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Metabolic pathways and immunometabolism in rare kidney diseases

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Grayson PC1,2, Eddy S3,4, Taroni JN2,5, Lightfoot YL1, Mariani L3,4, Parikh H2,6, Lindenmeyer MT7, Ju W3,4, Greene CS2,5, Godfrey B3,4, Cohen CD7, Krischer J2,6, Kretzler M3,4, Merkel PA2,8; Vasculitis Clinical Research Consortium, the European Renal cDNA Bank cohort, and the Nephrotic Syndrome Study Network. Ann Rheum Dis. 2018 Aug;77(8):1226-1233. doi: 10.1136/annrheumdis-2017-212935. Epub 2018 May 3.


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1 Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National Institutes of Health/NIAMS, Bethesda, Maryland, USA.

2 Vasculitis Clinical Research Consortium, Philadelphia, Pennsylvania, USA.

3 Division of Nephrology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

4 Nephrotic Syndrome Study Network Consortia, Ann Arbor, Michigan, USA.

5 Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6 Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.

7 Nephrological Center Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany.

8 Division of Rheumatology and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.


OBJECTIVES: To characterise renal tissue metabolic pathway gene expression in different forms of glomerulonephritis.

METHODS: Patients with nephrotic syndrome (NS), antineutrophil cytoplasmic antibody-associated vasculitis (AAV), systemic lupus erythematosus (SLE) and healthy living donors (LD) were studied. Clinically indicated renal biopsies were obtained at time of diagnosis and microdissected into glomerular and tubulointerstitial compartments. Microarray-derived differential gene expression of 88 genes representing critical enzymes of metabolic pathways and 25 genes related to immune cell markers was compared between disease groups. Correlation analyses measured relationships between metabolic pathways, kidney function and cytokine production.

RESULTS: Reduced steady state levels of mRNA species were enriched in pathways of oxidative phosphorylation and increased in the pentose phosphate pathway (PPP) with maximal perturbation in AAV and SLE followed by NS, and least in LD. Transcript regulation was isozymes specific with robust regulation in hexokinases, enolases and glucose transporters. Intercorrelation networks were observed between enzymes of the PPP (eg, transketolase) and macrophage markers (eg, CD68) (r=0.49, p<0.01). Increased PPP transcript levels were associated with reduced glomerular filtration rate in the glomerular (r=-0.49, p<0.01) and tubulointerstitial (r=-0.41, p<0.01) compartments. PPP expression and tumour necrosis factor activation were tightly co-expressed (r=0.70, p<0.01).

CONCLUSION: This study demonstrated concordant alterations of the renal transcriptome consistent with metabolic reprogramming across different forms of glomerulonephritis. Activation of the PPP was tightly linked with intrarenal macrophage marker expression, reduced kidney function and increased production of cytokines. Modulation of glucose metabolism may offer novel immune-modulatory therapeutic approaches in rare kidney diseases.