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Kidney Week

Abstract: TH-PO491

The Role of Renal Uric Acid Crystal Granulomas on CKD Progression in Mice and Humans

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Steiger, Stefanie, Hospital of the LMU Munich, Munich, Germany
  • Sellmayr, Markus, Hospital of the LMU Munich, Munich, Germany
  • Hernandez Petzsche, Moritz R., Hospital of the LMU Munich, Munich, Germany
  • Ma, Qiuyue, Hospital of the LMU Munich, Munich, Germany
  • Anders, Hans J., Hospital of the LMU Munich, Munich, Germany
Background

Tophaceous uric acid (UA) deposits are occasionally found on diagnostic kidney biopsies. Whether UA crystal granulomas are a cause or bystander of CKD is subject of debate. We hypothesized that renal UA granulomas associate with more severe interstitial fibrosis; therefore contribute to CKD progression. UA granulomas are mainly comprised of M1-macrophages. We thought to target a phenotype switch from M1- to M2-macrophages by activating adenosine receptor signaling in a mouse model of CKD with UA granulomas.

Methods

We screened 81,200 diagnostic kidney biopsies for the presence of UA granulomas to determine the prevalence and performed a case-control study to compare biopsies with and without granulomas for morphological abnormalities. Alb-creERT2/Glut9lox/lox (ki/ki) or Glut9lox/lox control mice were fed either a high-fat or chow diet with inosine. We assessed UA crystal deposits, GFR and the extent of kidney damage (MALDI-FTICR MS imaging, immunostaining, flow cytometry). Adenosine therapy was started after renal fibrosis had established.

Results

84 out of 81,200 kidney biopsies showed UA granulomas, which revealed significantly more glomerulosclerosis and interstitial fibrosis compared to control biopsies. Ki/ki mice on chow diet with inosine developed only hyperuricemia (HU), whereas ki/ki mice on high-fat diet with inosine developed HU + CKD compared to control mice. Indeed, urate nephropathy caused a significant GFR decline compared to HU or control mice. MALDI-FTICR MS imaging confirmed UA crystal deposits that were associated with tubular atrophy, interstitial fibrosis and macrophage infiltration. Histological analysis showed that UA granulomas occur after renal fibrosis had established. Adenosine therapy significantly reduced the number of renal UA granulomas due to less M1- but more M2-macrophages, a process that attenuated CKD progression.

Conclusion

Renal UA granulomas are found in 0,1% of diagnostic kidney biopsies and associated with more renal fibrosis and tubular atrophy. Our in vivo data revealed that UA granulomas form after renal fibrosis had established. M1-macropages are essential for UA granuloma formation, and interfering with a switch from M1- to M2-macrophages prevents CKD progression. Together, UA granulomas develop secondary to renal fibrosis but contribute to accelerated kidney atrophy and dysfunction.

Funding

  • Government Support - Non-U.S.