Rule, Andrew D. MD, MSc
When it comes to screening for chronic kidney disease (CKD), serum creatinine has gotten a bad rap.
Figure. Andrew D. Ru...Image Tools
Glomerular filtration rate (GFR)-estimating equations, particularly the Modification of Diet in Renal Disease (MDRD) Study equation, have been widely promoted to “fix” serum creatinine. But do they accomplish this? Are most patients benefitting from the use of estimated GFR (eGFR) whenever a serum creatinine test is ordered? In particular, is the diagnosis of chronic kidney disease adequately confirmed from a sustained eGFR less than 60 mL/min/1.73 m2?
Certainly, this simple classification system for CKD has led to more consistency in the literature and drawn attention to pre-end-stage renal disease (pre-ESRD). This is a good thing. Unfortunately, the drawbacks to eGFR are quite substantial and have not been adequately addressed.
Many of the drawbacks to eGFR can be easily remedied by using serum creatinine reference ranges when screening for CKD and by limiting the use of eGFR to patients with established CKD. Here are twelve points in defense of giving serum creatinine a second chance.
1. GFR Declines with Normal Aging1
Glomerular filtration rate has been shown to decline by 0.4 mL/min/1.73 m2 to 0.8 mL/min/1.73 m2 per year of age, with the rate varying by study and the descent accelerating in older age groups.
Due to the concurrent decline in muscle mass, an elevated serum creatinine level, on the other hand, conveniently reflects a decrease in GFR that is beyond what is expected with normal aging.
With a single eGFR threshold of 60 mL/min/1.73 m2, we over-diagnose CKD in older adults and potentially under-diagnose CKD in younger adults.
Pulmonary function tests are often reported with age-specific reference ranges to account for the normal loss of pulmonary function with aging. Should we not consider the same approach with kidney function?
Dependence on a single GFR threshold for defining CKD is often justified by the single 140/90 mmHg threshold used for hypertension. Unlike hypertension, though, where there are proven therapies for the rise in blood pressure with aging, we lack proven therapies for the decline in GFR with aging.
2. If Senescence Could Be Prevented, Serum Creatinine Would Not Change with Aging
Serum creatinine can be roughly viewed as muscle mass divided by glomerular filtration rate. Even if one argues that the decline in GFR with aging is a “disease,” should we not also be concerned about the loss of muscle mass (sarcopenia) with aging?
The only way for eGFR to remain constant with aging is if serum creatinine declines. The age coefficient present in GFR-estimating equations assumes that the loss of muscle mass with aging is inevitable. But why is this loss of muscle mass considered inevitable but the loss of GFR with aging not?
If we are going to be intellectually honest and consider all age-related physiological changes as “diseases,” then the goal of healthy aging should be to prevent both sarcopenia and GFR decline such that serum creatinine remain stable.
3. Patients with CKD Have a Lower GFR at the Same Serum Creatinine Level than Patients without CKD2
Defining CKD by estimated GFR is an inherently circular proposition. When the purpose of estimating GFR is to determine whether or not the patient has CKD, you first need to know if the patient has CKD in order to accurately estimate GFR.
This may occur, in part, because chronic kidney disease and the company it keeps (e.g., cardiovascular disease, liver disease, diabetes) is associated with sarcopenia and thus a lower GFR at the same serum creatinine level.
4. Estimated GFR Is Most Accurate in Patients with Elevated Serum Creatinine Levels
The MDRD equation was developed in referred CKD patients with elevated serum creatinine levels (at least 1.2 mg/dL in women and at least 1.4 mg/dL in men), not in patients with estimated GFR less than 60 mL/min/1.73 m2.3
It is in populations characterized by normal serum creatinine levels (kidney donors, early diabetics) where the MDRD equation has been found to underestimate GFR.4
5. Serum Creatinine Is a Marker of CKD Probability
To avoid the inherent circularity of using eGFR to classify chronic kidney disease, a more Bayesian approach would be helpful.
Instead of trying to infer glomerular filtration rate from serum creatinine, we should infer the probability of CKD from serum creatinine.
Other markers of CKD (e.g., albuminuria, elevated cystatin C) and CKD risk factors can help us determine whether or not a patient with a borderline serum creatinine level (approximately 1.0 to 1.3 mg/dL in women and 1.2 to 1.5 mg/dL in men) have chronic kidney disease.
6. Equations Misrepresent the Risk of CKD by Sex and Race5
But wait—equations were developed to fix serum creatinine for differences in sex and race.
The problem is that equations model sex and race as surrogates for creatinine generation (muscle mass). But in the screening setting, sex and race are also risk factors for CKD.
This leads to a higher prevalence of eGFR lower than 60 mL/min/1.73 m2 in women than men and in whites than blacks, even though metabolic complications of CKD, a rise in serum creatinine, and end-stage renal disease are more likely to occur in men than women and in blacks than whites.6,7
7. Estimated GFR Inflates the Risk of Adverse Outcomes5
Equations contain an age variable to model the decline in muscle mass with aging, but age is a potent predictor of mortality and cardiovascular disease independent of its correlation with muscle mass. Thus, the age variable in equations inflates risk estimates for adverse events predicted by glomerular filtration rate.
One can argue that we should only look at associations after adjusting for age and other demographics, but keep in mind, if you adjust for age, sex, and race, you have adjusted for everything that makes eGFR different from serum creatinine.
There is not a clear, meaningful difference between associations with eGFR adjusted for demographics and associations with serum creatinine adjusted for demographics.
8. The Risk of Adverse Outcomes Occurs at Lower Levels of eGFR in Older Adults than in Younger Adults8
Several studies have shown that there is not an increased risk for mortality and cardiovascular disease in older adults until the eGFR drops below 45 mL/min/ 1.73 m2. Some have argued for making that eGFR level the threshold for CKD in older adults.
Conversely, an estimated GFR less than 60 mL/min/1.73 m2 may be too low a threshold for younger adults. In a 20-year-old black male with a serum creatinine of 1.7 mg/dL, for example, should the physician only look at the reported “eGFR greater than 60 mL/min/ 1.73 m2” and ignore the elevated serum creatinine?
Having multiple eGFR thresholds to define chronic kidney disease for different age groups could be done, but a simpler and nearly equivalent approach is sex-specific serum creatinine thresholds.9
9. Change in eGFR is Not Meaningfully Different from Change in Serum Creatinine
Reviewing past serum creatinine levels is immensely helpful for identifying the onset of chronic kidney disease. A rising serum creatinine identifies persons with a glomerular filtration rate declining faster than is expected with normal aging. Equations are not clearly an improvement over serum creatinine in this setting.
Sex and race do not change over time, and change in age over time is by definition invariant. For equations to improve on serum creatinine, they would need to include variables that estimate change in muscle mass. Weight is perhaps the most practical to implement. Unfortunately, change in weight also reflects change in obesity and volume status.
10. Cystatin C, Like Serum Creatinine, Is Not a Pure Marker of GFR10
There have been claims that cystatin C is generated at a constant rate and thus is superior to serum creatinine as a marker of GFR. Indeed, cystatin C correlates with GFR better than serum creatinine, even among normal adults.11
But cystatin C has also been shown to be associated, independent of glomerular filtration rate, with inflammation, glucocorticoids, thyroid function, obesity, smoking, diabetes, age, sex, and race.10,12
It is unlikely that any endogenous marker is produced at a constant rate, is metabolically inert, is cleared only by filtration, and exists only to be discovered as a useful GFR marker. Cystatin C may be helpful for diagnosing CKD, but, just as with serum creatinine, we need to know the differential diagnosis for modest elevations.
11. The Diagnosis of CKD Should Be Based on More than a Borderline Serum Creatinine or eGFR Level
Systemic lupus erythematosus is not diagnosed based on an antinuclear antibody (ANA) level alone but in concordance with other biomarkers as well as clinical signs and symptoms.
In terms of CKD diagnosis, the physical exam and history provide insight into a patient's muscle mass for interpreting borderline serum creatinine levels. Modest elevation in serum creatinine can represent normal variation (muscle mass and dietary protein) or medication effects (angiotensin-converting enzyme inhibitors, trimethoprim).
We may also be able to improve CKD classification by basing the diagnosis on multiple tests. For example, the presence of any two of the following findings—elevated serum creatinine, elevated cystatin C, and albuminuria—could be deemed necessary for a positive diagnosis.
12. Most Laboratory Tests Are Reported with 'Health- Associated’ Reference Ranges, Not ‘Critical Values’13
With most laboratory tests, a clinician needs to know the reference range, which by convention is the 2.5th percentile to the 97.5th percentile for tests in which both low and high values can imply disease, such as serum creatinine.
Given the spectrum of human diversity, reference ranges are sometimes adjusted for age, sex, or race. The upper limit of normal for standardized serum creatinine does not change with age but is higher in men (1.3 mg/dL) than women (1.1 mg/dL).14.15
In the few cases where health-associated reference ranges have been replaced by critical values (e.g., dyslipidemia, blood pressure) there are proven therapies based on those critical values.
A Second Chance
These points are important because we need a clearer perspective on chronic kidney disease classification. It is obviously not helpful to tell persons with high-normal serum creatinine levels they have CKD if the primary management is “reassurance.”
The problems with equations are due to the fundamental limitations of serum creatinine, but looking at the serum creatinine level itself makes these limitations more transparent.
Much of the problem with serum creatinine in the past was caused by lack of assay standardization and failure to recognize that modest elevations can reflect serious disease.
Recognizing unequivocal chronic kidney disease in patients with elevated serum creatinine levels is enough of a challenge. Overstating the burden of CKD may be counterproductive to patient care and dilute appropriate referrals to nephrologists. Let us consider giving serum creatinine a second chance and, also, hold to having clinicians, not tests, diagnose diseases.
1. Poggio ED, Rule AD, Tanchanco R, et al. Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors. Kidney Int 2009;75: 1079–1087.
2. Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med 2004;141:929–937.
3. Kusek JW, Coyne T, de Velasco A, et al. Recruitment experience in the full-scale phase of the Modification of Diet in Renal Disease Study. Control Clin Trials 1993;14:538–557.
4. Stevens LA, Manzi J, Levey AS, et al. Impact of creatinine calibration on performance of GFR-estimating equations in a pooled individual patient database. Am J Kidney Dis 2007;50:21–35.
5. Rule AD, Bailey KR, Schwartz GL, Khosla S, Lieske JC, Melton LJ 3rd. For estimating creatinine clearance measuring muscle mass gives better results than those based on demographics. Kidney Int 2009;75:1071–1078.
6. Poggio ED, Rule AD. A critical evaluation of chronic kidney disease—should isolated reduced estimated glomerular filtration rate be considered a ‘disease?’ Nephrol Dial Transplantation 2009;24:698–700.
7. Foley RN, Wang C, Ishani A, Collins AJ. NHANES III: influence of race on GFR thresholds and detection of metabolic abnormalities. J Am Soc Nephrol 2007;18: 2575–2582.
8. Roderick PJ, Atkins RJ, Smeeth L, et al. CKD and mortality risk in older people: a community-based population study in the United Kingdom. Am J Kidney Dis 2009;53:950–960.
9. Poggio ED, Rule AD. Can we do better than a single estimated GFR threshold when screening for chronic kidney disease? Kidney Int 2007;72:534–536.
10. Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004;65:1416–1421.
11. Rule AD, Bergstralh EJ, Slezak JM, Bergert J, Larson TS. Glomerular filtration rate estimated by cystatin C among different clinical presentations. Kidney Int 2006;69: 399–405.
12. Stevens LA, Schmid CH, Greene T, et al. Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int 2009;75:652–660.
13. National Committee for Clinical Laboratory Standards. C28-A2: How to define and determine reference intervals in the clinical laboratory. Approved guideline, 2nd ed. 2000.
14. Rule AD, Gussak HM, Pond GR, et al. Measured and estimated GFR in healthy potential kidney donors. Am J Kidney Dis 2004;43:112–119.
15. Rule AD, Larson TS. Do we need another equation to estimate GFR from serum creatinine in renal allograft recipients? Nephrol Dial Transplantation 2008;23: 2427–2428.
© 2009 Lippincott Williams & Wilkins, Inc.