An accurate assessment of the renal function is essential in oncology patients to ensure safe prescribing of chemotherapy drugs, detecting kidney injury and assessing prognosis. oncologists often rely on formulae to estimate the GFR on the basis of serum creatinine and other parameters. In this study, we assessed the performance of six Egfr formulae, including Cockcroft-Gault, MDRD, C-MDRD, CKD-EPI and FAS. We found that all formula performed poorly and MDRD formula showed best agreements with mGFR. Furthermore, we found that inaccuracy of eGFR estimated using MDRD formula were more likely observed in elderly patients, as well as patients with higher eGFR. Besides, we constructed a nomogram to predict the risk of inaccuracy of eGFR.
Oncologists should pay attention to the limitation of eGFR formulae. In our study, the fraction of patients with eGFR absolute percentage error >30% is more than one-third in all formulae. Besides, all six formulae showed positive MPE, demonstrating that these eGFR formulae tended to overestimate mGFR in Chinese cancer patients, which is inconsistence with previous studies [10, 21]. MDRD showed lowest bias and lowest agreements with mGFR, nevertheless, 90% of the estimations calculated using MDRD formula showing an error of about ±36% of mGFR. Therefore, the accuracy was unacceptable in eGFR formula and it is inappropriate to apply eGFR formulae to all oncology patients, which had been. Previous studies also have criticized the performance of eGFR in estimating real renal function [22]. Oncologists should identify populations where eGFR formulae based on serum creatinine is not likely to provide an accurate estimate and thus alternative measurements of the GFR should be considered. We also assessed the modified MDRD formula for Chinese population in our study, however, C-MDRD did not perform better than original MDRD in our study. Larger population is needed to validate C-MDRD formula and further studies may focus on developing eGFR formula for Chinese cancer patients
There are multiple possible explanations of poor performance of eGFR in Chinese cancer patients, including the lack of an ethnic factors, different serum creatinine test methods and daily changing GFR in cancer patient. Besides, Oncology patients tended to have low muscle mass and reduced dietary protein intake, which would also influence the concentration of serum creatinine and thus the performance of eGFR formulae [23]. Some studies have demonstrated that the performance of eGFR formulae may be affected by age, weight and GFR [13, 14, 24].
BUN/Scr ratio may be an indicator of the accuracy of eGFR formulae. BUN/SCr ratio greater than 20 is known as a marker of pre-renal renal dysfunction [25]. Poggio et al. found that the MDRD formulae were not reliable in sick hospitalized patients, especially those with high BUN/SCr ratio [26]. However, little is known about the association of elevated BUN/SCr ratio and accuracy of eGFR formulae in oncology patients. We found that the MDRD formula was likely to be inaccurate in oncology patients with high BUN/SCr ratio. Possible explanation for our observations is that BUN/SCr ratio may rise in oncology patients with low rate of creatinine generation, and creatinine-based eGFR formulae would perform poorly accordingly.
Normal estimates of the GFR might not be actually that normal. In patients of higher eGFR, eGFR formula showed low accuracy and great degree of overestimation, which is consistent with reports from studies consisting of population with normal renal function, such as kidney donors [27, 28]. Most of the eGFR equations were derived from subjects with kidney disease, or in combined healthy/diseased populations. This may explain the overestimation of GFR in subjects with normal kidney function. Furthermore, kidney injury will be wrongly labeled as normal kidney function and the degree of renal damage will be underestimated, which encourages oncologists to make wrong decisions regarding the administration of iodinated contrast medium, employment of nephrotoxic drugs and the time to initiate renal replacement therapy. Besides, narrow therapeutic index is a pharmacokinetic characteristic of most chemotherapy agents. A well-known example of such agents is carboplatin, whose dose is adjusted by Calvert formula incorporating the GFR as an important variable [29]. As a consequence, overestimated GFR may result in overdosage of chemotherapy agents, particularly those agents which are entirely eliminated by the kidneys in unchanged active form. Ultimately, inaccurate assessment of the GFR means severe side effects, as well as increasing incidence of renal insufficiency, or even death.
An important facet of this study is that a nomogram was developed to predict the reliability of eGFR as calculated by the MDRD formula in oncology patients. The nomogram is a simple graphical prediction tool. By assigning points to the four variables, oncologists can assess the predictive risk of individuals. This provides clinically useful information and guide personalized clinical decision-making regarding whether to use accurate GFR measurements for oncology patients. Furthermore, our nomogram is constructed on the basis of readily available clinical data making it easy for clinicians to use. Internal validation indicated good performance with area under ROC of 0.732 and accurate calibration.
We acknowledge several limitations in this study. Firstly, due to the retrospective nature of our study, there might have been selection bias and unknown confounders in the analysis. Secondly, we used enzymatic creatinine assay in our study, and it may lead to bias when assessed Cockcroft-Gault formula which was developed by Jaffe assay. Finally, although the nomogram was validated internally by bootstrap resampling, external validation using an independent data set was required before routine use.