The Role of Endothelial Cell and Vascular Damage in the Development of Renal Radiation Injury

摘要

The kidney is one of the most radiosensitive organs, although the latent period before functional renal impairment after radiotherapy may be very long. Animal studies have consistently demonstrated progressive, dose-dependent deterioration of kidney function after local renal irradiation or total-body irradiation. The time of onset and rate of progression of damage are inversely related to dose. Re-treatment studies have demonstrated that even low "subthreshold" doses, which do not cause overt renal dysfunction within the animal's life span, do cause progressive occult damage which leads to decreasing re-treatment tolerance with increasing time from first treatment. After high single doses, tubular epithelial cell loss and necrosis are the predominant features, but vascular damage predominates after fractionated, more clinically relevant, doses or in the re-treatment situation. Structural vascular changes include the loss of fine capillary network structure in the cortex, capillary distension (in both the renal cortex and glomeruli), endothelial cell swelling and detachment, and glomerular thrombi. These structural changes are associated with increased vascular leakage and reduced renal perfusion, including apparently nonperfused glomeruli, both of which we have clearly demonstrated by perfusing irradiated mouse kidneys with high-molecular-weight fluorescein dextran. A progressive deterioration in human renal function has also been demonstrated in patients irradiated for abdominal malignancies. The extent of damage depends on the volume of kidney irradiated and on total dose. Prospective studies in the Netherlands Cancer Institute, using repeated external scintigraphic techniques, demonstrated progressive deterioration of tubular and glomerular function in the left kidneys of gastric non-Hodgkin's lymphoma patients treated to 40 Gy (1.5 Gy per fraction). Loss of function progressed at a rate of 2% per month to about 30% of pretreatment values at 3 to 5 years. Less severe renal impairment was seen in Hodgkin's lymphoma patients who received similar total doses to only 30 to 50% of the left kidney. Fifteen of those patients with prospectively documented renal radiation injury were further investigated using selective angiography and captopril renography to assess the type and extent of vascular changes. The renal angiography demonstrated structural and functional vascular changes in irradiated parts of the kidneys (truncated, tortuous vessels with evidence of stenosis and vascular leakage). The captopril renography also indicated renovascular hypertensive changes in some patients even after radiation doses presumed to be subthreshold for clinical nephropathy.