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

KEY POINTS: The pathophysiological mechanisms of diabetic kidney disease (DKD) with normal (nonalbuminuric DKD) versus moderately increased albuminuria (A-DKD) are not well-understood. Fatty acid biosynthesis and oxydation, gluconeogenesis, TCA cycle, and glucose-alanine cycle were more disturbed in patients with A-DKD compared with those with nonalbuminuric DKD with identical eGFR. DKD patients with and without microalbuminuria could represent different clinical phenotypes. BACKGROUND: The pathophysiological mechanisms of diabetic kidney disease (DKD) with normal versus moderately increased albuminuria (nonalbuminuric DKD [NA-DKD] and A-DKD) are currently not well-understood and could have implications for diagnosis and treatment. METHODS: Fourteen patients with NA-DKD with urine albumin–creatinine ratio <3 mg/mmol, 26 patients with A-DKD with albumin–creatinine ratio 3–29 mg/mmol, and 60 age- and sex-matched healthy controls were randomly chosen from a population-based cohort study (Nord-Trøndelag Health Study-3, Norway). Seventy-four organic acids, 21 amino acids, 21 biogenic acids, 40 acylcarnitines, 14 sphingomyelins, and 88 phosphatidylcholines were quantified in urine. One hundred forty-six patients with diabetes from the US-based Chronic Renal Insufficiency Cohort study were used to verify main findings. RESULTS: Patients with NA-DKD and A-DKD had similar age, kidney function, diabetes treatment, and other traditional risk factors. Still, partial least-squares discriminant analysis showed strong metabolite-based separation (R(2), 0.82; Q(2), 0.52), with patients with NA-DKD having a metabolic profile positioned between the profiles of healthy controls and patients with A-DKD. Seventy-five metabolites contributed significantly to separation between NA-DKD and A-DKD (variable importance in projection scores ≥1.0) with propionylcarnitine (C3), phosphatidylcholine C38:4, medium-chained (C8) fatty acid octenedioic acid, and lactic acid as the top metabolites (variable importance in projection scores, 2.7–2.2). Compared with patients with NA-DKD, those with A-DKD had higher levels of short-chained acylcarnitines, higher long-chained fatty acid levels with more double bounds, higher branched-chain amino acid levels, and lower TCA cycle intermediates. The main findings were similar by random forest analysis and in the Chronic Renal Insufficiency Cohort study. Formal enrichment analysis indicated that fatty acid biosynthesis and oxydation, gluconeogenesis, TCA cycle, and glucose-alanine cycle were more disturbed in patients with A-DKD compared with those with NA-DKD with identical eGFR. We also found indications of a Warburg-like effect in patients with A-DKD (i.e., metabolism of glucose to lactate despite adequate oxygen). CONCLUSION: DKD patients with normoalbuminuria differ substantially in their metabolic disturbances compared with patients with moderately increase albuminuria and could represent different clinical phenotypes.