Markus Sellmayr1, Moritz Roman Hernandez Petzsche1, Qiuyue Ma2, Nils Krüger1, Helen Liapis3, Andreas Brink4, Barbara Lenz4, Maria Lucia Angelotti5, Viviane Gnemmi6, Christoph Kuppe7, Hyojin Kim8, Eric Moniqué Johannes Bindels9, Ferenc Tajti7,8, Julio Saez-Rodriguez8,10, Maciej Lech1, Rafael Kramann7,11, Paola Romagnani5,12, Hans-Joachim Anders2, Stefanie Steiger2. 1. Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany. 2. Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany stefanie.steiger@med.uni-muenchen.de hjanders@med.uni-muenchen.de. 3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri (retired) and Arkana Laboratories, Little Rock, Arkansas. 4. Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 5. Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy. 6. Department of Pathology, University Hospital, Centre Hospitalier Régional Universitaire, Lille, France. 7. Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany. 8. Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule, Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany. 9. Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands. 10. Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University, and Heidelberg University Hospital, Heidelberg, Germany. 11. Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands. 12. Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy.
Abstract
BACKGROUND: The roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (1) asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (2) UA crystal granulomas may form due to pre-existing CKD; and (3) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression. METHODS: MALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD. RESULTS: Asymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective. CONCLUSIONS: Asymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.
BACKGROUND: The roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (1) asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (2) UAcrystal granulomas may form due to pre-existing CKD; and (3) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression. METHODS: MALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD. RESULTS: Asymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UAcrystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosineattenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective. CONCLUSIONS: Asymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UAcrystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.
Authors: Avi Goldberg; Fernando Garcia-Arroyo; Fumihiko Sasai; Bernardo Rodriguez-Iturbe; Laura Gabriela Sanchez-Lozada; Miguel A Lanaspa; Richard J Johnson Journal: Am J Nephrol Date: 2021-10-21 Impact factor: 4.605
Authors: Lisa K Stamp; Hamish Farquhar; Huai Leng Pisaniello; Ana B Vargas-Santos; Mark Fisher; David B Mount; Hyon K Choi; Robert Terkeltaub; Catherine L Hill; Angelo L Gaffo Journal: Nat Rev Rheumatol Date: 2021-07-30 Impact factor: 20.543