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Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease

Markus Sellmayr, Moritz Roman Hernandez Petzsche, Qiuyue Ma, Nils Krüger, Helen Liapis, Andreas Brink, Barbara Lenz, Maria Lucia Angelotti, Viviane Gnemmi, Christoph Kuppe, Hyojin Kim, Eric Moniqué Johannes Bindels, Ferenc Tajti, Julio Saez-Rodriguez, Maciej Lech, Rafael Kramann, Paola Romagnani, Hans-Joachim Anders and Stefanie Steiger
JASN December 2020, 31 (12) 2773-2792; DOI: https://doi.org/10.1681/ASN.2020040523
Markus Sellmayr
1Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
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Moritz Roman Hernandez Petzsche
1Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
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Qiuyue Ma
1Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
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Nils Krüger
1Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
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Helen Liapis
2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri (retired) and Arkana Laboratories, Little Rock, Arkansas
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Andreas Brink
3Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
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Barbara Lenz
3Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
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Maria Lucia Angelotti
4Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
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Viviane Gnemmi
5Department of Pathology, University Hospital, Centre Hospitalier Régional Universitaire, Lille, France
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Christoph Kuppe
6Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
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Hyojin Kim
7Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule, Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany
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Eric Moniqué Johannes Bindels
8Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands
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Ferenc Tajti
6Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
7Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule, Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany
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Julio Saez-Rodriguez
7Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule, Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany
9Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University, and Heidelberg University Hospital, Heidelberg, Germany
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Maciej Lech
1Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
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Rafael Kramann
6Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
10Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
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Paola Romagnani
4Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
11Nephrology and Dialysis Unit, Meyer Children’s University Hospital, Florence, Italy
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Hans-Joachim Anders
1Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
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Stefanie Steiger
1Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
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Significance Statement

The role of asymptomatic hyperuricemia in the progression of CKD has been unclear due to lack of animal models with clinically relevant uric acid (UA) levels. A new mouse model reveals that persistent asymptomatic hyperuricemia (approximately 15 mg/dl) does not cause CKD, nor accelerate progression, unless UA crystallizes in acidic tubular fluid. Crystallization initially causes tubular injury, inflammation, and interstitial fibrosis, and subsequently granulomatous interstitial nephritis with perilesional proinflammatory M1-like macrophage infiltrates. Modulating the M1-like macrophage phenotype, but not JAK/STAT inhibition, attenuates granulomatous nephritis.

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.

  • uric acid
  • granuloma
  • macrophages
  • inflammation
  • fibrosis
  • chronic kidney disease
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (12)
Journal of the American Society of Nephrology
Vol. 31, Issue 12
December 2020
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Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease
Markus Sellmayr, Moritz Roman Hernandez Petzsche, Qiuyue Ma, Nils Krüger, Helen Liapis, Andreas Brink, Barbara Lenz, Maria Lucia Angelotti, Viviane Gnemmi, Christoph Kuppe, Hyojin Kim, Eric Moniqué Johannes Bindels, Ferenc Tajti, Julio Saez-Rodriguez, Maciej Lech, Rafael Kramann, Paola Romagnani, Hans-Joachim Anders, Stefanie Steiger
JASN Dec 2020, 31 (12) 2773-2792; DOI: 10.1681/ASN.2020040523

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Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease
Markus Sellmayr, Moritz Roman Hernandez Petzsche, Qiuyue Ma, Nils Krüger, Helen Liapis, Andreas Brink, Barbara Lenz, Maria Lucia Angelotti, Viviane Gnemmi, Christoph Kuppe, Hyojin Kim, Eric Moniqué Johannes Bindels, Ferenc Tajti, Julio Saez-Rodriguez, Maciej Lech, Rafael Kramann, Paola Romagnani, Hans-Joachim Anders, Stefanie Steiger
JASN Dec 2020, 31 (12) 2773-2792; DOI: 10.1681/ASN.2020040523
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Keywords

  • uric acid
  • granuloma
  • macrophages
  • inflammation
  • fibrosis
  • chronic kidney disease

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