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OP0358 Why do not all chronic kidney disease patients get gout? impaired neutrophil chemotaxis in hyperuricemia-related ckd
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  1. Q. Ma1,
  2. M. Sellmayr1,
  3. F. Preitner2,
  4. H.-J. Anders1,
  5. S. Steiger1
  1. 1Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Nephrologisches Zentrum, München, Germany
  2. 2University of Lausanne, Center for Integrative Genomics, Lausanne, Switzerland

Abstract

Background One characteristic feature of acute gout is the infiltration of neutrophils into the inflamed joints, where they recognise monosodium urate (MSU) crystals leading to an acute inflammatory response. The development of chronic kidney disease (CKD) is associated with increased serum uric acid (UA) levels also known as hyperuricemia, a major risk factor for gout. Despite hyperuricemia, acute gout is less frequent in CKD patients. However, the effects of hyperuricemia on leukocyte chemotaxis in CKD are not fully understood.

Objectives We hypothesised that hyperuricemia affects neutrophil chemotaxis in CKD patients. Furthermore, we made use of a novel mouse model of chronic uric acid nephropathy.

Methods Human study: Serum was collected and neutrophils isolated from CKD patients or healthy subjects. Serum BUN (blood urea nitrogen), creatinine and uric acid levels were measured. Neutrophil transwell assays were carried out and the number of migrated neutrophils towards fMLP, human IL-8 determined by flow cytomentry. Animal study: Six week old Alb-creERT2;Glut9lox/lox mice (ki/ki) and mice without active Cre (+/+) were injected with tamoxifen. The ki/ki mice received either a high fat diet with Inosine (HFD+Ino) to induce hyperuricemia-associated CKD or a chow diet with Inosine (Chow+Ino) to induce only hyperuricemia without CKD. Control +/+mice either received HFD+Ino or Chow+Ino diet. After two weeks, all groups were injected either with MSU crystals or vehicle into a preexisting air pouch, a mouse model for acute gouty arthritis. After 12 hours, neutrophil infiltration and the extent of inflammation were assessed via flow cytometry, ELISA, and colorimetric assays.

Results Human study: Compared to healthy subjects, CKD stage 5 patients presented with significant higher levels of serum BUN (14.1 vs 52.1 mg/dl, p=0.001), creatinine (1.5 vs 9.3 mg/dl, p=0.001) and UA (2.3 vs 10.3 mg/dl, p=0.001). Neutrophils from CKD patients showed an impaired migratory ability due to the down-regulation of the adhesion molecules P-Selectin and αβIntegrin. Animal study: Two weeks post-HFD +Ino, ki/ki mice developed hyperuricemia-associated CKD (serum UA: 10–14 mg/dl; BUN: 80 mg/dl), whereas the ki/ki mice on Chow+Ino diet became hyperuricemic without CKD. Control +/+mice on both diets did neither develop hyperuricemia nor CKD. Interestingly, the number of infiltrating neutrophils into the air pouch was reduced in hyperuricemic ki/ki mice with CKD as well as in hyperuricemic ki/ki mice without CKD compared to +/+control mice. We observed less inflammation indicated by decreased IL-1β, TNFα, CXCL1 and myeloperoxidase levels, and a down-regulation of adhesion molecules on infiltrated neutrophils in hyperuricemic ki/ki mice with CKD compared to +/+control mice.

Conclusions Our data show that neutrophils from CKD patients are less able to migrate, which was consistent with data from our novel mouse model demonstrating that hyperuricemia impairs neutrophil chemotaxis in MSU crystal-induced inflammation. This indicated that the mechanism for defective neutrophil migration might be responsible for the lower incidence of acute gouty arthritis in hyperuricemic CKD patients.

Acknowledgements This work was supported by grants from the Deutsche Forschungsgemeinschaft and the LMUexcellent junior researcher fund.

Disclosure of Interest None declared

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