Serum kidney injury molecule 1 and β2-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes

Abstract

Aims/hypothesisAs part of the Surrogate Markers for Micro- and Macrovascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) programme we previously reported that large panels of biomarkers derived from three analytical platforms maximised prediction of progression of renal decline in type 2 diabetes. Here, we hypothesised that smaller (n ≤ 5), platform-specific combinations of biomarkers selected from these larger panels might achieve similar prediction performance when tested in three additional type 2 diabetes cohorts.MethodsWe used 657 serum samples, held under differing storage conditions, from the Scania Diabetes Registry (SDR) and Genetics of Diabetes Audit and Research Tayside (GoDARTS), and a further 183 nested case–control sample set from the Collaborative Atorvastatin in Diabetes Study (CARDS). We analysed 42 biomarkers measured on the SDR and GoDARTS samples by a variety of methods including standard ELISA, multiplexed ELISA (Luminex) and mass spectrometry. The subset of 21 Luminex biomarkers was also measured on the CARDS samples. We used the event definition of loss of >20% of baseline eGFR during follow-up from a baseline eGFR of 30–75 ml min−1 [1.73 m]−2. A total of 403 individuals experienced an event during a median follow-up of 7 years. We used discrete-time logistic regression models with tenfold cross-validation to assess association of biomarker panels with loss of kidney function.ResultsTwelve biomarkers showed significant association with eGFR decline adjusted for covariates in one or more of the sample sets when evaluated singly. Kidney injury molecule 1 (KIM-1) and β2-microglobulin (B2M) showed the most consistent effects, with standardised odds ratios for progression of at least 1.4 (p < 0.0003) in all cohorts. A combination of B2M and KIM-1 added to clinical covariates, including baseline eGFR and albuminuria, modestly improved prediction, increasing the area under the curve in the SDR, Go-DARTS and CARDS by 0.079, 0.073 and 0.239, respectively. Neither the inclusion of additional Luminex biomarkers on top of B2M and KIM-1 nor a sparse mass spectrometry panel, nor the larger multiplatform panels previously identified, consistently improved prediction further across all validation sets.Conclusions/interpretationSerum KIM-1 and B2M independently improve prediction of renal decline from an eGFR of 30–75 ml min−1 [1.73 m]−2 in type 2 diabetes beyond clinical factors and prior eGFR and are robust to varying sample storage conditions. Larger panels of biomarkers did not improve prediction beyond these two biomarkers.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4741-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Comparison of serum and urinary biomarker panels with albumin/creatinine ratio in the prediction of renal function decline in type 1 diabetes

“…The key findings from this study across the range of CKD stages were that serum biomarkers improve the prediction of future eGFR and progression to <30 ml min −1 [1.73 m] −2 beyond baseline eGFR. As in our past studies [11,21,22], a large number of the biomarkers evaluated showed highly significant associations with eGFR and its decline. However, almost all of the predictive information could be obtained using just a few of these intercorrelated biomarkers.…”

Prognostic value of serum and urine kidney injury molecule-1 in infants with urinary tract infection

“…Reference intervals for sKIM-1 are lacking for healthy individuals. McWiliams et al reported also diurnal variation of uKIM-1 levels, with higher values in the morning than in the evening [30]. In contrast, we found negative correlation of uKIM-1 with age.…”

“…In humans, the usefulness of blood (serum/plasma) KIM-1 was documented in AKI and CKD [21,26,28]. Circulating KIM-1 strongly predicted progression of CKD in patients with type 1 and type 2 diabetes [26,29,30] and was useful in allograft nephropathy [31]. A recent study by Schultz et al has also shown that pKIM-1 may predict the future decline of estimated glomerular filtration rate (eGFR) and risk of CKD in healthy middle-aged participants [32].…”

Precision medicine in type 2 diabetes

“…for this purpose. Most of tested new biomarkers, for example CRP, ferritin, adiponectin, fetuin, have predicted progression of hepatosteatosis or CVD , whereas others like KIM‐1 (kidney injury molecule 1) and B2M (β 2 ‐microglobulin) have predicted a rapid decline in kidney function . However, the overall effect of such markers on top of eGFR has been modest .…”