Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients

• Published in: EBioMedicine Vol. 26; no. C; pp. 68 - 77
• Main Authors: Hallan, Stein, Afkarian, Maryam, Zelnick, Leila R., Kestenbaum, Bryan, Sharma, Shoba, Saito, Rintaro, Darshi, Manjula, Barding, Gregory, Raftery, Daniel, Ju, Wenjun, Kretzler, Matthias, Sharma, Kumar, de Boer, Ian H.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-12-2017; Elsevier
• Subjects: Aconitic Acid - metabolism; Aged; Biopsy; Chronic kidney disease; Citric acid cycle; Citric Acid Cycle - genetics; Female; Gene expression; Gene Expression Regulation - genetics; Humans; Isocitrates - metabolism; Ketoglutaric Acids - metabolism; Kidney - metabolism; Kidney - pathology; Male; Metabolic Networks and Pathways - genetics; Metabolomics; Middle Aged; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - pathology; Renal Insufficiency, Chronic - urine; Research Paper; Succinic Acid - metabolism; Metabolomics; Citric acid cycle; Mitochondria; Chronic kidney disease; Gene expression
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.10.027

Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3–4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range−68% to +113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40–68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+74%, p=0.00009) and plasma 2-oxoglutarate concentrations (+12%, p=0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction.
•Urinary excretion rate and plasma concentration of 60 metabolites differed significantly in CKD patients versus controls.•Pathway analysis revealed that the citric acid cycle was the most significantly affected.•Expression of genes regulating TCA cycle was significantly reduced in kidney biopsies.
Chronic kidney disease (CKD) is very common and carries a high risk of complications and death. Patients with advanced disease have severe fatigue, organ dysfunction beyond the kidneys, and disturbances in sugar, protein and fat metabolism. We found many metabolites that differed significantly in kidney patients versus healthy controls. Analysis revealed that the citric acid cycle was the most significantly affected metabolic pathway. The citric acid cycle is performed in the cells` mitochondria and is the central metabolic hub where fuel molecules are converted into energy. This supports the view of CKD as a state of mitochondrial dysfunction.