Gunnar Sterner

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.

A cystatin C-based formula without anthropometric variables estimates glomerular filtration rate better than creatinine clearance using the Cockcroft-Gault formula.

In 1976, Cockcroft and Gault introduced a widely used formula comprising several anthropometric variables to compensate for the inadequacies of creatinine level as a marker of glomerular filtration rate (GFR). The present work investigates the possibility of introducing cystatin C‐based formulas without anthropometric variables to predict GFR, determined by an invasive “gold standard” procedure (iohexol clearance), and to compare the diagnostic efficiency of such formulas with that of Cockcroft and Gault. All 451 adult patients referred to the University Hospital for determination of GFR by iohexol clearance measurements during a period of 6 months were included in the study. Calculations of bias (median percent error), correlation (adjusted R2), and accuracy (percentage of estimates within 30 and 50% of iohexol clearance) were used in the comparison. The cystatin C‐based formula GFR (ml/min) = 89.12×cystatin C−1.675 had lower bias and higher accuracy in predicting GFR than the Cockcroft–Gault formula. If a cystatin C‐based formula including gender was constructed: GFR (ml/min) = 99.19×cystatin C−1.713×(0.823 for women), an even lower bias and higher accuracy were obtained. It is suggested that measurement of cystatin C should be used for the initial prediction of GFR of a patient.

Contrast-Medium-Induced Nephropathy Correlated to the Ratio Between Dose in Gram Iodine and Estimated GFR in ml/min

Purpose: To suggest a more precise tool when assessing the risk of contrast-medium-induced nephropathy (CIN), i.e. the ratio between contrast medium (CM) dose expressed in grams of iodine (g-I) and estimated glomerular filtration rate in ml/min (eGFR; based on equations using serum-creatinine (s-Cr), weight, height, age, and/or sex), here named I-dose/GFR ratio. Material and Methods: A Medline search of published CIN investigations reporting mean eGFR and mean dose of low-osmolality CM (LOCM) identified 10 randomized controlled prophylactic and 2 cohort coronary investigations, and 3 randomized and 1 cohort computed tomographic (CT) investigation. From the randomized trials, data were collected only from the placebo or control arms, unless there was no significant difference between the control and test groups. The mean I-dose/GFR ratio of each study was correlated with the mean frequency of CIN-1 (s-Cr rise⩾44.2 µmol/l or ⩾20–25%) and CIN-2 (oliguria or requiring dialysis). A maximum dose according to an I-dose/GFR ratio = 1 in patients with s-Cr ranging from 100 to 300 µmol/l was compared with that of Cigarroas formula and with a “European consensus” threshold published by the European Society of Urogenital Radiology, both using s-Cr alone to predict renal function. McCulloughs formula was used to assess the risk of CIN requiring dialysis at an I-dose/GFR ratio = 1 with LOCM. Results: The coronary investigations revealed a linear correlation with a correlation coefficient between the I-dose/GFR ratio and the frequency of CIN-1 and CIN-2 of 0.91 (P<0.001) and 0.84 (P = 0.001), respectively. At a mean I-dose/GFR ratio = 1, the regression line indicated a 10% risk of CIN-1 and a 1% risk of CIN-2. At a mean I-dose/GFR ratio = 3, the risk of CIN-1 and CIN-2 increased to about 50% and 15%, respectively. Pooled weighted data from the CT investigations revealed a 12% risk of CIN-1 at a mean I-dose/GFR ratio = 1.1 and no cases of CIN-2. The maximum CM dose according to an I-dose/GFR ratio = 1 was about 30–50% of that of both Cigarroas formula and the “European consensus” in elderly low-weight individuals, while it was similar for middle-aged individuals weighing about 90 kg. McCulloughs formula suggests that there will be an exponentially increasing risk of CIN requiring dialysis, but at an I-dose/GFR ratio = 1 and using LOCM it will not exceed 1% until GFR decreases below 30 ml/min in diabetics and below 20 ml/min in non-diabetics. Conclusion: Using the I-dose/GFR ratio may be a more expedient way of improving risk assessment of CIN than todays common practice of estimating CM dose from volume alone and renal function from s-Cr alone. Prospective studies based on individual patient data are encouraged to define the risk of CIN at various I-dose/GFR ratios and correlated to type of CM, examination, risk factors, etc.

Contrast media as markers of GFR

Abstract.Determination of the glomerular filtration rate (GFR) is generally considered as the most important parameter of quantifying renal function. The GFR is determined as renal or plasma clearance of an ideal filtration marker which is freely filtered by the kidney, does not undergo metabolism, tubular secretion or absorption. Markers that fulfil these demands are inulin, 51Cr-EDTA, 99mTc-DTPA, labelled or unlabelled contrast media. The renal clearance of inulin is the classic reference method for estimation of the GFR. This method is however not practical for routine clinical purposes. Radionucleids have therefore been used as alternative filtration markers since the 60s. Drawbacks related to radiation exposure especially in children and pregnant women and the safety in handling radiolabelled markers have led to an increasing interest in using non-radioactive markers. The development of simple and reliable methods to determine the concentration of contrast media in plasma and urine, such as high-performance liquid chromatography (HPLC) and X-ray fluorescence analysis have made this possible. The non-ionic low osmolar contrast medium iohexol has become the most commonly used contrast medium for GFR measurements in Europe. However, other contrast media with similar pharmacokinetics may be equally suitable as GFR markers.

Novel Assay of Metformin Levels in Patients With Type 2 Diabetes and Varying Levels of Renal Function Clinical recommendations

OBJECTIVE To study trough levels of metformin in serum and its intra-individual variation in patients using a newly developed assay. RESEARCH DESIGN AND METHODS Trough serum levels of metformin were measured once using liquid chromatography–tandem mass spectrometry (LCMSMS) in 137 type 2 diabetic patients with varying renal function (99 men) and followed repeatedly during 2 months in 20 patients (16 men) with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 body surface. RESULTS Patients with eGFR >60, 30–60, and <30 ml/min/1.73 m2 had median trough metformin concentrations of 4.5 μmol/l (range 0.1–20.7, n = 107), 7.71 μmol/l (0.12–15.15, n = 21), and 8.88 μmol/l (5.99–18.60, n = 9), respectively. The median intra-individual overall coefficient of variation was 29.4% (range 9.8–74.2). CONCLUSIONS Determination of serum metformin with the LCMSMS technique is useful in patients on metformin treatment. Few patients had values >20 μmol/l. Metformin measurement is less suitable for dose titration.

Does Post-angiographic Hemodialysis Reduce the Risk of Contrast-medium Nephropathy?

Objective: Several strategies have been employed to reduce the incidence of nephrotoxicity in connection with the administration of urographic contrast media. We present the results of a randomized study to explore the effect of a single hemodialysis treatment immediately after an angiographic examination. Material and Methods: The patients studied had moderately reduced renal function. Seventeen of the 32 patients had diabetic nephropathy and 15 had other renal diseases. They were randomly selected to undergo either hemodialysis or standard treatment following the angiographic examination. The glomerular filtration rate (GFR) was determined the day before and 1 week after administration of the contrast medium. All patients were hydrated and received oral calcium-channel blocking treatment before angiography. Results: Hemodialysis lowered the level of contrast medium in plasma by approximately 80%. In spite of this no significant difference in renal iohexol clearance was noted between groups treated and not treated with hemodialysis. Conclusions: The risk of a marked and sustained reduction in renal function after administration of an iodine contrast medium is low with modern angiographic techniques. Hemodialysis reduces levels of contrast media in plasma but does not reduce the incidence of contrast-medium-induced nephrotoxicity in the GFR range from 10 to 25 ml/min.

Prediction of relative glomerular filtration rate in adults: New improved equations based on Swedish Caucasians and standardized plasma‐creatinine assays

Objective. To evaluate newly developed equations predicting relative glomerular filtration rate (GFR) in adult Swedish Caucasians and to compare with the Modification of Diet in Renal Disease (MDRD) and Mayo Clinic equations using enzymatic and zero‐calibrated plasma creatinine assays. Material and methods. GFR was measured with iohexol clearance adjusted to 1.73 m2. One population sample (n = 436/Lund) was used to derive an equation based on plasma‐creatinine/age/gender, and a second with the addition of lean body mass (LBM). Both equations were validated in a separate sample (n = 414/Malmö). The coefficients of the equations were eventually fine‐tuned using all 850 patients and yielding Lund–Malmö equations without (LM) and with LBM‐term (LMLBM). Their performance was compared with the MDRDCC (conventional creatinine calibration), MDRDIDMS (isotope dilution mass spectroscopy traceable calibration) and Mayo Clinic equations. Results. The Lund equations performed similarly in both samples. In the combined set, the Mayo Clinic/MDRDCC resulted in +19.0/+10.2 % median bias, while bias for the other equations was<10 %. LMLBM had the highest accuracy (86 % of estimates within 30 % of measured GFR), significantly (p<0.001) better than for MDRDIDMS (80 %). In men with BMI<20 kg/m2, MDRDIDMS/LM had +46 %/+19 % median bias. MDRDIDMS also overestimated GFR by 22 %/14 % in men/women above 80 years of age. The LMLBM equation had<10 % bias irrespective of BMI, age or GFR except for a 15 % negative bias at GFR⩾90 mL/min/1.73 m2. Conclusion. The newly developed Lund–Malmö equations for GFR estimation performed better than the MDRDIDMS and Mayo Clinic equations in a Swedish Caucasian sample. Inclusion of an LBM term improved performance markedly in certain subgroups.

Revised equations for estimating glomerular filtration rate based on the Lund-Malmö Study cohort

Abstract Objective. To increase the accuracy of estimated GFR (eGFR) from creatinine overall and at measured GFR ≥90 mL/min per 1.73 m2 by revising the Lund-Malmö (LM) equations, to elaborate on more complex forms to improve the LM and CKD-EPI equations further, and to assess benefits of adding lean body mass (LBM). Material and methods. Swedish Caucasians (n = 850, 376 women; median 60, range 18–95 years) referred for GFR measurement (plasma iohexol-clearance: median 55, range 5–173 mL/min/1.73 m2) constituted the Lund-Malmö Study cohort. Bias, precision, accuracy, expressed as median absolute percentage difference and percentage of estimates ±10% (P10) and ±30% (P30) of measured GFR, and classification ability with respect to five GFR stages were compared with the original LM, CKD-EPI and MDRD equations. Results. LM Revised overall performed better than LM Original without LBM due to increased accuracy at measured GFR ≥90 mL/min/1.73 m2. Further extensions of the CKD-EPI or LM equations did not substantially improve overall performance. In particular, the performance of LM Revised at measured GFR ≥90 mL/min/1.73 m2 could not be improved further without decreasing accuracy and classification ability at lower GFR-levels. Adding LBM to the equations had no strong effect on accuracy. Conclusion. Comparisons with the CKD-EPI and MDRD equations suggest that the LM equations are superior for the present Swedish population, due to markedly higher accuracy of the LM equations at measured GFR <30 mL/min/1.73 m2. However, the LM equations cannot be recommended for use in general clinical practice until validated in other populations.

Serum cystatin C advantageous compared with serum creatinine in the detection of mild but not severe diabetic nephropathy

Objective.  To determine whether serum cystatin C is more accurate than serum creatinine in the detection of diabetic nephropathy, also after adjustment for age.

Determining 'true' glomerular filtration rate in healthy adults using infusion of inulin and comparing it with values obtained using other clearance techniques or prediction equations.

Objective. To determine ‘true’ glomerular filtration rate (GFR) in healthy adults as renal clearance following infusion of inulin, and compare that result with those obtained using other markers and clearance techniques and with estimations of GFR using creatinine-based prediction equations. Material and methods. Twenty healthy volunteers (11 females) with a median age of 27 years (range 19–36 years) received bolus doses of inulin and iohexol i.v. and 16 blood samples were taken after injection. Then, inulin and iohexol were infused to give stable plasma concentrations and blood and urine samples were collected. Residual bladder volume was estimated using ultrasound scanning. Plasma and urine concentrations of inulin and iohexol were determined using chromatography and resorcinol methods, respectively. Different methods of GFR determination were compared as well as four formulae for GFR estimation based on serum creatinine. Results. ‘True’ GFR, i.e. renal clearance of inulin during its infusion, was a median of 117 ml/min/1.73 m2 (inter-quartile range 106–129 ml/min/1.73 m2). Similar values of GFR were obtained with renal clearance of iohexol during its infusion and also with plasma (body) clearance of inulin or iohexol following bolus injections and using 16 or five plasma samples. Endogenous creatinine clearance was higher (p<0.001) than true GFR (median 23 ml/min/1.73 m2). Plasma clearance of iohexol and inulin based on their concentrations in four blood samples underestimated their renal clearance considerably. All four creatinine-based formulae markedly underestimated renal inulin clearance. Conclusions. Plasma and renal clearance of iohexol and inulin were similar in healthy adults. Underestimation of GFR was noted when plasma clearance of iohexol and inulin was based on four but not five or more blood samples. Some prediction equations underestimate true GFR to such an extent that caution must be taken when using them to evaluate normal or high GFR values.