March 2010
Feature Story

Anne Paxton

Determining the proper dose of a therapeutic drug is an inexact science under the best of circumstances. But when a patient has impaired renal function, it becomes fraught with added difficulties. The dose of any drug that’s excreted by the kidneys must be adjusted to take into account the patient’s glomerular filtration rate, or GFR, but serum creatinine assays can provide only an imprecise “best guess” at that value.

Important progress in producing better estimated GFRs (eGFRs) and better drug dosing for kidney patients has been made over the past few months. The National Kidney Disease Education Program completed a five-year national effort to standardize serum creatinine assays by establishing calibration traceability to an isotope dilution mass spectrometry (IDMS) reference measurement procedure. In a related initiative, the NKDEP issued recommendations for improving drug dosing in patients with impaired kidney function via a September 2009 educational advisory titled “Chronic Kidney Disease and Drug Dosing: Information for Providers.”

The NKDEP educational advisory took almost a year of consultations among a group of clinical chemists, pharmacists, FDA representatives, nephrologists, and clinical pharmacists, says Andrew S. Narva, MD, director of the NKDEP. “The issue here is not with the clinical chemists; it’s with educating the clinicians who are dosing the patients.”

Standardization has been critical in addressing a long-standing prob­lem: the variability of eGFR values. “Laboratories are very good at having internal consistency within the lab for one instrument or another, but there wasn’t a central standard by which to compare creatinine values across labs,” says Lesley Stevens, MD, assistant professor of medicine at Tufts University School of Medicine and an attending nephrologist at Tufts Medical Center.

In addition, serum concentration of creatinine is influenced by factors other than the GFR, such as differences in rate of generation related to muscle mass and diet, as well as differences in the rate of tubular secretion. “In part, creatinine clearance overestimates GFR, so some laboratories would have added a ‘fudge factor’ into the creatinine assay so the creatinine result would be higher, and the creatinine clearance result lower and therefore more similar to the GFR,” Dr. Stevens points out. The standardization of creatinine calibration to an IDMS reference produces a lowering of creatinine values by 10 percent to 20 percent for most methods, though it’s not possible to use a single correction factor to back-calculate to the non-standardized value, since the impact differs across laboratories and methods.

“Standardization and recalibration of methods—efforts that started in 2005—have largely been accomplished by the major manufacturers of creatinine assays,” says Greg Miller, PhD, a consultant to the CAP Chemistry Resource Committee, chair of the laboratory working group of the NKDEP, and professor of pathology at Virginia Commonwealth University, Richmond. He did an informal survey of the major manufacturers in July 2009 and found that those who had not finished recalibrating would be selling in the fall the last lot numbers of reagents calibrated against the older methods. “So anything currently on the market should be recalibrated to be traceable to IDMS.”

That progress has been confirmed by the College’s LN24 series, the Creatinine Accuracy Calibration Verification/ Linearity Survey, conducted twice a year, which uses fresh-frozen serum to mimic patient serum reaction characteristics, he says. “So it gives a good estimate of how methods do.” The November 2009 Survey showed most laboratories in good agreement on creatinine values. “There may be a few outliers out there, but in the first half of 2010, recalibration should be complete.”

Over the past decade, Dr. Narva says, the clinical chemistry community has adopted routine reporting of estimated kidney function using the MDRD Study equation, based on the Modification of Diet in Renal Disease Study. “That is basically the international standard for estimating kidney function, although prior to standardization it would give a different result depending on what creatinine method is being used, and different patient characteristics can produce different results.”

The MDRD Study equation, derived from a population of 1,628 men and women with CKD, estimates GFR adjusted for body surface area, or BSA—i.e., mL/min per 1.73 square meters of BSA. The equation has been re-expressed for use with the recently standardized serum creatinine values.

Laboratories should be aware of the need to switch to the IDMS-traceable version of the MDRD Study equation, Dr. Miller notes. “There are two versions of the MDRD equation, the original and revised. The revised was modified to be used with IDMS-traceable creatinine methods. Laboratories should check to make sure they’ve switched over to the IDMS-traceable version of the equation. Assuming they are using the right equation, since the methods are now all standardized, the variability in eGFR should be reduced; they should get the same numerical value no matter what method laboratories use.”

However, drug dosage recommendations by pharmaceutical manufacturers have been based on a different equation: the Cockcroft-Gault formula. Derived from a study population of 249 men, the Cockcroft-Gault equation estimates creatinine clearance not adjusted for body surface area. Because the creatinine method used in the development of the equation is no longer in use, and samples from the study are not available, the Cockcroft-Gault equation cannot be re-expressed for IDMS-traceable creatinine values. In fact, there’s no version of the Cockcroft-Gault that has been validated with standardized creatinine. “It’s an old equation, established with a relatively small population, and there is no version of it that can be used with the IDMS,” Dr. Narva says.

So the drug dosage advice in package inserts hasn’t caught up with what is now standard practice in the clinical laboratory. There is no perfect fix for this problem, Dr. Narva says. “There’s not one simple correction and conversion value that you can simply plug in and go from one to the other. If you are dosing drugs based on the Cockcroft-Gault, you can’t simply take those values and multiply by some estimating variable and come out with MDRD.”

The Food and Drug Administration provides guidance to industry as to when it needs a pharmacokinetic study for a drug, usually because the drug is cleared through the kidneys, Tuft’s Dr. Stevens says. However, the studies themselves can be a source of variability affecting the drug dosage recommendations. “Even if a drug had exactly the same properties, if different creatinine assays were used in the pharmacokinetic studies, the results would have looked different. You would really never know,” Dr. Stevens says. “Then when those pharmacokinetic studies were translated into drug labels, those labels were used in practice and would be translated differently for use with patients because of differences in the creatinine assays among individual clinical labs.”

The new educational advisory from the NKDEP on drug dosing follows on from the standardization effort, Dr. Miller says. “The real issue with drug dosing is that labeling from the pharmaceutical manufacturers is based on creatinine clearance, and that’s not the same as GFR. It is highly correlated, but the number is usually a little higher for CC than for GFR. So there’s been a lot of concern raised over switching to using an eGFR calculator with the MDRD Study equation when the drug labeling says to use an estimate of GFR based on CC.”

“Clinical questions arising from creatinine standardization made it clear that we needed to address the drug dosing issue,” Dr. Narva says. “Creatinine standardization has been a major effort by our laboratory working group in collaboration with the clinical chemistry community, and it was moving forward very quickly. Creatinine values were changed in some facilities, and there was a lot of anxiety among pharmacists and providers about dosing drugs in patients with kidney disease, because in some cases there was concern that inappropriate doses would result from plugging new creatinines into the traditional formula for estimating kidney function.”

From a clinical perspective, drug dosing is difficult, Dr. Stevens notes, because there’s so much individual variation in response to a drug. “If we have a patient, we treat them, and they don’t get better, is it because we got the eGFR wrong and I didn’t give them enough drug? If they have a toxicity to a medication, is it because I got the eGFR wrong and gave too much, or is it because of the way their body responded to this specific drug?”

The NKDEP recommendations are important in this regard, she says. “I think the recommendations will greatly facilitate the use of any adjustment.” Since chronic kidney disease is a problem affecting more than 13 percent of the U.S. population, she points out, clinicians and providers should definitely be aware of the NKDEP creatinine standardization and recommendations for drug dosing.

Dr. Stevens believes the FDA should decide that to make dosage recommendations for new drugs, standardized creatinine should be used, and the best way to estimate kidney function should be used. “Given the science, they should use standardized creatinine and best estimates of kidney function for recommendations on new drugs going forward, and maybe even make some recommendations going backwards on drugs that have already been approved—although that’s a more complicated issue.”

Says Dr. Miller: “We do know NKDEP is interacting with FDA to develop the guidelines. It’s uncertain when they will be issued. They probably will not retroactively affect the whole pharmacopoeia that they currently use.” The NKDEP advisory says that while the FDA or manufacturers may decide to perform studies for some drugs, it will “not be possible” to re-express all current drug-dosing recommendations for use with standardized creatinine values.

Much of the concern about drug dosing, Dr. Narva says, was focused on the chemotherapy drug carboplatin, which is highly toxic. “What was happening is in some facilities there was actually a pushback against creatinine standardization because of this issue.” The pushback was from people who wanted a value they could continue to use to dose carboplatin in the same way as previously. “But since creatinine was not standardized, people were getting different estimates of kidney function at different facilities. What was perceived by many providers and pharmacists as the gold standard, the Cockcroft-Gault, was hardly a gold standard.”

Creatinine standardization, however, is an unqualified good thing, he emphasizes, and the challenge is to help providers understand both the uses of estimating kidney function and the limits.

The laboratory working group that developed the NKDEP advisory has always tried to lay out issues in an educational way, not as a clinical guideline, Dr. Narva notes. “This is simply an educational advisory, authored by a subcommittee of the working group, to help people make clinical judgments that are as informed as possible.”

One reason for that, he adds, is that a formal guideline would require an official vetting process, which would have delayed publication significantly. An educational advisory was a way to provide some guidance to clinicians in a more timely manner. “The problem is that the data on drug safety that the FDA has, and the dosing guidance prior to 2007–2008, is based mostly on the Cockcroft-Gault estimates of kidney function, so they’re very uncomfortable changing the packet inserts because they don’t have the MDRD data.” They are trying to reconstruct those data, but in many cases they may not know what technique was used to do the creatinine assay, he says. “We’re talking about drugs that were approved many years ago. And there are going to be some data gaps that you can’t fill.”

It’s difficult to use creatinine by itself, because there’s a highly nonlinear relationship between creatinine and GFR, Dr. Miller says. eGFR is almost always going to be more reliable than creatinine by itself. “As you approach kidney failure, the estimates, as well as the serum level, become less reliable, so we will frequently have creatinine clearance measured rather than rely on estimations.” If a patient has lost muscle mass, which is not uncommon in cancer patients, then estimates or the serum level don’t work as well, he adds. Patients on highly toxic drugs often have their creatinine clearance measured.

Measuring creatinine clearance is somewhat complex logistically and involves measuring the creatinine in the blood, and then having the patient collect urine for 24 hours. “Then you measure the creatinine in the urine and calculate the rate at which the creatinine cleared based on the concentrations.” Nevertheless, it’s a test commonly performed in all laboratories.

Now that creatinine has been standardized, the NKDEP’s laboratory working group has turned to other standardization efforts. The next step in improving the evaluation of kidney function is tackling urinary albumin measurement, Dr. Miller says. “That’s another laboratory test very commonly used to evaluate kidney function, and we have a number of investigations underway by the laboratory working group to understand the issues associated with this test.” He hopes data being collected over the next couple of years “will allow us to make some concrete recommendations to the manufacturers of urinary albumin methods how to improve standardization. But there is less data on albumin than there was on creatinine when that project was started.”

There will be a transition period for laboratories to get comfortable using the MDRD Study data. But from Dr. Miller’s perspective it’s important for labs to recognize that serum creatinine measurements are now largely standardized and they need to be using the correct MDRD Study equation. “I would guess some labs are using revised creatinine methods but still using old equations and getting too-high values for eGFR.” But the less variability there is in eGFR, he says, the more clinical laboratories will help ensure uniform clinical practices that benefit patients.

Related Links

• CKD and drug dosing NKDEP recommendations
• Which estimate of kidney function is best for drug dosing?