Discussion
In this nationwide study of patients diagnosed with diabetes, we compared the magnitude of the association of eGFR estimated with four different equations (Cockcroft-Gault, MDRD, CKD-EPI or CKD-EPI-NR) with 4-year all-cause mortality. We found that overall, MDRD had the strongest association with death, either when patients were classified in KDIGO stages based on MDRD eGFR, or when the overall discriminative capacity of the four equations was compared using ROC analysis.
These are clinically relevant results because they may influence the decision about which equation to use when caring for Latin-American patients with diabetes. In addition to the use of different biomarkers or their combinations for the estimation of GFR, the mathematical expression employed may have a relevant influence on the performance of eGFR to predict not just advanced CKD, but also death and other serious adverse clinical outcomes in patients with diabetes. For example, an analysis of data from the US National Health and Nutrition Survey (NHANES) found the CKD-EPI-based calculation of eGFR to better predict the risk of death, as compared with the MDRD-based calculation, or to serum creatinine concentrations.21 Similarly, a study in Italy found the CKD-EPI eGFR to better stratify patients with diabetes according to their total and cardiovascular mortality risk.22 The contrast between these results and ours highlights the different performance of eGFR equations when applied to different populations.
The finding that in our sample more advanced CKD stages according to CKD-EPI showed a relatively weaker association with death may be related to the fact that this equation classified a much larger proportion of patients as having advanced CKD. Hence, many lower risk subjects could have been classified in these stages, which resulted in a lower OR. Other studies have found large discrepancies in the proportion of individuals being classified as having advanced CKD depending on the eGFR equation employed.23
The difference between MDRD and the other equations in terms of association with death was much larger among patients of black race, providing support for the use of this equation in black Latin-American patients. Unexpectedly, even in black patients, the CKD-EPI equation that does not include race had a stronger association with mortality than the original version with race. One prior study in Brazil had found the use of CKD-EPI equations without race/ethnicity adjustment to be more appropriate for the Brazilian population.24 This finding may have major implications, as patients of African descent tend to have a lower overall prevalence of CKD,25 but a higher incidence of end-stage renal disease26 compared with other races. Many biological and social factors have been postulated to explain this apparent paradox, but imprecision in GFR estimation with race adaptation could be one contributor. Recent evidence suggests that the use of cystatin C for eGFR estimation in black patients may provide an even better prediction of the end-stage renal failure and mortality risk associated with low eGFR.27
Implications
Our results have clinical implications for professionals treating patients with diabetes in Colombia and other countries of similar demographics, especially countries with a sizeable population of African origin. First, they highlight the importance of always performing a thorough evaluation of renal function since diabetes diagnosis, including but not restricted to eGFR. Second, they suggest that in such context the estimation of GFR with MDRD may provide a more accurate estimation of mortality risk, so that even if less patients are classified in more advanced CKD stages, the limited resources available in our countries will be better focalized to those patients who really are at increased risk.
It is also important to highlight that eGFR is only one of a portfolio of CKD risk assessment tools that frequently must include other markers such as urinary albumin/creatinine ratio, cystatin C, 24-hour urinary albumin excretion and others. Thus, it is not possible to expect a single marker to perform well in all patients.
In terms of directions for future research, our results can be expanded and complemented by longer follow-up of the Colombian population, by the replication of our analyses in other Latin-American countries and/or by the incorporation of new and emerging CKD markers. Nonetheless, they do encourage the routine assessment of renal function and inform the choice of the tool to do so.
Strengths and limitations
Our study involved a nationwide sample, and laboratory and demographic variables were obtained from a centralized, curated database of all patients diagnosed with diabetes in Colombia. The primary endpoint of all-cause death is unequivocal, and the survival status of each participant was ascertained against official sources. Despite the potential limitations of self-reported race, previous studies have demonstrated a consistent association between self-reported race and health outcomes in Colombia.28 Even though a 4-year follow-up might be insufficient to evaluate association between exposures like eGFR and mortality, the sample size was large enough to allow us to reveal existing differences in the association of the different eGFR equations with mortality. One relevant limitation is the absence of cystatin C measurements to perform a comparison of the equations using this newer biomarker. However, the penetration of this test in the Colombian system is still very low and did not permit us to undertake such analyses. Finally, our study is subject to the limitations of all routinely collected data studies, in which the data were not initially collected to answer the specific research question.
In summary, our results suggest that GFR estimated with the MDRD equation may have a stronger association with all-cause mortality in Latin-American patients with diabetes, especially if they are of black race.