Kidney Biomarkers and Decline in eGFR in Patients with Type 2 Diabetes

Discussion

We used a large, well defined patient population with type 2 diabetes and recent acute coronary syndrome from the EXAMINE trial to evaluate the predictive utility of baseline cystatin C, uKIM-1, and uNGAL and short-term changes of urinary biomarkers in identifying patients at risk of eGFR decline. Baseline cystatin C and change in uNGAL were associated with eGFR decline, but the addition of urinary biomarkers did not improve risk prediction, discrimination, or reclassification. Cystatin C marginally improved risk prediction although the difference was not statistically significant. These results support the growing body of evidence that static measurements of urinary tubular injury markers do not improve prediction of CKD progression beyond standard clinical factors and laboratory measures (27,28). We uniquely demonstrate that monitoring for changes in these biomarkers did not improve clinical prediction of eGFR decline either. This may reflect an absence of clinical utility but also reflects the excellent predictive ability of traditional risk factors including demographics, comorbidities, and baseline eGFR which left little room for meaningful improvement in discrimination and calibration.

Evidence on the utility of kidney biomarkers in predicting eGFR decline is evolving. An early study of 96 patients in 2009 reported that uNGAL was an independent risk marker for CKD progression with modest sensitivity and specificity (20). Similarly, uNGAL and uKIM-1 were higher in a study of 303 patients with diabetes with rapid progression of CKD (defined as >25% annual decrease in eGFR) compared with individuals without rapid progression (18). These initial findings evaluated association only and did not assess improvement in predictive modeling. More recent studies include a matched case-control study of 135 patients with advanced CKD (18), a cohort study of 260 Native Americans (21), and an observational study of >3000 participants with preexisting CKD enrolled in the Chronic Renal Insufficiency Cohort Study (CRIC) (19). Like our study, each uniformly failed to demonstrate useful improvement in clinical prediction models that included demographic factors, eGFR, and proteinuria. Similarly, CRIC also reported a high C-statistic for a base model alone (19). The results of these studies varied with respect to independent associations of biomarker concentrations with CKD progression. Limitations of these studies include small sample sizes and heterogeneous populations with diverse causes of CKD. Additionally, only single biomarker concentrations rather than changes over time or multimarker models were analyzed.

This analysis builds on prior results by providing data from the largest cohort of individuals with diabetes and acute coronary syndrome studied to date. In contrast to CRIC, we analyzed individuals with and without preexisting CKD. Baseline Cystatin C was independently associated with CKD. Although the degree of improvement was marginal, it supports the clinical utility of novel glomerular filtration markers in predicting eGFR decline when serum creatinine alone is unreliable, and suggests that glomerular filtration markers may be more helpful than tubular injury markers in predicting kidney function decline. This is biologically plausible because a low GFR at baseline may reasonably be expected to be a better discriminator of further GFR loss than concomitant tubular injury.

Our study is unique in measuring longitudinal changes of urinary biomarkers. The apparent decrease in biomarker concentration over time must be interpreted cautiously given that only 75% of subjects had measurements at both baseline and 6 months. This decline could represent recovery of kidney function after hemodynamic insult and contrast during the initial hospitalization. However, assay drift is unlikely given that biomarkers were batch analyzed.

Higher uNGAL and uKIM-1 over 6 months were positively associated with an increase in the risk of eGFR decline in crude models, but only the change in uNGAL at 6 months was independently associated with progression. These findings are consistent with a small study of critically ill patients with severe AKI requiring RRT in whom a decline in uNGAL was associated with improved risk prediction and increased odds of kidney recovery (28). Previous studies have not reported on serial measurements; thus, it is unknown whether a 6-month change in urinary biomarker concentration is a sufficiently long interval to assess for associations with eGFR decline. Additional studies are needed to expand upon these findings.

The lower proportion of incident micro- and macroalbuminuria detected in individuals with greater increases in uNGAL and uKIM-1 was unexpected. This may be attributable to the positive correlation with higher baseline urinary albumin excretion in individuals with higher baseline biomarker concentrations diminishing the relative change across quartiles. Many confounding factors influence changes in proteinuria and the ability to accurately capture these changes over time. It is well known that albuminuria fluctuates randomly or in association with hemodynamic changes, kidney insults, and medication management. These points are especially relevant in this cohort of patients with diabetes with recent hospitalization for acute coronary syndrome (29). Additionally, a high proportion of individuals were on renin-angiotensin inhibitors at baseline. These agents were continued in most subjects throughout follow-up (30) and are therefore less likely to influence the results. Lastly, these results should be interpreted cautiously given the high percentage of missing data on urinary albumin excretion.

Strengths of this study include the large population of high-risk individuals with type 2 diabetes and recent acute coronary syndrome in which it is reasonable to expect a sufficient proportion to experience eGFR decline. Additionally, the majority of individuals had baseline eGFR>20 ml/min per 1.73 m². At this level of eGFR baseline biomarkers and their change over time should be predictive of eGFR decline. Several limitations should also be noted. Only 98 individuals (1.8%) had CKD progression and the median follow-up was 1.5 years. A small proportion of subjects that reached the end point had baseline eGFR<20 ml/min per 1.73 m². Although measurement error could have contributed to these end points, this is unlikely given that the majority required dialysis. Similarly, an even smaller subgroup of subjects with a baseline eGFR<15 ml/min per 1.73 m² reached the end point due to the initiation of dialysis alone. The initiation of chronic dialysis is a clinical decision influenced by symptoms of uremia, comorbidities, and patient preferences. The inherent subjectivity of this end point relative to the more objective end point of achieving an eGFR<15 ml/min per 1.73 m² or 50% decline in eGFR is an additional limitation that may have limited the potential of biomarkers to predict the outcome. Previous studies of biomarkers reported event rates as high as 32% (20). However, this study was in a small cohort of white Europeans with severe baseline CKD and a high proportion of GN who were followed for >1.5 years (20), whereas event rates were 20% after 3.2 years of follow up in CRIC (19). Although we identified nearly 100 events, the relatively low event rate suggests that most individuals had relatively stable nephropathy without significant baseline kidney disease. Our findings are thus best interpreted within the context of similarly low-risk populations of individuals with and without CKD and may not be generalizable to populations at high risk of eGFR decline.

Both the severity and cause of CKD have been shown to influence baseline and change in biomarkers (11). Biomarkers, especially uNGAL, may be differentially elevated in IgA nephropathy, autosomal dominant polycystic kidney disease, and diabetic nephropathy (11). Although our study population was uniformly diagnosed with diabetes, whether diabetes was responsible for eGFR decline in all cases is uncertain. Lastly, data on proteinuria was missing in a high proportion and biomarker concentrations were available at 6 months in only 75%. Although missing values were imputed and results should be unbiased, this procedure could have introduced error.

In summary, this study of individuals with type 2 diabetes and recent acute coronary syndrome provides further evidence that clinical prediction models of standard clinical risk factors, eGFR, and proteinuria robustly predict eGFR decline. Although novel biomarkers may provide clinical utility in prediction of decline in eGFR in other settings such as AKI or glomerular disease, our data suggest that single or repeated measures of novel kidney biomarkers of glomerular filtration and tubular injury offer at most minimal incremental prognostic value for the short-term prediction of eGFR decline in type 2 diabetes. Additional data from diverse populations on serial measures of kidney biomarkers over time are needed to further assess utility in risk stratification and prediction modeling.