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Kidney Week

Abstract: PO0617

Asymptomatic Hyperuricemia, a Regulator of Innate Immunity in CKD

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Steiger, Stefanie, Division of Nephrology, Department of Medicine IV, LMU Hospital, Munich, Germany
  • Ma, Qiuyue, Division of Nephrology, Department of Medicine IV, LMU Hospital, Munich, Germany
  • Romagnani, Paola, Department of Biomedical Experimental and Clinical Sciences Maria Serio, Univerisity of Florence, Florence, Italy
  • Anders, Hans J., Division of Nephrology, Department of Medicine IV, LMU Hospital, Munich, Germany
Background

Asymptomatic hyperuricemia (HU) is common in patients with chronic kidney disease (CKD) but the causative role of HU on CKD progression remains controversial. Two large multi-center randomized controlled trials, CKD-FIX and PERL study, have now disproven a causal relation. On the other hand, a causative role of HU exists with gout but a rapid correction of HU with urate lowering therapy can also elicit acute gout attacks. This suggests a more complex role of HU in this context. Hence, we hypothesized that soluble uric acid (sUA) has immunomodulatory effects on neutrophil function during the immune response to monosodium urate (MSU) crystals.

Methods

Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were injected with tamoxifen and placed either on a chow or acidogenic diet with inosine to induce HU with or without CKD. After 3 weeks, MSU crystals or vehicle were injected into air pouches or postcapillary venules in the cremaster muscle of transgenic mice. Leukocyte infiltration and the extent of inflammation were assessed by flow cytometry, intravital microscopy, and ELISA. Blood neutrophils were isolated from CKD stage G2-4 and G5D patients or healthy individuals and neutrophil transwell migration assays performed.

Results

We found that HU impaired leukocyte recruitment into MSU crystal-injected air pouches of mice with or without CKD. Intravital microscopy revealed that HU specifically reduced leukocyte adhesion, extravasation, and tissue inflammation. The CKD-mediated attenuation of MSU crystal-induced inflammation was fully reversible by treating HU with urate lowering therapy. In neutrophils isolated from healthy individuals, sUA diminished β2 integrin activation and expression, and hence impaired neutrophil migration ex vivo. This process was dependent on the intracellular uptake of sUA via the urate transporter SLC2A9/GLUT9. An impaired migratory capability was also observed in neutrophils from CKD patients.

Conclusion

We identify sUA as an endogenous modulator of innate immunity. HU modulates neutrophil migration by altering efficient β2 integrin activation via SLC2A9 in gouty arthritis related or unrelated to CKD. This process provides a molecular explanation for several previously unexplained clinical phenomena in the context of gout and renal failure.

Funding

  • Government Support - Non-U.S.