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Tacrolimus in acute renal failure: does L-arginine-infusion prevent changes in renal hemodynamics?
1Department of Medicine, Division of Nephrology, University Hospital Wuerzburg, Josef-Schneider-Strasse 2, 97080 Wuerzburg, Germany. k.lopau@medizin.uni-wuerzburg.de
Abstract:
Nephrotoxicity is one of the main side effects of calcineurin-inhibitors. The influence of tacrolimus on the renal vasculature has not been well described. We have therefore examined the effects of tacrolimus on renal functional parameters as well as the contribution of the NO-system in a model of ischemic acute renal failure (ARF). Induction of ARF was achieved by clamping both renal arteries of female Sprague-Dawley rats. During the experiment, RBF, GFR, MAP, RVR and FENa were determined during infusion of vehicle, TAC, TAC and the NOS-activator L-arginine, and TAC and NOS-inhibition due to L-NMMA. TAC induced a significant rise in RVR with further decrease of RBF and GFR. Simultaneous L-arginine-infusion could reverse these effects during the infusion without complete restoration to preischemic levels. NOS-inhibition increased MAP and RBF without any effect on GFR. FENa did not differ significantly between the groups. Tacrolimus in the situation of ischemic acute renal failure causes vasoconstriction of pre- and postglomerular vessels with a further deterioration of renal function. L-arginine abolishes the functional deterioration, most likely due to increased NO-liberation.
Insights
Tacrolimus worsens kidney function in acute renal failure by constricting blood vessels. Supplementing with L-arginine helps restore function, suggesting nitric oxide plays a key role in mitigating tacrolimus-induced nephrotoxicity.
Area of Science:
- Nephrology
- Pharmacology
- Physiology
Background:
- Calcineurin-inhibitors like tacrolimus are associated with nephrotoxicity.
- The specific effects of tacrolimus on renal vasculature in acute renal failure (ARF) are not well understood.
Purpose of the Study:
- To investigate the impact of tacrolimus on renal functional parameters in a model of ischemic ARF.
- To determine the role of the nitric oxide (NO) system in mediating these effects.
Main Methods:
- Acute renal failure was induced in rats by clamping renal arteries.
- Renal blood flow (RBF), glomerular filtration rate (GFR), mean arterial pressure (MAP), renal vascular resistance (RVR), and fractional excretion of sodium (FENa) were measured.
- Rats received infusions of vehicle, tacrolimus (TAC), TAC with L-arginine (NOS-activator), or TAC with L-NMMA (NOS-inhibitor).
Main Results:
- Tacrolimus significantly increased RVR, leading to decreased RBF and GFR.
- L-arginine infusion partially reversed the functional deterioration caused by tacrolimus.
- NOS inhibition increased MAP and RBF but did not affect GFR.
Conclusions:
- Tacrolimus causes vasoconstriction of renal vessels, worsening kidney function in ischemic ARF.
- L-arginine administration mitigates tacrolimus-induced functional decline, likely through enhanced nitric oxide liberation.