ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 3045

Immunometabolism in ANCA-Associated Glomerulonephritis

Peter C. Grayson1, Sean Eddy2, Viji Nair2, Hemang Parikh3, Maja Lindenmeyer4, Laura Mariani2, Huateng Huang2, Wenjun Ju3, Casey Greene5, Clemens Cohen4, Jeffrey Krischer3, Matthias Kretzler2, Peter A. Merkel6 and Felix H. Eichinger2, 1National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 2Division of Nephrology, University of Michigan, Ann Arbor, MI, 3University of South Florida, Tampa, FL, 4University of Munich, Munich, Germany, 5Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 6Division of Rheumatology, University of Pennsylvania, Philadelphia, PA

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: , , ,

Session Information

Date: Tuesday, November 15, 2016

Title: Vasculitis III: Pathogenic Mechanisms

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Mounting an inflammatory response requires immune cells to undergo major changes in metabolism. Mediators such as cytokines can specifically alter the metabolism of different immune cell populations, thereby influencing the inflammatory response. This study characterized global patterns of immunometabolic response in renal tissue from patients with ANCA-associated vasculitis (AAV).

Methods: The study population consisted of patients with AAV (granulomatosis with polyangiitis and microscopic polyangiitis) recruited from the European Renal cDNA Bank (ERCB) cohort (n=80), patients with nephrotic syndrome recruited from the ERCB (n=61), patients from a North American based cohort (n=126); and healthy living kidney donors (n=37). Kidney biopsies performed as routine clinical care were micro-dissected into glomerular and tubulointerstitial compartments. Whole genome gene-expression profiling across the two tissue compartments was conducted on Affymetrix microarray platforms. 104 genes representing the critical enzymes of glucose metabolism and 26 genes related to specific immune cell populations were selected for analysis. Differential gene expression was compared between patients with AAV and both living donors and patients with nephrotic syndrome. Correlation analyses were performed to study potential relationships between genes related to metabolic response and genes related to immune response. A false discovery rate (FDR) of <0.05 defined statistical significance.

Results: Every enzyme in the pentose phosphate pathway (e.g. G6PD) and key regulatory genes of glycolysis (e.g. enolases, hexokinases) were significantly upregulated in the glomerular and tubulointerstitial compartments from patients with AAV compared to controls and patients with nephrotic syndrome. Glucose transporter receptor expression significantly differed among patients with AAV and comparators. Genes related to the Krebs cycle, glutaminolysis, and fatty acid oxidation were significantly downregulated in kidney samples from patients with AAV. Several immune response genes were differentially upregulated in kidney biopsies from patients with AAV, most strikingly macrophage-related markers (e.g. CD14, CD68, CD163). Strong correlations (r= 0.45-0.82; p<1.0E-07) were observed in the glomerular compartment between specific pentose phosphate pathway enzymes (G6PD, TKT), enzymes that regulate glycolysis (PKM, PFKFB3), and macrophage-related markers (CD14, CD68).

Conclusion: Distinct alterations in cellular metabolism are observed in the renal transcriptome from patients with ANCA-associated glomerulonephritis, reflective of metabolic reprogramming. Global patterns of gene expression suggest increased utilization of glucose and decreased oxidative phosphorylation in patients with AAV relative to comparators. The strong correlation between markers of glycolysis and macrophage-related markers suggest that altered immunometabolism may play a role in the pathophysiology of kidney disease in AAV. Modulation of glucose metabolism may offer a novel approach to treatment of AAV.

Disclosure: P. C. Grayson, None; S. Eddy, TheromFisher, Abbvie, Merck, Lilly, Pfizer, Gilead, 1; V. Nair, None; H. Parikh, None; M. Lindenmeyer, None; L. Mariani, None; H. Huang, None; W. Ju, None; C. Greene, None; C. Cohen, None; J. Krischer, None; M. Kretzler, None; P. A. Merkel, Bristol Myers Squibb, 2,CaridianBCT, 2,Celgene, 2,Chemocentryx, 2,Genentech/Roche, 2,GlaxoSmithKline, 2,Kypha, 2,Bristol-Myers Squibb, 5,Chemocentryx, 5,Genentech/Roche, 5,GlaxoSmithKline, 5,PrinicipioBio, 5,Auven, 5,Proteon Therapeutics, 5; F. H. Eichinger, None.

To cite this abstract in AMA style:

Grayson PC, Eddy S, Nair V, Parikh H, Lindenmeyer M, Mariani L, Huang H, Ju W, Greene C, Cohen C, Krischer J, Kretzler M, Merkel PA, Eichinger FH. Immunometabolism in ANCA-Associated Glomerulonephritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/immunometabolism-in-anca-associated-glomerulonephritis/. Accessed .

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