In a recent study published in AJKD, Shaffi et al evaluated the efficacy of different GFR estimating equations in a large cohort of solid organ transplant recipients. First author Dr. Kamran Shaffi (KS) discusses the study with Dr. Vinay Nair (eAJKD), eAJKD Advisory Board member.
eAJKD: What inspired the idea of this study?
KS: Physicians use estimated GFR for day-to-day management of solid organ transplant recipients to implement CKD stage based guidelines, to dose medications and to predict graft survival in kidney transplant recipients. Furthermore, estimated GFR is used as an outcome in research studies. However, there is no consensus as to which equation is best in estimating GFR in solid organ transplant recipients. We wanted to assess the performance of the creatinine-based GFR estimating equations in a large cohort comprising of various types of solid organ transplant recipients and to assess whether the CKD-EPI and the MDRD Study equation, the two most commonly used equations in the general population, are as accurate in solid organ transplant recipients as they are in the general population.
eAJKD: As you mentioned, prior studies have evaluated creatinine based GFR estimation equations in transplant populations and revealed mixed results. How is your study different from what has been done before?
KS: Our study is different from the previous studies in a number of ways. We performed a comprehensive systematic review to identify all creatinine-based GFR estimating equations and studied their development methodology in detail. We studied the performance of these equations in a large cohort comprising of various types of solid organ transplant recipients in whom GFR was measured by urinary clearance of iothalamate in the vast majority and serum creatinine measured by a method that was traceable to isotope-dilution mass spectrometry (IDMS) in all.
We used various metrics to comprehensively assess bias, precision and accuracy of the equations and identified a subset of the equations that performed the best in our cohort. We statistically compared the performance of the CKD-EPI and the MDRD study equations with the alternative equations by evaluating the absolute differences rather than relative differences of various metrics as the relative differences can sometimes overestimate the effect size. Finally, we performed an extensive subgroup analysis to study the performance of these equations according to subgroups based on various demographic, clinical and biochemical characteristics.
Most of the studies performed in the past were performed in the era when serum creatinine was measured using assays that were not traceable to IDMS and therefore their results have limited utility today.
eAJKD: I would assume that creatinine may be a worse biomarker in kidney transplant recipients as they would be more likely to have inflammatory disease within the kidney (rejection, polyoma nephropathy, pyelonephritis). Did GFR equations behave differently in kidney transplant recipients compared to other solid organ transplant recipients?
KS: There was wide variation between the performance of the equations in various solid organ transplant recipients. However, performance of the CKD-EPI and the MDRD Study equations in kidney transplant recipients was similar to performance in other solid-organ transplant recipients (see Shaffi et al, Table S6). Furthermore, performance in organ transplant recipients was similar to performance in the general population. We postulate that in the current era of immunosuppression, kidney transplant recipients are not very different from the general population as far as the non-GFR determinants of creatinine are concerned.
eAJKD: Did your study population have data on cystatin C? It would be interesting to see how cystatin C based formulas compare to creatinine based as the study by Masson et al revealed a benefit of using cystatin C in combination with creatinine over the 2009 creatinine based CKD EPI equation.
KS: We did not have data on cystatin C in our cohort. Our study revealed that creatinine based equations still lack in precision and the addition of cystatin C in GFR estimation might solve this problem.
eAJKD: The lack of minorities is a limitation of your study. Do you think the GFR formulas need to be tested in a minority transplant population or is there enough data to clinically extrapolate your results to a minority population?
KS: In a previously published systematic review, it was shown that the CKD-EPI and the MDRD study equations with race modifications were most accurate in various populations outside of North America, Europe and Australia. It is plausible that these equations with race modifications would perform as well in the transplant population from that ethnicity. However, studies should be conducted to comprehensively evaluate the performance of the equations in transplant recipients from various ethnic backgrounds.
eAJKD: As you mentioned the FDA recommends use of the Cockcroft-Gault equation for drug development programs and in package inserts although it is not as accurate as the MDRD Study or CKD EPI equations. Since drug dosing is based on Cockcroft-Gault, which formula do you suggest clinicians use to dose medications in transplant patients?
KS: This has been a controversial issue. Drug package inserts and the FDA recommend the Cockcroft-Gault (CG) equation for drug dosing. However, the CG equation estimates creatinine clearance and thus might overestimate GFR. Furthermore, CG was developed using non-standardized creatinine, which is higher than standardized creatinine and is no longer available. There was no race variable in the CG equation, and it was assumed that the creatinine clearance of females would be 85% that of the males. All these factors would likely result in systematic error and inaccurate classification of the level of renal function.
Our group has shown previously that the MDRD Study equation without BSA modification identified drug dose reductions for 15 commonly used drugs more accurately than the CG equation when compared to mGFR. We concluded that the MDRD Study equation could be used for pharmacokinetic studies and drug dose adjustments.
For these reasons, we think that the CKD-EPI and the MDRD Study equation would be more suitable for estimating GFR in organ transplant recipients as well as the general population. In fact, the FDA has published a guidance paper for the pharmaceutical industry recommending use of either the CG equation to estimate CrCl or the MDRD Study equation to estimate GFR for assigning subjects to categories of renal impairment and for pharmacokinetic studies.
eAJKD: Your data suggests that transplant patients are not so different than those with CKD when it comes to GFR estimation. If a new formula comes along do you think it needs to be validated in transplant patients or is there enough data to suggest that transplant patients actually do behave similarly to the non-transplant CKD population?
KS: Most transplant centers now use steroid free regimens and there is a trend towards decreasing the burden of immunosuppression earlier, therefore, the non-GFR determinants of serum creatinine might not be very different from that in the general population. This might explain the results of our study, where performance of the CKD-EPI and the MDRD Study equations were similar in solid organ transplant patients and the general population. However, we would suggest that new equations developed for the general population also be tested in organ transplant recipients.