We would like to thank Levey and colleagues for their correspondence on our Perspectives article (Porrini, E. et al. Estimated GFR: time for a critical appraisal. Nat. Rev. Nephrol. 15, 177–190 (2019)1), which argues that our conclusion that estimated glomerular filtration rate (eGFR) is not a reliable tool for assessment of renal function is flawed (Levey, A. et al. Strengths and limitations of estimated and measured GFR. Nat. Rev. Nephrol. https://doi.org/s41581-019-0213-9 (2019)2). Here, we provide a response to the points made in their correspondence.
First, they suggest that the inclusion of studies that did not use standardized assays for creatinine or cystatin C in our analysis led to unreliable estimates of the accuracy of eGFR equations. However, poor correlations between creatinine levels and measured GFR (mGFR) have been observed with creatinine measurements obtained using both standardized and nonstandardized assays1. Stevens et al.3 reported comparable percentage of eGFR values that are within ±30% of mGFR values (P30) for eGFRs based on creatinine levels measured in the same samples using either standardized or nonstandardized assays (80% and 83%, respectively). Additional studies that used either nonstandardized4,5,6,7 or standardized8,9,10 creatinine assays showed comparable P30 values for eGFR. Assay standardization therefore clearly does not improve the performance of eGFR formulas.
Second, they argue that we underestimated error in mGFR compared with “true GFR”. To our knowledge, it is not possible to define ‘true GFR’, and no rationale exists to suggest that inulin clearance is the ‘gold standard’ for GFR measurement. To which method was the clearance of inulin compared to establish it as the gold standard? This is unknown. Also, inulin clearance is not a perfect method for measuring GFR because inulin undergoes both renal and extrarenal clearance, which might lead to overestimation of GFR11. Thus, the level of error in mGFR compared with ‘true GFR’ is supposition rather than fact. By contrast, error in eGFR compared with mGFR is real, wide and frequent; a fact that has been largely overlooked.
The systematic review by Soveri et al.12 that analysed diverse methods used to measure GFR is a landmark publication. However, the authors compared studies using a single point with others using multiple points to measure GFR. This approach is not correct because accuracy and precision increase with the numbers of points taken. Their overall analysis that combines different studies must therefore be examined in detail and with caution. In fact, the plasma clearance of iohexol seems to be comparable to the plasma clearance of inulin when multiple blood samples are taken for the analysis of GFR13,14. Moreover, Soveri et al.12 conclude that “there is enough evidence to consider the renal clearance of iothalamate and renal or plasma clearances of EDTA and the plasma clearance of iohexol as reliable alternatives to the inulin clearance”.
Third, we fully agree with Levey and colleagues that a performance goal for eGFR equations of P10 > 90% (that is, 90% of eGFR values within 10% of mGFR values) is unrealistic given that the average error of eGFR equations is as wide as ±30%, or even larger. However, methods of evaluating formulas that estimate GFR must be adapted to the needs of patients and not to the evident limitations of eGFR equations. The error in eGFR that we tolerate in nephrology would be unacceptable in other areas of medicine. How many patients with hypertension would be diagnosed as normotensive (or vice versa) if we used a sphygmomanometer with an error of 30–50%?
Fourth, a P30 of 80–90%, which Levey and colleagues consider to be acceptable for many clinical decisions, means that most eGFR values differ from mGFR values by ±30%. It is difficult to accept that such variation, which would equate to ±20‒30 ml/min/1.73 m2 in a patient with a mGFR of 60 ml/min/1.73 m2, will not have consequences in the clinic (Supplementary Fig. 1). Indeed, there is evidence that this level of error in eGFR has important consequences including overdosing or underdosing of toxic drugs15, erroneous classification of chronic kidney disease (CKD) stages10, accepting kidney donors with low GFR and rejecting potential donors with adequate kidney function16. Unfortunately, use of cystatin C rather than creatinine or a combination of cystatin C and creatinine to estimate GFR does not improve the accuracy of eGFR values, as discussed in our Perspectives article1,9,10. The consequences of this lack of precision and accuracy of eGFR equations in the clinic must not be overlooked.
In contrast to Levey and colleagues, we think there is enough evidence to conclude that in specific clinical conditions, the error in eGFR values obtained using any of the current formulas is unacceptable as it could have severe consequences.
Porrini, E. et al. Estimated GFR: time for a critical appraisal. Nat. Rev. Nephrol. 15, 177–190 (2019).
Levey, A. et al. Strengths and limitations of estimated and measured GFR. Nat. Rev. Nephrol. https://doi.org/s41581-019-0213-9 (2019).
Stevens, L. A. et al. Impact of creatinine calibration on performance of GFR estimating equations in a pooled individual patient database. Am. J. Kidney Dis. 50, 21–35 (2007).
Barroso, S. et al. Accuracy of indirect estimates of renal function in advanced chronic renal failure patients. Nefrologia 26, 344–350 (2006).
Froissart, M. et al. Predictive performance of the modification of diet in renal disease and Cockcroft–Gault equations for estimating renal function. J. Am. Soc. Nephrol. 16, 763–773 (2005).
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Poggio, E. D. et al. Performance of the modification of diet in renal disease and Cockcroft–Gault equations in the estimation of GFR in health and in chronic kidney disease. J. Am. Soc. Nephrol. 16, 459–466 (2005).
Murata, K. et al. Relative performance of the MDRD and CKD- EPI equations for estimating glomerular filtration rate among patients with varied clinical presentations. Clin. J. Am. Soc. Nephrol. 6, 1963–1972 (2011).
Luis-Lima, S. et al. Estimated glomerular filtration rate in renal transplantation: the nephrologist in the mist. Transplantation 99, 2625–2633 (2015).
Luis-Lima, S. et al. Chronic kidney disease staging with cystatin C or creatinine-based formulas: flipping the coin. Nephrol. Dial. Transplant. 34, 287–294 (2019).
Frennby, B. et al. The use of iohexol clearance to determine GFR in patients with severe chronic renal failure — a comparison between different clearance techniques. Clin. Nephrol. 43, 35–46 (1995).
Soveri, I. et al. Measuring GFR: a systematic review. Am. J. Kidney Dis. 64, 411–424 (2014).
Gaspari, F. et al. Glomerular filtration rate determined from a single plasma sample after intravenous iohexol injection: is it reliable? J. Am. Soc. Nephrol. 7, 2689–2693 (1996).
Gaspari, F. et al. Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate. J. Am. Soc. Nephrol. 6, 257–263 (1995).
Hornum, M. & Feldt-Rasmussen, B. Drug dosing and estimated renal function - any step forward from effersoe. Nephron 136, 268–272 (2017).
González-Rinne, A. et al. Impact of errors of creatinine and cystatin C equations in the selection of living kidney donors. Clin. Kidney J. https://doi.org/10.1093/ckj/sfz012 (2019).
The authors acknowledge research support from the DIABESITY working group of the ERA-EDTA, the IMBRAIN (CIBICAN) project (FP7-RE6-POT-2012-CT2012-31637- IMBRAIN) funded under the 7th Framework Programme (capacities); Instituto de Salud Carlos III (ISCIII) grants PI13/00342 and PI16/01814 to E.P. and A.T., and REDINREN RD16/0009 and PI10/02428 grants to E.P. and A.T.; and funding from the Instituto Reina Sofia de Investigacion (IRSIN) and FEDER (both to A.T.). S.L.-L. is a research fellow supported by ISCIII grant JR18/00027 for the Juan Rodés Grant. E.P. is a researcher supported by the ISCIII Ramón y Cajal Programme and Fundación Caja Canarias grant DIAB05.
The authors declare no competing interests.