There is only one disorder for which the federal government covers treatment regardless of a patient's age: end-stage renal disease. At a price tag of about $20 billion a year, it takes a huge chunk of the Medicare budget and promises to swallow up an ever-increasing share. Over the past two decades, the incidence of end-stage kidney disease in the U.S. has quadrupled.
Given the stakes, and given that kidney disease can often be treated if detected early, estimated glomerular filtration rate, or eGFR, might seem to be a shoo-in as a screening test. A value calculated from the patient’s serum creatinine levels, eGFR is widely viewed as a good indicator of early kidney disease.
Indeed, in the last few years, the Kidney Disease Outcomes Quality Initiative and the National Institutes of Health’s National Kidney Disease Education Program have strongly recommended that clinical laboratories automatically report eGFR when serum creatinine is reported.
But in at least a few state legislatures, that recommendation has been translated into a legislative mandate, even as doubts about the reliability and specificity of eGFR have burgeoned. The key question about eGFR has become: Just how far is it from perfect?
“Creatinine has been measured for more than 50 years and used as an indicator of kidney function. It’s extremely commonly ordered as part of a comprehensive basic metabolic panel, which is done on a high percentage of inpatients and outpatients,” says Gregory Miller, PhD, a consultant to the CAP Chemistry Resource Committee and professor of pathology at Virginia Commonwealth University, Richmond.
“It turns out, however, that very small changes in creatinine—even in what’s normally considered the reference interval—are consistent with patients who have significant loss of kidney function. That makes it difficult for physicians to recognize patients in the early stages, because the changes in creatinine are relatively small.”
“By relating it to eGFR and also taking into account age, sex, and race, you provide a much better interpretation of creatinine,” Dr. Miller says.
Screening for kidney disease may be an idea whose time has come. “If you look at heart disease and stroke, the rates have been declining over the last 20 years pretty dramatically, largely related to the hypertension intervention and cholesterol education programs sponsored by NIH and changing diets,” says John Eckfeldt, MD, PhD, professor of pathology and vice chair for clinical affairs at the University of Minnesota Medical Center, Fairview, in Minneapolis.
“Renal disease is going in the exact opposite direction. Probably driven by the epidemic of obesity and diabetes, it’s going up 10 or 15 percent a year, so it’s going to become a bigger and bigger health care issue and financial burden on the health care system.”
“If we can slow the progression —even if we can’t stop it—if we can get to them before they end up at stage four with GFRs in the 20s, that would help. Once the GFR is down below about 20 mL/min/1.73 m2, they will need long-term dialysis or a kidney transplant to survive.”
Nevertheless, pathologists were taken somewhat by surprise in 2004 when bills started appearing in several state legislatures to actually require clinical laboratories to calculate eGFR whenever they tested a patient’s creatinine level. In Tennessee and New Jersey, the measures became law in 2005, before the CAP’s public policy position was formulated later that year. In 2006, eGFR mandate legislation in more than a dozen states was countered by joint advocacy campaigns of the CAP and the state pathology societies.
“Although early detection is a good thing, mandating specific equations or formulas for laboratory testing by law is not an appropriate way to approach clinical medicine,” says Paula Szypko, MD, chair of the CAP’s Federal and State Affairs Committee.
Dr. Szypko, a pathologist at North State Pathology Associates, High Point, NC, agrees that eGFR testing is appropriate in certain clinical situations. But in other cases, she says, “it can just lead to confusion and perhaps bad decisions with regard to patient care.”
Other laboratory tests are on the horizon that may supersede some of the equations being used now, she says, stressing that it is not feasible to change state laws every time medical practices change. “This is something that needs to be dealt with in the medical community, not the houses of the state legislatures.”
In the states where mandatory eGFR was proposed, advocates have portrayed it as a public health measure, says Barry Ziman, CAP director of state affairs. But eGFR is different from mandatory newborn screening tests. “There has to be a determination attached to this calculation about when it is medically appropriate,” he says. “To universally mandate this test is not in the best interest of medical care because it would be dictating a medical judgment and really micromanaging patient care. It’s politicizing what should be the practice of medicine.”
Last year, the CAP helped mobilize a response that included working with the state medical societies and introducing a resolution against a legislated mandate for eGFR at the American Medical Association annual meeting, where the House of Delegates adopted it without dissent. Action by state pathology groups led to similar bills in several states being defeated or substantially amended. Amended eGFR bills were enacted in three states in 2006—Pennsylvania, Louisiana, and Connecticut. Only one state, Michigan, enacted an eGFR mandate for Medicaid patients, without the negotiated compromise language that pathologists had agreed to in the legislative process.
Amid signs that other states are backing off from the proposed legislation, the CAP’s legislative staff and officials are continuing to work with external parties to build a consensus that this legislation should not be promoted in the states, Ziman says.
“The clinical laboratory has an essential role to play in identifying patients with early chronic kidney diseases for which there are recognized therapies,” says Anthony A. Killeen, MD, PhD, chair of the CAP Chemistry Resource Committee and associate professor of laboratory medicine and pathology at the University of Minnesota Medical School. “The selection of test methodologies is something that pathologists and medical laboratory directors are qualified to establish for their institutions.”
The element of medical judgment is more critical with eGFR because the equations used to calculate it are not applicable to every patient, he says. “For children, perhaps elderly patients over 70 or 75, pregnant women, acutely ill hospitalized patients, and patients who have known renal disease—eGFR calculations may not be suitable for those scenarios.”
People with a lot of muscle mass relative to their body size, such as trained athletes or body builders, also tend to have spuriously low eGFRs and thus tend to look like they have much worse renal function than they really have, because the amount of muscle mass determines how much creatinine the body produces and thereby their steady state serum creatinine concentration, Dr. Eckfeldt notes.
Complicating the matter is the reality that some older laboratory information systems cannot be programmed easily to take creatinine values routinely and calculate eGFR. “So that puts a burden on some laboratories and again makes mandated reporting of eGFR very difficult, if not impossible,” Dr. Killeen says.
The main difficulty: The equation includes negative fractional exponents that are difficult for some computers to handle. “In my own community hospital,” Dr. Szypko says, “we had a request to implement eGFR into our laboratory reporting system and it’s taken several months to get to where we’re almost ready to do it.”
Though any system released in the past 10 years is probably okay, Dr. Eckfeldt says, “you’d be surprised how many older laboratory information systems are running out there in some, especially smaller, hospitals.”
And calculating eGFR becomes problematic if the LIS can’t do it easily, he says. “You can perform the calculation by buying a $25 programmable calculator and performing the estimating equation in it. But that’s a manual step, someone would have to do the calculation, mistakes would be made in data entry, and it’s not clear it’s really worth all the time and effort.”
Crucial information needed to calculate eGFR besides serum creatinine are age, gender, and race, and this information may not be available to the laboratory performing the creatinine measurements, CAP president Thomas Sodeman, MD, pointed out in a letter to Connecticut legislators last year.
“Without access to patient information that is in the sole possession of the treating physician,” he wrote, “the legal requirements of the legislation would establish a significant liability on the laboratory to perform a calculation that is dependent upon external, treating physicians who have no legal obligations under the legislation.”
In fact, there are circumstances when a laboratory might choose not to report eGFR, Dr. Miller says. “For example, on inpatients the estimating equation is less accurate, and with acute renal failure it’s really not appropriate.” It’s arguably inappropriate to keep reporting eGFR repeatedly for inpatients, he adds. “When you get creatinine measured several times a day, that information may be more distracting than helpful.” [The NKDEP Web site
(http://nkdep.nih.gov/labprofessionals/index.htm) contains detailed information on other limitations of eGFR results.]
Most professional clinical laboratory organizations have been against the legislative approach or neutral on it, says Dr. Eckfeldt. “But they’re not against the reporting of eGFR—they’re just against legislation forcing laboratories to report it in every case where a serum creatinine is measured.”
Some laboratory scientists, however, go further in challenging the trend to report eGFR automatically. In a recent opinion piece in Clinical Chemistry, Petrie M. Rainey, MD, PhD, professor of pathology at the University of Washington Medical Center, notes that eGFR has high false-positive rates, and confirmatory tests are not readily available. In his view, providing an eGFR with every creatinine measurement is “an untested medical intervention that is being proposed for national and international implementation despite the lack of clinical trials or other pilot studies.”
Dr. Rainey writes, “Until we have more consistent creatinine measurements and a prediction equation with better diagnostic accuracy in healthy populations, use of eGFR should be limited to screening high-risk individuals and to following patients with known CKD.”
On one thing there is universal consensus: Early detection of renal disease is an important public health goal. “There are a lot more-accurate tests for measuring renal function, but they are much more costly and complicated to perform, and serum creatinine is widely measured in routine primary care settings and eGFR is reasonably predictive of renal function,” Dr. Eckfeldt says. Nephrologists are “pretty much in accord on universal eGFR reporting—that it’s not a perfect indicator of renal function, but it’s a pretty good indicator,” he says.
“The whole point is to try to get early recognition of renal disease before it becomes an obvious problem for the patient, because the sooner you make a diagnosis, the sooner you can intervene and prevent further deterioration of renal function.”
“Even slowing the rate of decline in renal function is helpful,” he adds, “because the patient may die of something else before requiring a renal transplant or chronic dialysis, both of which create morbidity for the patient and are a huge economic issue, now estimated to cost the federal government well over $20 billion per year.”
Primary care and general internal medicine physicians are a little more resistant than nephrologists to the use of eGFR for screening, Dr. Eckfeldt says. “It’s sort of one more thing they have to talk to patients about in a limited reimbursement system when they don’t have much time to spend with their patients discussing preventive health care issues. But the goal is to prevent renal disease from progressing to the point that the patient needs transplant or dialysis. I think it’s a worthy goal.”
There will be false-positives that then have to be worked up, he notes. “But on the other hand, there may be people with early chronic renal failure who would never have been picked up and who with early treatment might escape needing a transplant or chronic dialysis.”
“That’s one reason why most nephrologists are on board,” he adds. “They are the ones who get patients referred to them late. If they had seen them five or 10 years earlier, they could have helped them.”
Cystatin C may prove to be a more reliable glomerular filtration marker than serum creatinine, and a working group in the International Federation of Clinical Chemistry and Laboratory Medicine is addressing standardization of cystatin C.
In the meantime, many groups are collaborating to address the problem of interlaboratory variability of creatinine testing. “eGFR allows you to better correlate creatinine measurements to patients’ true kidney function, because pathologists and other physicians monitor kidney function by glomerular filtration rate. But in order for eGFR to be optimized, the variability in creatinine needed to be eliminated,” Dr. Miller explains.
“Different manufacturers’ instruments have been giving clearly different serum creatinine results,” Dr. Killeen says, pointing to the final 2003 CAP Comprehensive Chemistry Survey that used fresh-frozen serum to eliminate differences between instruments caused by matrix effects. “Now the manufacturers are working fairly diligently toward harmonization of calibration. The goal will be to have serum creatinine measurements that are consistent in the vast majority of laboratories in the country.”
The original formula for eGFR was based on measurements of creatinine on Beckman Coulter instruments, Dr. Eckfeldt says. “That method is now known to yield values biased high by about five percent for creatinine of about 1.0 mg/dL, so the original MDRD formula for eGFR [developed from the Modification of Diet in Renal Disease research study] had worked into it a calibration offset of roughly five percent—roughly 0.05 mg/dL.”
“When a creatinine instrument or reagent vendor changes its method’s calibration to match high-level IDMS [isotope dilution mass spectrometry] reference method values, you need to use a slightly different eGFR formula to get unbiased eGFR values,” Dr. Eckfeldt says. “This situation has led to some confusion in the field as to what is the appropriate eGFR formula to be using.”
Laboratories using methods that have not been standardized to an IDMS reference method should use the original MDRD equation to report eGFR, Dr. Miller says, because many routine methods have a bias similar to that of the Beckman Coulter method used to develop the MDRD equation. “It is not necessary to wait for the method manufacturer to complete the recalibration to be IDMS-traceable in order to report eGFR,” he says.
As the manufacturers begin to shift their calibration to more-accurate creatinine concentration values, which is beginning to happen, “they will have to coordinate their calibration changes closely with the clinical laboratory so the laboratory changes to the new MDRD formula at the right time,” Dr. Eckfeldt says. “It’s very simple to change to the new IDMS-traceable MDRD formula, but you have to know when to do it.”
Eliminating the variability among creatinine methods has been a key goal of the National Kidney Disease Education Program Laboratory Working Group since it began in late 2002. It has collaborated with the CAP and the National Institute of Standards and Technology, or NIST, to prepare human serum-creatinine reference materials, prepared from fresh-frozen serum pools, with acceptable commutability with native clinical specimens in routine methods.
A new NIST fresh-frozen serum reference material, which has been designated NIST SRM 967, is ready for release. It is designed primarily for use by manufacturers for internal calibration of their instruments, reagents, and calibrators. In fact, the manufacturers have been eagerly awaiting the release because “this reference material will literally allow creatinine to be the same everywhere in the world,” says Dr. Miller, who is chair of the Laboratory Working Group.
“The next step after the release of the product will be to ensure the manufacturers are aware of it and to encourage them to incorporate it in their internal calibration processes, which I believe they will all do,” he says.
The Laboratory Working Group then plans to continue educating laboratories on which equation to use to make sure they report the correct eGFR. “Most of the current creatinine methods are a little high relative to the reference method, so after all the methods are standardized, most will have results a little lower than they had before standardization. The recalibration required a modification in the estimating equation to get the correct eGFR when measuring creatinine with a standardized method,” Dr. Miller explains.
The formulation of the CAP’s LN24 specimens, used in the CAP Calibration Verification/Linearity Survey, is the same one NIST used in its Standard Reference Material. The LN24 Survey provides an accuracy-based assessment of a lab’s serum creatinine measurements in the normal and slightly elevated range, which is the concentration range most important for accurate estimation of GFR using estimating equations. Labs enrolled in this Survey can identify the bias of their in-house creatinine measurements and take any actions needed to ensure their values coincide with those established by IDMS reference methods.
“CAP LN24 is a very important tool in assessing ongoing accuracy of all methods under real field conditions,” Dr. Eckfeldt says. The NKDEP Laboratory Working Group has endorsed LN24’s use.
Standardization may or may not resolve the debate over eGFR as a screening tool, but it will improve the uniformity of creatinine results measured by different methods in different laboratories and reduce some of the variability observed in eGFR results. For now, Dr. Szypko says: “eGFR is a calculation that can be useful in detecting chronic kidney disease at an early stage. However, there are limitations to this calculation, and it needs to be interpreted in the whole clinical context.”