Effect of elevated serum uric acid on cisplatin-induced acute renal failure.
Marked hyperuricemia is known to cause acute renal failure via intrarenal crystal deposition. However, recent studies suggest mild hyperuricemia may have vasoactive and proinflammatory effects independent of crystal formation. We therefore tested the hypothesis that mild hyperuricemia might exacerbate renal injury and dysfunction in a model of cisplatin-induced acute renal failure in the rat. Cisplatin was administered to normouricemic and hyperuricemic rats (the latter generated by administering the urate oxidase inhibitor, oxonic acid). Recombinant urate oxidase (rasburicase) was administered in a third group to assess the effect of lowering uric acid on outcomes. Other control groups include normal rats and hyperuricemic rats without cisplatin-induced injury. Cisplatin induced injury of the pars recta (S3) segment of the proximal tubule in association with a mild monocyte infiltration. Hyperuricemic rats showed significantly greater tubular injury and proliferation with significantly greater macrophage infiltration and increased expression of monocyte chemoattractant protein-1. However, renal function was not different between normouricemic and hyperuricemic rats with cisplatin injury. Treatment with rasburicase reversed the inflammatory changes and lessened tubular injury with an improvement in renal function (relative to the hyperuricemic group). No intrarenal crystals were observed in any groups. These data provide the first experimental evidence that uric acid, at concentrations that do not cause intrarenal crystal formation, may exacerbate renal injury in a model of acute renal failure. The mechanism may relate to a proinflammatory pathway involving chemokine expression with leukocyte infiltration.
Roncal
Carlos A
CA
Division of Nephrology, Hypertension, and Transplantation and North Florida/South Georgia Veterans Health System, Pathology and Laboratory Medicine Service, University of Florida, Gainesville 32610-0224, USA.
Mu
Wei
W
Croker
Byron
B
Reungjui
Sirirat
S
Ouyang
Xiaosen
X
Tabah-Fisch
Isabelle
I
Johnson
Richard J
RJ
Ejaz
A Ahsan
AA
D058186:Acute Kidney Injury / Q000097:blood* / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D018932:Chemokine CCL2 / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D033461:Hyperuricemia / Q000097:blood / Q000139:chemically induced; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014503:Urate Oxidase; D014527:Uric Acid / Q000097:blood*
D000970:Antineoplastic Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D014527:Uric Acid; D014503:Urate Oxidase; D002945:Cisplatin