Related Experiment Videos
Hyperuricemia exacerbates chronic cyclosporine nephropathy
1Division of Nephrology, University of Washington Medical Center, Seattle 98185, USA.
Insights
Elevated uric acid levels worsen cyclosporine (CSA) induced kidney damage in rats. This exacerbation is linked to the renin-angiotensin system and reduced nitric oxide, not crystal formation.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Hyperuricemia is a common complication of cyclosporine (CSA) treatment.
- Chronic hyperuricemia is linked to tubulointerstitial disease and vasoconstriction, suggesting a role in CSA nephropathy.
Purpose of the Study:
- To investigate the hypothesis that hyperuricemia contributes to chronic cyclosporine nephropathy.
- To determine the effect of elevated uric acid on CSA-induced kidney injury in a rat model.
Main Methods:
- Cyclosporine nephropathy was induced in rats using CSA (15 mg/kg/day) for 5-7 weeks.
- Hyperuricemia was induced by co-administering oxonic acid with CSA.
- Histological and functional assessments were performed, with control groups receiving vehicle or oxonic acid alone.
Main Results:
- CSA treatment led to mild hyperuricemia, arteriolar hyalinosis, tubular injury, and interstitial fibrosis.
- Co-administration of oxonic acid with CSA (CSA-OA) resulted in higher uric acid levels and more severe kidney damage.
- Both CSA and CSA-OA groups showed increased renal renin and decreased nitric oxide synthases (NOS1 and NOS3), with more pronounced changes in the CSA-OA group. Intrarenal urate crystals were absent.
Conclusions:
- Increased uric acid exacerbates cyclosporine-induced nephropathy in rats.
- The mechanism involves activation of the renin-angiotensin system and inhibition of intrarenal nitric oxide production.
- Intrarenal urate crystal deposition is not the mechanism by which hyperuricemia worsens CSA nephropathy.
Background:
Hyperuricemia frequently complicates cyclosporine (CSA) therapy. The observation that longstanding hyperuricemia is associated with chronic tubulointerstitial disease and intrarenal vasoconstriction raised the hypothesis that hyperuricemia might contribute to chronic CSA nephropathy.
Methods:
CSA nephropathy was induced by the administration of CSA (15 mg/kg/day) for 5 and 7 weeks to rats on a low salt diet (CSA group). The effect of hyperuricemia on CSA nephropathy was determined by blocking the hepatic enzyme uricase with oxonic acid (CSA-OA). Control groups included rats treated with vehicle (VEH) and oxonic acid alone (OA). Histological and functional studies were determined at sacrifice.
Results:
CSA treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular injury and striped interstitial fibrosis. CSA-OA treated rats had higher uric acid levels in association with more severe arteriolar hyalinosis and tubulointerstitial damage. Intrarenal urate crystal deposition was absent in all groups. Both CSA and CSA-OA treated rats had increased renin and decreased NOS1 and NOS3 in their kidneys, and these changes are more evident in CSA-OA treated rats.
Conclusion:
An increase in uric acid exacerbates CSA nephropathy in the rat. The mechanism does not involve intrarenal uric acid crystal deposition and appears to involve activation of the renin angiotensin system and inhibition of intrarenal nitric oxide production.