American Association for Clinical Chemistry
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NACB - Scientific Shorts
NACB - Scientific Shorts (formerly NACB Blog)
By Callum Fraser, PhD
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The MDRD (Modification of Diet in Renal Disease) Study equation is widely used to estimate glomerular filtration rate (GFR) and many laboratories report this every time a serum creatinine is requested. However, it has been widely reported that such calculated values underestimate GFR when creatinine is “normal” or “near-normal”.  A recent study in the American Journal of Kidney Diseases [1] compared the performance of the newer CKD Epidemiology Collaboration (CKD-EPI) and the MDRD Study equations for GFR,   and concluded that CKD-EPI equation [2] is more accurate than the MDRD Study equation overall, and across most subgroups.

 

How many more equations will be proposed over time to estimate GFR - what’s wrong with using serum creatinine alone?

 

There are many equations for estimation of GFR in the literature. The rationale for the adoption of these has always been that serum creatinine is of limited value for the detection of early deterioration in GFR.  This is said to be because creatinine concentrations rise over the upper reference limit only when GFR has already decreased by at least 50%.

 

However, it has been known for many years that this negative view of serum creatinine is actually dogma rather than fact.  The alleged difficulties are simply due to the marked biological individuality of serum creatinine. Creatinine has very low within-subject biological variation and large between-subject biological variation [3]. In consequence, the span of creatinine concentrations found in any healthy individual occupies only a small part of the dispersion of the conventional population-based reference interval.  As a result, individuals can have values for serum creatinine concentration that are highly unusual for them (showing deteriorating GFR) but these values will still lie well within the population-based reference interval. Such values will not be flagged by laboratories nor considered worthy of note by clinicians or other health care workers.

 

How can that situation be improved? Recently, on behalf of the IFCC Committee on Reference Intervals and Decision Limits, a group published a detailed paper on reference intervals for serum creatinine concentrations and gave population-based data for both males and females, aged 18–74 years, each as a single interval [4].  The authors considered that that these might be adopted by any laboratory serving a similar population and using a method of comparable specificity that is traceable to the creatinine reference system (an important issue, per se).  But, the problems of interpretation would remain using such a simple set of reference values. What is required to make traditional reference intervals of higher clinical utility is to ensure that the between-subject biological variation is as small as possible compared to the within-subject variation.  This is what stratification of reference values achieves.  A study which shows the requirement for age and gender stratified reference intervals for creatinine has been published by Kallner et al [5].  If such well-stratified reference intervals were available, they would be of value in aiding in diagnosis, screening, and case-finding and there might then be less need for estimates of GFR based on equations, although these, as a tool for addressing the major public health issue of CKD, have undoubtedly proven effective in enabling direction of patients into care pathways and in raising the profile of this problem.   However, such estimates, because they are based on creatinine and other factors such as age, gender, and ethnicity, intrinsically have a larger uncertainty of measurement. 

 

The ultimate reference interval is a person-specific one and this is particularly germane for monitoring individuals over time.  Changes in results in an individual are not satisfactorily monitored using population-based reference intervals, even when stratified. What is required is the recognition that changes in results are due to analytical and within-subject biological variation as well as improvement or deterioration.  It is easy to calculate the Reference Change Value (RCV) required to assess the significance of change in any individual using a simple formula based on analytical imprecision and the well-documented biological variation for creatinine [3].  Such RCV should be developed by laboratories and used in their reporting systems instead of, or as well as, stratified reference intervals. Then, the conclusion in a recent superb Editorial [6] which should be made compulsory reading for all laboratory staff, nephrologists and the many others involved in CKD - the reality is that serum creatinine is still a very good measure of GFR and is by far the most sensitive serum biomarker for detecting small GFR changes in an individual - could be translated into everyday practice.

 

References

  1. Stevens LA, Schmidt CH, Greene T, et al. Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2.Am J Kid Dis 2010;56:486-95.
  2. Levey AS, Stevens LA, Schmidt CH, et al.  A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12.
  3. Fraser CG. Biological Variation: From Principles to Practice. Washington, DC AACC Press, 2001.
  4. Ceriotti F, Boyd JC, Klein G, et al.  Reference intervals for serum creatinine concentrations: assessment of available data for global application. Clin Chem 2008;54:559–66.
  5. Kallner A,  Ayling PA, Khatami Z. Does eGFR improve the diagnostic capability of S-creatinine concentration results? A retrospective population based study. Int J Med Sci 2008;5:7-19.
  6. Dalton RN.  Serum creatinine and glomerular filtration rate: perception and reality. Clin Chem 2010;56:687–9.
 

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Posted by
On 2/10/2011

Concerning the comment on 1/26 at 4:46pm: Where creatinine, inulin, iothalamate, cystatin C, come from is largely irrelevant to renal function. These are simply markers for glomerular filtration, with hopefully minimal influence by tubular secretion or reabsorption. It is absolutely important that their production (physiologic or by injection) and therefore their blood concentration be constant so that changes in blood represent decreases in glomerular filtration. Let me add to some of my points made above (1/26 at 9:27). 1. Despite being regarded as a "gold standard" renal function test, the actual GFR is highly variable and has many shortcomings as a test for detecting nephron loss. 2. The eGFR is really (proportional to) an age, gender, and race normalized serum creatinine and has the potential be much better than the GFR. If we interpreted eGFR as a normalized serum creatinine, it would be far more clinically useful. 3. All values of the eGFR must ultimately be reported. If we abandon the fruitless attempts to make it agree with the GFR (MDRD, CKD-EPI, and what next?) and interpret it as a normalized creatinine, we will be on the path to enlightenment. By the way, this blog needs to include a block requiring our names, as many (except Dr Miller) did not do so. John Toffaletti, Duke Univ Med Center

Posted by
On 1/30/2011

I fully appreciate Dr.Fraser's timely article. Although, introduction of eGFR has brought clinical attention among the family practitioners, internists and the budding physician on the importance of early diagnosis of ailing kidney to do the needful well in time, its introduction has increased worries and apprhension(in many cases non-founding) for kidney diseases and the outcome, which are not existing in reality. This has happened because of eGFR's underestimation of real GFR of the subjects' kidneys.Proponents object by saying that eGFR has helped the nephrologist to get the patients with early impaired renal functions at the very base line stage to implement timely management and in doing so it is always possible that there would be few unnecessary 'cries'. These are not the unnecessary cries but these are the genuine concern among the community and excesses of abuse of medical referrals and the cost involved besides generating unnecessary worries among the people referred. A wise and sincere physician who respects Hipocrates' Oath and practises ethically can easily find by monitoring serial creatinine of an individual or having a look on the serum creatinine pattern of the individual whose blood was subjected to routine testing on numerous occasions for various clinical reasons, detect if there is any deterioration of his or her kidney health. Our duty as a practising physician is not only to show how much new things we know but also to show what basic knowledge can help us to take care of our patients clinically and psychosocially as as per WHO definition -'Health is defined as not merely absence of disease or infirmity but also well being of an individual physically, psychologically, socially and spirirually'. This comment was approved by the NACBLOG editorial board. Please remember to add your name and affiliation!

Posted by
On 1/27/2011

Dr. Fraser has very well summarized the limitation of central 95% reference intervals for interpreting creatinine results. Very few laboratories report appropriate age, gender and race stratified reference intervals for creatinine. Consequently, as good as creatinine is as a marker of kidney function change in an individual, a very large percentage of people with significant CKD have gone undetected and untreated. Inadequate identification of people with CKD is a fundamental clinical practice problem that our nephrologist colleagues have addressed by asking laboratories to report eGFR along with creatinine. eGFR is an estimate, is not a patient’s actual GFR, and is unreliable in well identified clinical situations (see www.nkdep.nih.gov). However, in many situations, eGFR enables a patient’s creatinine concentration to be appropriately interpreted regarding risk for CKD. Reporting both creatinine and eGFR provides the information needed for patient care. Greg Miller, Virginia Commonwealth University

Posted by
On 1/26/2011

It appears to me that this marker would be more useful if we could relate it to the organ that produces creatine that being primarily skeletal muscle. Instead of arcane formulas that relate serum creatine to gender and age - - relate it instead to lean body mass which could be a surrogate for skeletal muscle. This comment was approved by the NACBLOG editorial board. Please remember to add your name and affiliation!

Posted by
On 1/26/2011

I heartily agree with Dr Fraser's article, especially that within-individual monitoring of serum creatinine may be the best available test for detecting changes in renal function. What is so surprising is the widespread misunderstandings about creatinine, GFR, clearance measurements, and eGFR, even among the experts, many of whom have spoken at our AACC Annual Meetings. Just a few other points to make: 1. serum creatinine and GFR are inherently different parameters and no equation will ever reliably predict one from the other. The CKD-EPI eGFR vs GFR (ref 2 above) still looks like a dart-board used by drunks at a bar; 2. The actual GFR has many shortcomings as a diagnostic test (eg, large overlap between health and disease) and is far from the ultimate renal-function test (see Nephron Clin Pract 2010; 115: c117-c181 and Point of Care 2011 in press); and 3. The eGFR is really a normalized serum creatinine that could be much more useful if interpreted as such and NOT as a surrogate for GFR. This comment was approved by the NACBLOG editorial board. Please remember to add your name and affiliation!