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Determining the Glomerular Filtration Rate—An Overview

  • Elke Schaeffner
    Correspondence
    Address correspondence to Elke Schaeffner, MD, MSc, Institute of Public Health Charité, Universitätsmedizin Berlin, Seestrasse 73, Haus 10, Berlin D-13347, Germany.
    Affiliations
    Institute of Public Health Charité, Universitätsmedizin Berlin, Berlin, Germany
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Published:September 16, 2017DOI:https://doi.org/10.1053/j.jrn.2017.07.005
      Correct determination of glomerular filtration rate (GFR) as an indicator of kidney function bears great importance because clinical decision-making depends on it at many occasions. During the last years, a huge body of literature has been published on estimation and measurement of GFR. The increasing pace with which novel estimation formulae, current and newer biomarkers, assay standardization procedures as well as invasive measurement methods of GFR were published, has been overwhelming for many clinicians. This concise review summarizes central issues in determining kidney function by listing some of the most important publications. It explains fundamental principles in GFR estimation and measurement, the influence of clinical characteristics on endogenous biomarkers, and obstacles in biomarker assessment. Thus, it is thought to be a guide for clinicians through the confusing jungle of GFR determination.

      Introduction and Purpose

      Glomerular filtration rate (GFR) is still considered the best indicator of kidney function worldwide. Exact assessment of GFR is crucial for several reasons: GFR determines the stage of chronic kidney disease (CKD), as the staging system is based on GFR. This staging system has several clinical implications, such as drug dosing, the application of potentially nephrotoxic contrast agents, the timing of renal replacement therapy, the appropriateness of living organ donation, and also the labeling of the diagnosis “CKD,” which has insurance (and therefore financial) and psychological implications.
      During the last 5 to 10 years, different groups have worked to optimize GFR assessment, which has led to a variety of publications about GFR estimation or measurement. In an endeavor to come as close as possible to the true GFR, several novel GFR estimation formulae (eGFR) have been developed. This new abundance of estimation formulae makes it difficult for the physician to decide which formula may be the right one for her/his patients especially because formulae yield different GFR results in the same individuals. In this context, the role of the endogenous biomarker the GFR formula is based on has been studied in more detail. After decades of creatinine as the one and only endogenous biomarker, cystatin C has been analyzed extensively in terms of its performance to assess GFR. Besides, “newer” markers such as beta trace protein (BTP) or beta2 microglobulin, for example, are also being analyzed in terms of their GFR prediction ability. Another factor which adds to the quality to GFR assessment is standardization of the laboratory assay which after many years has finally been achieved for creatinine and cystatin C.
      A huge body of literature also exists for GFR measuring (mGFR) methods which are supposed to be closer to the true GFR compared with the estimated and serve as “gold standards” whenever a new estimation formula is developed. GFR measurement methods however use different exogenous markers and also different protocols and are often described as “cumbersome” in the literature and therefore not suitable for daily routine.
      This concise review gives an overview about the methods of GFR estimation and measurement (eGFR und mGFR) most often used, their advantages, disadvantages, and clinical indications as well as their applicability in terms of feasibility.

      Measuring Kidney Function (mGFR)

      In contrast to GFR estimation, measuring GFR is regarded as the more precise method for determining kidney function and is therefore frequently referred to as “gold standard.” This gold standard method principally involves a clearance method. The one that is still most often used in Germany is the creatinine clearance. In this case, urine is collected over a certain period of time—usually 24 hours (with 12 hours also being possible)—to record the urinary creatinine concentration. In addition, the creatinine level needs to be determined from the serum at the beginning or end of the collection period as well. Because of improper urine collection, this method is extremely error prone—particularly with outpatients—and usually leads to the GFR being overestimated. It is therefore astonishing that the method has managed to retain its place in clinical routine despite its well-known inaccuracy.
      • Soveri I.
      • Berg U.B.
      • Bjork J.
      • et al.
      Measuring GFR: a systematic review.
      Another, more precise option is the application of an intravenous exogenous filtration marker, with subsequent measurement of its plasma clearance (possibly in combination with the urinary clearance). After application, blood is drawn at defined intervals (see Fig. 1).
      Figure thumbnail gr1
      Figure 1Two-compartment model. Two-compartment model depicting decreasing levels of plasma iohexol (yellow boxes) over time (hours) after application of contrast agent (iohexol). The fast component (steep slope) represents organ perfusion and the slow component (flat slope) represents peripheral perfusion. If eGFR is above 50 mL/min, sampling can be done after 4 hours (circle). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      Here, a distinction is made in a 2-compartment model between a “fast component” and a “slow component” phase, with the former corresponding to the “central” distribution of the marker in the blood and organs and the latter to its distribution in the peripheral areas (i.e., areas with less blood circulation, such as muscle or fatty tissue) and the renal elimination of the contrast medium from the blood.
      Table 1 summarizes the best-known exogenous filtration markers with their respective advantages and disadvantages. In addition to inulin clearance, which can certainly be regarded as the gold standard among gold standards, there are also iodine-containing contrast media such as iothalamate or iohexol, although they cannot be used in patients with an iodine allergy. Particularly in Europe, there has been a noticeable trend toward iohexol plasma clearance in the last 2 years. The main reason for this is that the method is relatively easy to perform—a fact that contradicts the widespread opinion that invasive measurements of kidney function are elaborate and cumbersome and therefore impractical for routine clinical practice.
      Table 1Comparison of Exogenous Filtration Markers
      MarkersAdvantagesDisadvantages
      InulinGold standard among gold standards, no side effectsExpensive

      Difficult to keep in solution, urinary clearance necessary
      IothalamateInexpensive, long half-life period, also possible without urinary clearanceExpensive if not radioactive; contains iodine; probable tubular secretion
      IohexolInexpensive, sensitive assay; permits a low dose; regarded as more precise than iothalamate clearance; no urinary clearance; single-sample technique possibleContains iodine
      Cr-EDTAWidely available in EuropeComplicated storage when radioactive
      DTPAWidely available in the United StatesComplicated storage when radioactive
      Cr-EDTA, chromium ethylenediaminetetraacetate; DTPA, diethylenetriaminepentaacetic acid.
      Feasibility is crucial, especially for elderly patients or patients with multiple comorbidities. For example, the fact that—even without urinary clearance—iohexol clearance is regarded as a more precise method than iothalamate clearance (which can also be carried out without urinary clearance) is extremely relevant.
      • Delanaye P.
      • Jouret F.
      • Le Goff C.
      • Cavalier E.
      Concordance between iothalamate and iohexol plasma clearance.
      Moreover, iohexol clearance can also be determined using the “single sample technique,”
      • Jacobsson L.
      A method for the calculation of renal clearance based on a single plasma sample.
      which only requires a single blood sample instead of multiple after the marker is given intravenously and is therefore based on a “one-compartment” instead of a “2-compartment” model. The exact time that the blood sample is drawn generally depends on the eGFR value determined in advance. However, it always falls within the slow component phase and ignores the fast component (Fig. 1): The worse the kidney function, the later the sampling time (after 4 hours if eGFR > 50, after 7 hours if eGFR = 25-50, after 24 hours if eGFR < 25 mL/minute/1.73 m2). The iohexol concentration can be determined by means of high-performance liquid chromatography or mass spectrometry. While routine use of iohexol clearance has yet to be established in Germany, it has already been common practice for some time in large parts of Scandinavia. Two recommendable overview articles in this context explain in greater detail exactly how to perform the measurements and why iohexol is preferable to other markers.
      • Delanaye P.
      • Ebert N.
      • Melsom T.
      • et al.
      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?.
      • Delanaye P.
      • Melsom T.
      • Ebert N.
      • et al.
      Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Part 2: why to measure glomerular filtration rate with iohexol?.
      Concerns about side effects or nephrotoxicity of iodine-containing filtration markers can be ruled out. All procedures are regarded as safe and can be used without reservation, even in cases where there is severely restricted kidney function as the applied volume is very low.
      Although the more frequent usage of GFR measurements would be desirable, particularly in clinical situations of greater complexity (some of them will be described in the following), it is important to remember that the measurement itself is nothing more than a diagnostic test method (albeit one that comes closer to “real GFR” than an estimation formula). Besides, it is true that different gold standard procedures should not be compared with one another because they often supply different results depending on the marker and the measurement report. Standardization of GFR measurement methods will thus be an important future goal.
      Examples of clinically complex situations for which mGFR is more helpful than eGFR include patients who exhibit discrepant results between a creatinine-based and a cystatin C–based GFR. Scenarios could be a normal creatinine but elevated cystatin C because of different causes: That is, an elderly woman with low muscular mass who has CKD
      • Loesment-Wendelmuth A.
      • Schaeffner E.
      • Ebert N.
      Two elderly patients with normal creatinine and elevated cystatin C - a case report.
      or a patient being treated with chemotherapy for lymphoma. In the first case, creatinine is dependent on muscle mass and thus not a suitable marker to detect reduced kidney function in this particular patient, and in the second scenario, cystatin C is influenced (elevated) by the chemotherapy falsely suggesting impaired kidney function. Other cases of complexity include the condition of multimorbidity, especially in the elderly (and therefore at a stage in which endogenous biomarkers can be affected by inflammation or other “non-GFR determinants”), potential kidney donors, cachexia and anorexia, liver cirrhosis, and suspected hyperfiltration. We will take a closer look at non-GFR determinants and their significance further in the following.

      Estimating Kidney Function (eGFR)

      In most countries (apart from Scandinavia), GFR is usually estimated in routine clinical practice using mathematical formulae. In the last 5 years, this has resulted in a plethora of publications on new estimation formulae—in an ongoing endeavor to eliminate the deficiencies of previous formulae. Table 2 shows only a compilation of the newer formulae, along with a reference to the populations in which these formulae were developed. This is important because estimation formulae can only apply for the group of people they were derived from. In other words, an estimation formula that was only developed in sick people (e.g., Modification of Diet in Renal Disease [MDRD] study) underestimates GFR in healthy people. Conversely, a formula that was principally developed in healthy people would overestimate GFR in sick people. The same is true of age: Formulae only apply from or until the specific age of the group of people in which the formulae were developed and validated.
      Table 2Compilation of Newer Estimation Formulae
      Estimation FormulaPublishedGold StandardDeveloped inAgeCKD? Non-CKD?
      Cockcroft-Gault(crea)
      • Cockcroft D.W.
      • Gault M.H.
      Prediction of creatinine clearance from serum creatinine.
      197624-h urine collection249 men18-92Both
      MDRD(crea)
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • Roth D.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.
      1999Iothalamate, Iohexol1,62851 (<70)CKD
      CKD-EPI(crea)
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      2009Iothalamate, Iohexol8,25447Both
      Lund-Malmö(crea)
      • Bjork J.
      • Grubb A.
      • Sterner G.
      • Nyman U.
      Revised equations for estimating glomerular filtration rate based on the Lund-Malmo Study cohort.
      2011Iohexol85060CKD
      CKD-EPI(crea/cysC)
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      2012Iothalamate, Iohexol5,35247Both
      CKD-EPI(cysC)
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      2012Iothalamate, Iohexol5,35247Both
      Schwartz(cysC)
      • Schwartz G.J.
      • Schneider M.F.
      • Maier P.S.
      • et al.
      Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C.
      2012Iohexol6001-16CKD
      BIS1(crea)
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      2012Iohexol57070+ (78)Both
      BIS2(crea/cysC)
      • Schaeffner E.S.
      • Ebert N.
      • Delanaye P.
      • et al.
      Two novel equations to estimate kidney function in persons aged 70 years or older.
      2012Iohexol57070+ (78)Both
      FAS(crea)
      • Pottel H.
      • Hoste L.
      • Dubourg L.
      • et al.
      An estimated glomerular filtration rate equation for the full age spectrum.
      2016Iohexol, Iothalamate, Inulin6,8702-100Both
      FAS(cysC, crea/cysC)
      • Pottel H.
      • Delanaye P.
      • Schaeffner E.
      • et al.
      Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C.
      2017Iohexol, Iothalamate, Inulin6,1322-100Both
      CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; Crea, creatinine; cysC, cystatin C; FAS, full age spectrum.
      In summary, the following can be stated with respect to Table 2: First of all, it is evident that apart from creatinine, the biomarker cystatin C has been gaining in importance over the last few years. Multiple external validation studies have shown that especially the combination of creatinine and cystatin C—particularly in certain populations like the elderly—results in more precise and accurate GFR determination than 1 marker alone.
      • Shlipak M.G.
      • Mattes M.D.
      • Peralta C.A.
      Update on cystatin C: incorporation into clinical practice.
      Second, it becomes clear that, as mentioned previously, it is mainly iohexol that is being used as an exogenous biomarker, especially for the development of estimation formulae in European work groups.
      Third, it is important to point out the promising “full age spectrum” (FAS) formulae,
      • Pottel H.
      • Hoste L.
      • Dubourg L.
      • et al.
      An estimated glomerular filtration rate equation for the full age spectrum.
      • Pottel H.
      • Delanaye P.
      • Schaeffner E.
      • et al.
      Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C.
      which are the first formulae that can be used for the entire age spectrum from 2 to 100 years, thereby addressing the problem of biologically implausible creatinine jumps in age-specific formulae. What is meant by that is the fact that a 16-year-old boy whose GFR had been estimated using the Schwartz formula will experience a sudden “jump” of his GFR the moment he turns 17 or 18 years since then an adult formula will be used (Schwartz formula only validated until the age of 16 years). The approach of the FAS equations is new as it uses the distribution of serum creatinine and cystatin C in the normal population. Constants (“Q”) for both endogenous biomarkers creatinine and cystatin C were defined depending on age (resembling percentiles). An intergenerational application is a tempting approach for the physician. However, there is still a lack of external validations in various populations (children, adolescents, adults, and elderly) that are needed to justify their comprehensive use.
      BTP and beta-2 microglobulin have also been included in the search for the optimum endogenous biomarker, albeit with disappointing results so far. Too many uncertainties with respect to disadvantages related to production, glomerular filtration, tubular secretion, extrarenal elimination, and assay procedures have prevented these 2 markers from achieving widespread use.
      • White C.A.
      • Ghazan-Shahi S.
      • Adams M.A.
      Beta-trace protein: a marker of GFR and other biological pathways.
      A central aspect is the lack of standardization among available assays for both markers which results—as could be shown for BTP recently—in significant differences in BTP-based eGFRs.
      • White C.A.
      • Akbari A.
      • Eckfeldt J.H.
      • et al.
      Beta-trace protein assays: a comparison between nephelometric and ELISA methodologies.
      The importance of assay standardization will be discussed further in the following.

      Non-GFR Determinants

      Non-GFR determinants are factors that can influence endogenous biomarkers such as creatinine or cystatin C independently of GFR. However, this influence can erroneously shift the GFR value upward or downward. For this reason, it is important to be aware of non-GFR determinants, so that GFR results can be better interpreted in certain clinical situations.
      Somewhat simplified, it can be said that—for creatinine—muscle mass and everything associated with it (i.e., including age, gender, race, nutrition, and so on) represents the best-known non-GFR determinant. In contrast to this, cystatin C is regarded as independent of muscle mass, which is certainly advantageous in the elderly and adolescents in particular, both of which are at stages of life that involve greater changes in muscle mass. Cystatin C, however, appears to be primarily affected by inflammatory conditions. This also explains why cystatin C values tend to be measured too high in cases of obesity (a condition in which fat cells mimic a “cluster” of inflammatory processes). The purpose of Table 3 is to provide a simplified overview of the best-known non-GFR determinants. On the whole, however, we must acknowledge that there are a great many other non-GFR determinants that we are not (yet) fully aware of. Continued research of non-GFR determinants is highly relevant because this allows both GFR estimation based on endogenous biomarkers, as well as eGFR-associated prediction of subsequent—such as cardiovascular—events to be better understood. In addition, mGFR appears to be advantageous in the context of non-GFR determinants as well because it is not affected by them.
      Table 3Non-GFR Determinants and Their Effect on Creatinine and Cystatin C
      Non-GFR DeterminantsCreatinineCystatin C
      AgeDecrease/increaseLess decrease
      Female genderDecreaseLess decrease
      RaceAfrican American: increaseNo change
      Hispanics: decreaseNo change
      Body habitus
       MuscularIncreaseHardly any change
       AmputationDecreaseNo change
       ObesityNo changeIncrease
      Chronic illness
       Malnutrition, inflammationDecreaseIncrease
       DiabetesRather decreaseIncrease
      MedicationIncrease under cimetidine, antibioticsIncrease under high cell turnover (chemo), high doses of steroids
      Diet
       VegetarianDecreaseNo change
       Cooked meatIncreaseNo change
      GFR, glomerular filtration rate.
      Although certainly somewhat mechanistic, Table 4 shows an attempt to match certain groups of people with the biomarker or method best suited to them. Its main purpose is to once again create sensitivity for common problems and laboratory constellations in which mGFR may serve as the better method (e.g., falsely low creatinine due to cachexia, falsely high cystatin C in chemotherapy patients). The physician should therefore never focus exclusively on the laboratory value alone, but instead should always take into account habitus, gender, age, underlying disease, comorbidities, and medication of the patient. It also bears pointing out that there is not yet a specific formula/biomarker for pregnant women or kidney transplant recipients.
      Table 4Endogenous Biomarkers and mGFR Depending on Specific Populations
      PopulationCreatinineCysCCrea/CysCmGFR
      Children(X)XX
      AdultsXXX
      Elderly (70+)X(X)
      ObesityX
      Anorexia/cachexia (Crea ↓)X?X
      Competitive athletes (Crea > CysC)XX
      Chemotherapy (CysC > Crea)XX
      Kidney transplant patients(X)??X
      Liver cirrhosisX?
      • Mindikoglu A.L.
      • Dowling T.C.
      • Magder L.S.
      • et al.
      Estimation of glomerular filtration rate in patients with cirrhosis by using new and conventional filtration markers and dimethylarginines.
      X
      Suspected hyperfiltrationX
      Pregnancy????
      Crea, creatinine; CysC, cystatin C; mGFR, measuring glomerular filtration rate.
      “X” denotes the best evidence; “(X)”, medium evidence; “X?”, assumptions due to very limited evidence; and “?”, no evidence.

      Standardization of Assays

      The standardization of laboratory assays is extremely important when endogenous biomarkers such as creatinine and cystatin C are used. With regard to creatinine, this means that an enzymatic method or isotope dilution mass spectrometry (IDMS traceable) should be used.
      Kidney Disease: Improving Global Outcomes (KDIGO) Work Group
      KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.
      The more and more frequently used colorimetric Jaffe method is regarded as being less precise and generally measures creatinine values that are slightly elevated compared with the enzymatic method. However, it is somewhat less expensive and is usually corrected today, making the difference relatively slight. With cystatin C, it is important for laboratories to use an assay that is calibrated according to the international standard (ERM–DA471/IFCC).
      Kidney Disease: Improving Global Outcomes (KDIGO) Work Group
      KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.
      This standardization was introduced in 2010, whereby initially only the nephelometric Siemens assay corresponded to this standardization.
      • Grubb A.
      • Blirup-Jensen S.
      • Lindstrom V.
      • et al.
      First certified reference material for cystatin C in human serum ERM-DA471/IFCC.
      In the meantime, other companies have also standardized their cystatin C assays successfully,
      • Ebert N.
      • Delanaye P.
      • Shlipak M.
      • et al.
      Cystatin C standardization decreases assay variation and improves assessment of glomerular filtration rate.
      a fact that must be seen as representing considerable progress because it is known that calibration allows for better precision and accuracy and less bias in determining the biomarker values as well as better comparability between laboratories.
      • Inker L.A.
      • Eckfeldt J.
      • Levey A.S.
      • et al.
      Expressing the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) cystatin C equations for estimating GFR with standardized serum cystatin C values.
      • Delanaye P.
      • Pieroni L.
      • Abshoff C.
      • et al.
      Analytical study of three cystatin C assays and their impact on cystatin C-based GFR-prediction equations.

      Conclusion

      Kidney function can be determined using either estimation formulae or measuring methods. With respect to measuring methods, there is a whole series of other clearance markers besides the gold standard of inulin clearance. In this regard, there has been a noticeable trend toward the use of iohexol as an exogenous filtration marker. The amount of effort needed is manageable thanks to the use of the single-sample technique. Particularly in more complex cases (discrepant laboratory results of creatinine and cystatin C, specific populations), measuring GFR is recommended. However, this presupposes the establishment of a corresponding infrastructure at many centers.
      Concerning GFR estimation, which is carried out much more frequently in routine clinical practice, a number of new estimation formulae have been developed in the past few years and clinicians should be aware that they cannot always be used interchangeably. After being the primary filtration marker for decades, creatinine has now been joined by cystatin C in recent years. Cystatin C offers advantages to certain patients, such as the fact that it is independent of muscle mass. In this context, physicians should become more aware of the significance of “non-GFR determinants” for interpreting GFR values. Also worth mentioning are the new FAS formulae, which are being applied as the first formulae for all age categories, although they are still waiting for external validation before being used area-wide. As a rule, laboratories should only use standardized assays, even if this reality is still in the distant future. However, they are available for creatinine and—since just a few years ago—for cystatin C as well.

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