS Mean bias <10%, median bias <5%, the proportion of errors in the index measurements that did not exceed 30% (P30) ≥80%, and P10 ≥50% were set as requirements for sufficient accuracy. Based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, the quality of evidence across studies was rated for each index method. Renal clearance of iothalamate measured GFR with sufficient accuracy (strong evidence). Renal and plasma clearance of 51Cr-EDTA and plasma clearance of iohexol were sufficiently accurate to measure GFR (moderately strong evidence). Renal clearance of DTPA, renal clearance of iohexol, and plasma clearance of inulin had sufficient accuracy (limited evidence). Endogenous creatinine clearance was an inaccurate method (strong evidence), as was plasma clearance of DTPA (limited evidence). The evidence to determine the accuracy of plasma iothalamate clearance was insufficient. With the exception of plasma clearance of inulin, only renal clearance methods had P30 >90%. LIMITATIONS The included studies were few and most were old and small, which may limit generalizability. Requirements for sufficient accuracy may depend on clinical setting. CONCLUSIONS At least moderately strong evidence suggests that renal clearance of 51Cr-EDTA or iothalamate and plasma clearance of 51Cr-EDTA or iohexol are sufficiently accurate methods to measure GFR.

Contrast media as markers for glomerular filtration: a pharmacokinetic comparison of four agents.

In this study methods for the assay of the iodine-containing radiographic contrast agents metrizoate, amidotrizoate and iothalamate found in serum and urine have been developed. The method involved reverse-phase high-pressure liquid chromatography with spectrophotometric detection. This technique was used to compare the clearance of these agents, in a group of healthy female volunteers, after a single small-dose injection (5 ml, 2275-3235 mg). In the period 0-4 h after injection, serum elimination was approximated by a two-compartment model. However, a full description of drug fate in the body required at least three compartments. Plasma clearance was significantly different between agents with means of 191, 130, 144 and 121 ml/min for metrizoate, amidotrizoate, iothalamate and iohexol, respectively, whereas no difference was found between the renal/plasma clearance ratio. Protein binding measured with equilibrium dialysis did not suggest binding to serum proteins by any of these agents irrespective of concentration.

Glomerular filtration rate in pregnancy: a study in normal subjects and in patients with hypertension, preeclampsia and diabetes

We have studied renal function during pregnancy using plasma clearance of iohexol to determine the glomerular filtration rate (GFR). In normal pregnancy, GFR was elevated by 40% throughout pregnancy and during the first week post partum, and fell to levels similar to those in non-pregnant women within 1 month. The development of GFR in diabetic pregnant women and in women with gestational hypertension was similar to that recorded in normal pregnancy. In subjects with preeclampsia the rise in GFR observed in normal pregnancy was absent, and no change in GFR was recorded after delivery. We conclude that the development of proteinuria and fluid retention typical of preeclampsia is paralleled by a deterioration of GFR.

Age dependence of renal function: clearance of iohexol and p-amino hippurate in healthy males

Iohexol, a newly developed non-ionic contrast agent, has been recently documented as a reliable glomerular filtration marker. This study describes the age dependence of the single injection clearance of iohexol in a sample of healthy male volunteers ranging from 21 to 77 years of age. In parallel, renal plasma flow was studied by measuring the total clearance of p-amino hippuric acid administered as a continuous infusion. In subjects older than 50 years a negative correlation to age was found for both p-amino hippuric acid and iohexol clearance, with a reduction of 52 ml/min and 12 ml/min per decade, respectively, whereas no age dependence was found for younger subjects. Correlation between p-amino hippuric acid and iohexol clearances was 0.81. However, the filtration fraction, defined as the ratio of iohexol to p-amino hippuric acid clearance, was higher in the elderly subjects. A consistent discrepancy was found between total and renal clearances of p-amino hippuric acid, indicating significant renal metabolism. Renal clearance of creatinine was poorly correlated to iohexol clearance and did not show any relationship to age.

Towards common reference intervals in clinical chemistry. An attempt at harmonization between three hospital laboratories in Skåne, Sweden.

Abstract The population sample of the Kristianstad survey, a reference intervals survey in the county of Kristanstad, was used to establish new reference intervals in clinical chemistry at the laboratories of the Central Hospital in Kristianstad, the University Hospital in Lund and the University Hospital in Malmö. Three-hundred and fifty nine subjects, male and female, aged 20–80+ years, were invited to participate in the study, with a participation rate of 70 %. Up to 70 analyses were performed on each subject, general clinical chemistry parameters in all three laboratories, specialized analyses where available. Separate a priori exclusion criteria were defined for each test. In addition, the test pattern of each individual was evaluated for signs of preclinical disease. Twelve cases of preclinical disease were discovered and clinically confirmed. Details on all test methods are presented along with information concerning instruments used, calibration procedures, methods of calculation and obtained reference intervals. Although the methods were in general calibrated against acknowledged reference materials, in some instances differences were found that made common reference intervals across all laboratories impossible. Problems relating to the practical use of international recommendations and the establishment of reliable reference intervals are discussed.

A simple chemical method for the quantification of the contrast agent iohexol, applicable to glomerular filtration rate measurements.

We present a method for the quantification of the contrast agent iohexol in serum. Iohexol is deiodinated by alkaline hydrolysis and the released iodine subsequently measured according to the ceric arsenite method. The assay requires 50 microliters of serum and has a high capacity as it involves few analytical steps. The high precision (2% CV) and sensitivity make the method applicable to the recently developed procedure for the determination of glomerular filtration rate, which is based on the assessment of the clearance of iohexol from serum. The method is simple and rapid and requires no expensive equipment.

Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research : a review. Part 1 How to measure glomerular filtration rate with iohexol?

While there is general agreement on the necessity to measure glomerular filtration rate (GFR) in many clinical situations, there is less agreement on the best method to achieve this purpose. As the gold standard method for GFR determination, urinary (or renal) clearance of inulin, fades into the background due to inconvenience and high cost, a diversity of filtration markers and protocols compete to replace it. In this review, we suggest that iohexol, a non-ionic contrast agent, is most suited to replace inulin as the marker of choice for GFR determination. Iohexol comes very close to fulfilling all requirements for an ideal GFR marker in terms of low extra-renal excretion, low protein binding and in being neither secreted nor reabsorbed by the kidney. In addition, iohexol is virtually non-toxic and carries a low cost. As iohexol is stable in plasma, administration and sample analysis can be separated in both space and time, allowing access to GFR determination across different settings. An external proficiency programme operated by Equalis AB, Sweden, exists for iohexol, facilitating interlaboratory comparison of results. Plasma clearance measurement is the protocol of choice as it combines a reliable GFR determination with convenience for the patient. Single-sample protocols dominate, but multiple-sample protocols may be more accurate in specific situations. In low GFRs one or more late samples should be included to improve accuracy. In patients with large oedema or ascites, urinary clearance protocols should be employed. In conclusion, plasma clearance of iohexol may well be the best candidate for a common GFR determination method.

Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: ‘Shrunken pore syndrome’

Abstract The plasma levels of cystatin C, β2-microglobulin, beta-trace protein, retinol binding protein (RBP) and creatinine were determined in plasma samples from 111 randomly selected patients with eGFRcystatin C ≤ 60% of eGFRcreatinine and from 55 control patients with 0.9eGFRcreatinine ≤ eGFRcystatin C ≤ 1.1eGFRcreatinine (eGFRcystatin C ≈ eGFRcreatinine). The concentration ratios of cystatin C/creatinine, β2-microglobulin/creatinine, beta-trace protein/creatinine and RBP/creatinine were significantly higher in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine than in patients with eGFRcystatin C ≈ eGFRcreatinine. When the patients were divided into three groups with different estimated GFR intervals (≤ 40, 40–60 and ≥ 60 mL/min/1.73m2) the concentration ratios of cystatin C/creatinine, β2-microglobulin/creatinine, and beta-trace protein/creatinine were significantly higher in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine than in patients with eGFRcystatin C ≈ eGFRcreatinine for all GFR intervals. Similar results were obtained when the population without pregnant women was studied as well as the subpopulations of men or of non-pregnant women. Populations of pre-eclamptic women and pregnant women in the third trimester display similar results. Since the production of these four proteins with sizes similar to that of cystatin C is not co-regulated, the most likely explanation for the simultaneous increase of their creatinine-ratios in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine is that their elimination by glomerular filtration is decreased. We suggest that this is due to a reduction in pore diameter of the glomerular membrane and propose the designation ‘Shrunken pore syndrome’ for this pathophysiological state.

GFR estimation based on standardized creatinine and cystatin C : A European multicenter analysis in older adults

Abstract Background: Although recommended by the Kidney Disease Improving Global Outcomes, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPICR) creatinine equation was not targeted to estimate glomerular filtration rate (eGFR) among older adults. The Berlin Initiative Study (BIS1CR) equation was specifically developed in older adults, and the Lund-Malmö revised (LMRCR) and the Full Age Spectrum (FASCR) equations have shown promising results in older adults. Our aim was to validate these four creatinine equations, including addition of cystatin C in a large multicenter cohort of Europeans ≥70 years. Methods: A total of 3226 individuals (2638 with cystatin C) underwent GFR measurement (mGFR; median, 44 mL/min/1.73 m2) using plasma iohexol clearance. Bias, precision (interquartile range [IQR]), accuracy (percent of estimates ±30% of mGFR, P30), eGFR accuracy diagrams and probability diagrams to classify mGFR<45 mL/min/1.73 m2 were compared. Results: The overall results of BIS1CR/CKD-EPICR/FASCR/LMRCR were as follows: median bias, 1.7/3.6/0.6/−0.7 mL/min/1.73 m2; IQR, 11.6/12.3/11.1/10.5 mL/min/1.73 m2; and P30, 77.5%/76.4%/80.9%/83.5% (significantly higher for LMR, p<0.001). Substandard P30 (<75%) was noted for all equations at mGFR<30 mL/min/1.73 m2, and at body mass index values <20 and ≥35 kg/m2. LMRCR had the most stable performance across mGFR subgroups. Only LMRCR and FASCR had a relatively constant small bias across eGFR levels. Probability diagrams exhibited wide eGFR intervals for all equations where mGFR<45 could not be confidently ruled in or out. Adding cystatin C improved P30 accuracy to 85.7/86.8/85.7/88.7 for BIS2CR+CYS/CKD-EPICR+CYS/FASCR+CYS/MEANLMR+CAPA. Conclusions: LMRCR and FASCR seem to be attractive alternatives to CKD-EPICR in estimating GFR by creatinine-based equations in older Europeans. Addition of cystatin C leads to important improvement in estimation performance.

Accuracy diagrams: a novel way to illustrate uncertainty of estimated GFR

Abstract Most studies that validate GFR equations present accuracy results stratified by measured GFR (mGFR; diagnostic correctness) or by estimated GFR (eGFR; diagnostic predictiveness) only, without a clear distinction in interpretation. The accuracy of a GFR equation is normally reported in percent (e.g. P30), but is often misinterpreted when stratified by eGFR. The aim of the study was to develop new accuracy measures and diagrams that allow straightforward interpretations and illustrations of the uncertainty in eGFR in clinical practice. We applied quantile regression to the distribution of estimation errors for two creatinine-based GFR equations, LM-REV and CKD-EPI, in a clinical cohort (n = 3495) referred for GFR measurement (plasma clearance of iohexol). Measures of bias and precision and accuracy intervals (AIs) were expressed in mL/min/1.73 m2. Diagrams with AIs were chosen as a novel way to present the error margin in eGFR at a pre-specified certainty level. It was shown that creatinine-based equations are still quite inaccurate in that large estimation errors could not be ruled out with satisfactory certainty. As an example, the 75% AI for the most accurate equation, LM-REV, was approximately ±10 mL/min/1.73 m2 at eGFR = 45 mL/min/1.73 m2, whereas it ranged between −13 and +20 mL/min/1.73 m2 at eGFR = 90 mL/min/1.73 m2. Accuracy intervals presented in diagrams can be used to illustrate the uncertainty of eGFR. Future validation studies should assess the variability in the predictiveness of eGFR across populations and clinical settings using tools and performance measures that are easy to interpret.