Variability in estimated glomerular filtration rate and the risk of major clinical outcomes in diabetes: Post hoc analysis from the ADVANCE trial

Abstract

There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes (T2D). We assessed the association between 20‐month eGFR variability and the risk of major clinical outcomes in T2D among 8241 participants in the ADVANCE trial. Variability in eGFR (coefficient of variation [CVeGFR]) was calculated from three serum creatinine measurements over 20 months. Participants were classified into three groups by thirds of CVeGFR: low (≤6.4; reference), moderate (>6.4 to ≤12.1) and high (>12.1). The primary outcome was the composite of major macrovascular events, new or worsening nephropathy and all‐cause mortality. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow‐up of 2.9 years following the 20‐month period, 932 (11.3%) primary outcomes were recorded. Compared with low variability, greater 20‐month eGFR variability was independently associated with higher risk of the primary outcome (HR for moderate and high variability: 1.07, 95% CI: 0.91–1.27 and 1.22, 95% CI: 1.03–1.45, respectively) with evidence of a positive linear trend (p = .015). These data indicate that eGFR variability predict changes in the risk of major clinical outcomes in T2D.

Modeling Chronic Kidney Disease in Type 2 Diabetes Mellitus: A Systematic Literature Review of Models, Data Sources, and Derivation Cohorts

“…While widely used in general population CKD models that model declining kidney function based on CKD stages defined by eGFR [12,34,132], eGFR has only recently received increased attention in CKD models in T2DM as the understanding of eGFR trajectories and their link with albuminuria in patients with diabetes has improved. This understanding includes the non-linear and potentially nonprogressive shape of eGFR trajectories, the link between speed of eGFR decline and clinical outcomes, and the possibility for both eGFR and albuminuria to worsen independently of each other [14][15][16][17][18][19][20][21]136].…”

“…The classical phenotype of CKD, both with and without T2DM, has been a linear decline in estimated GFR (eGFR) in the presence of persistent albuminuria [14]. Alternative disease trajectories have recently been described, including eGFR declines in diabetes in the absence of albuminuria [15] as well as non-linear, non-progressive, and variable eGFR trajectories [16,17], with the latter being linked to outcomes such as ESKD, initiation of RRT, and mortality [18,19]. While CKD remains a progressive disease in most patients, CKD is not irreversible and may regress, to the extent that CKD regression and death are more probable with advancing age than CKD progression and kidney failure [20,21].…”

A synergistic effect of variability in estimated glomerular filtration rate with chronic kidney disease on all-cause mortality prediction in patients with type 2 diabetes: a retrospective cohort study

“…In line with our findings, Al-Aly et al [26] reported that previous variability in eGFR significantly predicted mortality in patients with an eGFR < 60 mL/min/1.73 m 2 . In patients with DM, Tseng et al [21] reported that variability in eGFR significantly predicted the composite outcome of dialysis and mortality in patients with CKD, and Jun et al [23] also reported that variability in eGFR significantly predicted the composite outcome but not mortality alone. The strength of our study is that we demonstrated that variability in eGFR has a synergistic effect with CKD on the prediction of the primary endpoint of all-cause mortality in patients with type 2 DM.…”

“…Perkins et al [22] reported that eGFR variability could significantly predict mortality in patients with stage 3 CKD. However, a recent post hoc analysis from the ADVANCE trial reported that eGFR variability was significantly associated with the primary outcome, including major macrovascular events, new or worsening nephropathy and all-cause mortality, but eGFR variability was not significantly associated with all-cause mortality as a secondary outcome in patients with type 2 DM [23]. These inconsistent results might be explained by the various CKD stages and presence of DM in the study population.…”

Interpreting Estimated GFR Variability and Its Clinical Significance

“… 7 Consistent with this, prior studies have demonstrated that greater eGFR variability associates with new or worsening kidney disease and higher risk of dialysis, cardiovascular disease events, and all-cause mortality. 7 , 8 , 9 …”