Effects of enhanced oxygen release from hemoglobin by RSR13 in an acute renal failure model

Effects of enhanced oxygen release from hemoglobin by RSR13 in an acute renal failure model.BackgroundAcute renal failure is believed to be caused, in some circumstances, by impaired oxygen delivery to the outer medulla. This study examined the effect of RSR13, a synthetic allosteric modifier of hemoglobin oxygen-binding affinity, on renal function in a setting of acute renal failure in rats.MethodsAn in vivo model of acute renal failure in the rat produced by reduced renal mass, salt restriction, volume depletion, prostaglandin inhibition, and radiocontrast administration was used. A computer-based simulation of oxygen tensions along the nephron was utilized to interpret the findings. Mechanistic studies were subsequently performed using oxygen-sensitive electrodes and 31P nuclear magnetic resonance (NMR) spectroscopy to define the effect of RSR13 on renal function in the setting of compromised acute renal failure.ResultsRSR13 did not attenuate acute renal failure in this model; rather, serum creatinine increased to a greater degree in the RSR13-treated rats than in rats receiving saline vehicle as the control (P < 0.05). Simulations explained this finding under conditions of severe medullary hypoxia. Mechanistic studies demonstrated marked worsening of medullary hypoxia following RSR13 under conditions similar to our experimental model. Furosemide pretreatment to reduce the imbalance between oxygen supply and demand markedly attenuated the basal-medullary hypoxia produced in the presence of indomethacin and RSR13 (P < 0.01). Additionally, 31P NMR studies demonstrated renal adenosine 5′-triphosphate (ATP) depletion in rats with acute renal failure treated with RSR13 (45% decrease, P < 0.01); again, this effect of RSR13 was completely prevented by pretreatment with furosemide.ConclusionsUnder conditions of severe renal medullary hypoxia, induced in part by indomethacin-mediated reductions in outer medullary blood flow, the administration of RSR13 can exacerbate acute renal dysfunction. However, reducing the rate of oxygen consumption by inhibiting sodium transport with furosemide pretreatment or post-treatment appears to be functionally protective.