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Metabolic pathways and immunometabolism in rare kidney diseases
  1. Peter C Grayson1,2,
  2. Sean Eddy3,4,
  3. Jaclyn N Taroni2,5,
  4. Yaíma L Lightfoot1,
  5. Laura Mariani3,4,
  6. Hemang Parikh2,6,
  7. Maja T Lindenmeyer7,
  8. Wenjun Ju3,4,
  9. Casey S Greene2,5,
  10. Brad Godfrey3,4,
  11. Clemens D Cohen7,
  12. Jeffrey Krischer2,6,
  13. Matthias Kretzler3,4,
  14. Peter A Merkel2,8
  15. the Vasculitis Clinical Research Consortium, the European Renal cDNA Bank cohort, and the Nephrotic Syndrome Study Network
  1. 1Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National Institutes of Health/NIAMS, Bethesda, Maryland, USA
  2. 2Vasculitis Clinical Research Consortium, Philadelphia, Pennsylvania, USA
  3. 3Division of Nephrology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
  4. 4Nephrotic Syndrome Study Network Consortia, Ann Arbor, Michigan, USA
  5. 5Department 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. 6Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
  7. 7Nephrological Center Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany
  8. 8Division of Rheumatology and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Peter C Grayson, National Institutes of Health, Bethesda, MD 20892, USA; peter.grayson{at}nih.gov

Abstract

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.

  • systemic vasculitis
  • lupus nephritis
  • granulomatosis with polyangiitis

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors PCG, SE, JK, MK and PAM designed the study. YLL, MTL, W-JJ, BG, CDC collected the data and performed the experiments. PCG, SE, JNT, HP, CSG, JK, MK and PAM performed the statistical analysis. PCG, SE, JNT, YLL, LM, HP, CSG, JK, MK and PAM analysed the data. PCG, SE, JNT, YLL, JK, MK and PAM wrote the manuscript. All authors approved the final version of the manuscript.

  • Funding The Vasculitis Clinical Research Consortium (VCRC), U54 AR057319, and the Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54 DK083912, are part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research (ORDR), NCATS and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). This research was also supported through the Intramural Research Program at the NIAMS. Additional funding and/or programmatic support for this project has also been provided by the Else Kröner-Fresenius Foundation (ERCB), VCRC, University of Michigan, the NephCure Kidney International and the Halpin Foundation and the Applied Systems Biology Core at the University of Michigan George M O’Brien Kidney Translational Core Center. Dr Taroni is supported by the University of Pennsylvania Training Program in Rheumatic Diseases (NIAMS T32AR007442).

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval The study was approved by the ethics committees for the European Renal cDNA Bank (ERCB) and the Nephrotic Syndrome Study Network Consortium (NEPTUNE). Ethics approval for the gene expression studies was provided by the University of Michigan (HUM0002468).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement CEL files are accessible in GEO under reference numbers: GSE104948, GSE104954 and GSE108113.

  • Presented at Part of this manuscript was presented at the 2016 ACR/ARHP Annual Meeting.

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