Metabolic Differences in Diabetic Kidney Disease Patients with Normoalbuminuria versus Moderately Increased Albuminuria.

Abstract

The pathophysiological mechanisms of diabetic kidney disease with normal versus moderately increased albuminuria (NA-DKD and A-DKD) are currently not well understood and could have implications for diagnosis and treatment. 14 NA-DKD patients with urine albumin/creatinine ratio <3mg/mmol, 26 A-DKD patients with albumin/creatinine ratio 3-29mg/mmol, and 60 age- and sex-matched healthy controls were randomly chosen from a population-based cohort study (HUNT-3, Norway). 74 organic acids, 21 amino acids, 21 biogenic acids, 40 acylcarnitines, 14 sphingomyelins, and 88 phosphatidylcholines were quantified in urine. 146 diabetic patients from the US-based CRIC study were used to verify main findings. NA-DKD and A-DKD had similar age, kidney function, diabetes treatment and other traditional risk factors. Still, partial least-square discriminant analysis (PLS-DA) showed strong metabolite-based separation (R2 0.82, Q2 0.52) with NA-DKD positioned between healthy controls and A-DKD patients. 75 metabolites contributed significantly to separation between NA-DKD and A-DKD (VIP scores ≥1.0) with propionyl-carnitine (c3), phosphatidylcholine C38:4, medium-chained (C8) fatty acid octenedioic acid, and lactic acid as top metabolites (VIP scores 2.7-2.2). Compared to NA-DKD, A-DKD had higher short-chained acylcarnitines, higher long-chained fatty acids with more double-bounds, higher branched-chain amino acids, and lower TCA-cycle intermediates. Main findings were similar by random-forest analysis and in the CRIC cohort. Formal enrichment analysis indicated that fatty acid biosynthesis and oxydation, gluconeogenesis, TCA cycle, and glucose-alanine cycle were more disturbed in A-DKD patients compared to NA-DKD with identical eGFR. We also found indications of a Warburg-like effect in A-DKD, i.e., metabolism of glucose to lactate despite adequate oxygen. DKD patients with normo-albuminuria differ substantially in their metabolic disturbances compared to patients with moderately increase albuminuria and could represent different clinical phenotypes.