P1000URINE MYO-INOSITOL AS A NOVEL PROGNOSTIC BIOMARKER FOR DIABETIC KIDNEY DISEASE

Abstract

Abstract Background and Aims Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESRD). Metabolomics has been increasingly applied to identify the cause of CKD, as it can present epigenetics and suggest corresponding treatment options. Only a few metabolomics studies were conducted in DKD patients, and the results are inconclusive. We investigated the association between urine metabolites and renal disease progression and mortality in DKD, using 800 MHz NMR spectroscopy based targeted metabolomics profiling. Method Prospectively stored urine samples from consecutive patients with DKD stage 1 to 5 (n=208) and their healthy controls (n=26) were analyzed. Cross-sectional associations were evaluated between eGFR or urine protein creatinine ratio (UPCR) and 26 urinary metabolites. Multivariable adjusted Cox models were conducted for the risk prediction of ESRD and mortality. The receiver-operating characteristic (ROC) analyses were used to assess the additive effect of each metabolite to predict the progression to ESRD. Results ESRD occurred in 103 (44.0%) patients and 65 (27.8%) deaths occurred during median 4.5 years (IQR, 2.06–6.58) follow-up period. The median fold change in 9 metabolites (glucose, mannose, myo-inositol, glycerol, lactate, fumarate, creatine, taurine and choline) in patient group revealed a trend corresponding to DKD stages. Linear regression showed that myo-inositol had a strongest association with eGFR. The relationship between the competitive metabolites and outcomes (ESRD and mortality) was investigated by multivariate Cox models after adjusting for the baseline covariates. Of these, 4 metabolites (myo-inositol, glycerol, fumarate, oxoisocaproate) had predictive values for ESRD, and among them, only myo-inositol retained predictive significance in mortality (adjusted HR 1.004, 95% confidence interval 1.002-1.006, P < 0.001). At ROC analysis, urinary myo-inositol had additive effect to serum creatinine concentration and UPCR in the prediction for ESRD progression (NRI = 2.9%, P = 0.03; IDI = 35.1%, P = 0.02). Conclusion These results suggest that myo-inositol can be a predictive biomarker for the risk of ESRD progression and mortality in DKD. Further studies are needed to elucidate the pathophysiological roles of myo-inositol in DKD.