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

Marco Colombo,Samira Bell,David Dunger,Fiona Green,Stuart J Mcgurnaghan,Luke A K Blackbourn,John R Petrie,Paul M Mckeigue,John Chalmers,Andrew Collier,John A Mcknight,R Neil Dalton,Sandra Macrury,Helen M Colhoun

doi:10.1007/s00125-019-05081-8

Abstract

Aims/hypothesisWe examined whether candidate biomarkers in serum or urine can improve the prediction of renal disease progression in type 1 diabetes beyond prior eGFR, comparing their performance with urinary albumin/creatinine ratio (ACR).MethodsFrom the population-representative Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) we sampled 50% and 25% of those with starting eGFR below and above 75 ml min−1 [1.73 m]−2, respectively (N = 1629), and with median 5.1 years of follow-up. Multiplexed ELISAs and single molecule array technology were used to measure nine serum biomarkers and 13 urine biomarkers based on our and others’ prior work using large discovery and candidate studies. Associations with final eGFR and with progression to <30 ml min−1 [1.73] m−2, both adjusted for baseline eGFR, were tested using linear and logistic regression models. Parsimonious biomarker panels were identified using a penalised Bayesian approach, and their performance was evaluated through tenfold cross-validation and compared with using urinary ACR and other clinical record data.ResultsSeven serum and seven urine biomarkers were strongly associated with either final eGFR or progression to <30 ml min−1 [1.73 m]−2, adjusting for baseline eGFR and other covariates (all at p<2.3 × 10−3). Of these, associations of four serum biomarkers were independent of ACR for both outcomes. The strongest associations with both final eGFR and progression to <30 ml min−1 [1.73 m]−2 were for serum TNF receptor 1, kidney injury molecule 1, CD27 antigen, α-1-microglobulin and syndecan-1. These serum associations were also significant in normoalbuminuric participants for both outcomes. On top of baseline covariates, the r2 for prediction of final eGFR increased from 0.702 to 0.743 for serum biomarkers, and from 0.702 to 0.721 for ACR alone. The area under the receiver operating characteristic curve for progression to <30 ml min−1 [1.73 m]−2 increased from 0.876 to 0.953 for serum biomarkers, and to 0.911 for ACR alone. Other urinary biomarkers did not outperform ACR.Conclusions/interpretationA parsimonious panel of serum biomarkers easily measurable along with serum creatinine may outperform ACR for predicting renal disease progression in type 1 diabetes, potentially obviating the need for urine testing.

Highlights

To facilitate the early identification of those most at risk of decline in future renal function, most clinical guidelines recommend the use of regular serum creatinine measurement and equations such as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) or Modification of Diet in Renal Disease (MDRD) equations for estimation of GFR [1]
Following on from that study, we extended the evaluation to (1) include study participants with higher starting eGFRs; (2) measure the best biomarkers from our first study i.e. KIM1 and CD27, and measure new candidate biomarkers chosen from recent reports from large well-conducted studies; and (3) evaluate a more sensitive serum kidney injury molecule 1 (KIM-1) assay using single molecule array (SIMOA) technology, hypothesising that it would be detectable before microalbuminuria in those progressing to renal function decline
The median change in eGFR was a fall of 0.8 ml min−1 [1.73 m]−2 per year

Summary

Introduction

To facilitate the early identification of those most at risk of decline in future renal function, most clinical guidelines recommend the use of regular serum creatinine measurement and equations such as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) or Modification of Diet in Renal Disease (MDRD) equations for estimation of GFR [1]. Guidelines advocate regular urinary testing for albumin/creatinine ratio (ACR) since there is extensive evidence that albuminuria is a strong risk factor for progression of diabetic kidney disease (DKD). It has been widely discussed that ACR lacks specificity and sensitivity for progressive decline in eGFR. In Scotland, for example, while 86% of those with type 1 diabetes had eGFR in the past year, only 62% had ACR measured [10]

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Conclusion