Prevention of radiation nephritis with renal artery infusion of vasoconstrictors. Experimental and preliminary clinical studies.

Abstract

Numerous radiobiologic experiments have documented the validity of the original observations (1, 2) that the state of oxygenation at the time of irradiation markedly influences radiation response. Clinical attempts to exploit this so-called “oxygen effect” have taken a number of forms. These include efforts at increasing tumor oxygenation by respiration of oxygen under hyperbaric (3) as well as ambient conditions (4, 5). A similar objective was approached by the intra-arterial infusion of hydrogen peroxide (6). Conversely, the reduction of normal tissue toxicity by production of ischemia was the design of tourniquet application proximal to the irradiation site for soft-tissue sarcomas and bone neoplasms in the extremities (7, 8). The present study is an attempt to attenuate the radiosensitivity of the normal kidney by creating hypoxia during irradiation with the intra-arterial infusion of a vasoconstrictor agent. Preclinical experiments in dogs, previously reported in part (9), have demonstrated a significant protection against the development of radiation nephritis. A clinical trial has been undertaken, and in this paper our initial experience in patients is reviewed, together with the completed canine investigations. Preclinical Research Physiological studies in dogs on the effect of renal artery infusion with epinephrine are illustrated in Figure 1. Epinephrine infusion was shown to result in a marked decrease in renal blood flow, a fall in renal venous pH and oxygen saturation, and a rise in the lactate/pyruvate ratio in the venous blood. These changes indicate a significant degree of renal ischemia and tissue anoxia which was rapidly reversible with cessation of the epinephrine infusion. Additional canine investigations established that single ischemia-producing infusions of epinephrine of ten to fifteen minutes duration did not cause functional or histologic changes in normal kidneys and confirmed that 1,500 rads delivered in a single treatment resulted in severe damage within three months (10, 11). Arteriographie and radioisotope renogram alterations due to epinephrine infusion in normal dog kidneys are illustrated in Figures 2 and 3. The renograms have been obtained with a gamma scintillation camera as described elsewhere (12, 13). The final series of experiments consisted of evaluating the potential protection afforded irradiated kidneys by renal artery epinephrine infusion. The technic, as previously described (9), involved the percutaneous introduction of an arterial catheter into the renal artery of one kidney via the femoral artery. Epinephrine in normal saline was infused for five minutes at the rate of 1.3 µg per minute to produce ischemia. Without interruption of the infusion, 1,500 rads was then administered simultaneously to both kidneys in a single dose (60Co). At completion of irradiation, the infusion was discontinued and the catheter removed.