Long-term effects of total-body irradiation on the kidney of Rhesus monkeys.

PURPOSE: To investigate the long-term effects of total-body irradiation (TBI) on kidneys in non-human primates. METHODS AND MATERIALS: The kidneys of Rhesus monkeys were histologically examined at 6-8 years after TBI with low single doses of 4.5-8.5Gy or two fractions of 5.4Gy. The kidneys of age-matched non-irradiated monkeys served as controls. Irradiation was performed on adult monkeys aged about 3 years; 6-8 years later animals were sacrificed and the kidneys removed and processed for histology. A semi-quantitative scoring system was used to evaluate overall histological damage. Glomerular changes were also morphometrically analysed according to previously published criteria. In selected dose groups (pro)thrombotic and inflammatory changes were investigated by immunostaining cryosections with antibodies against von Willebrand factor (vWF), leukocytes and macrophages. RESULTS: Histological changes were generally mild and only seen in kidneys irradiated with doses higher than 7 Gy. Glomerular changes were characterized by increased mesangial matrix and capillary dilatation. Tubulo-interstitial changes included hypercellularity, fibrosis and mild tubular atrophy. The mean glomerular area expressing vWF protein in the irradiated kidneys was not different from that in the age-matched controls. Numbers of infiltrating leukocytes were not significantly different between irradiated kidneys and controls. However, slightly increased numbers of macrophages were present in the renal cortex after irradiation. CONCLUSIONS: Renal damage after TBI of Rhesus monkeys with single doses of 4.5-8.5 Gy or two fractions of 5.4 Gy was mild, even after follow-up times of 6-8 years.

Effects of total-body irradiation on growth, thyroid and pituitary gland in rhesus monkeys.

PURPOSE: To investigate the effect of total-body irradiation (TBI) on growth, thyroid and pituitary gland in primates. METHODS AND MATERIALS: Thirty-seven rhesus monkeys (mean age 3.1+/-0.6 years) received either a low-dose (4-6 Gy) TBI (n = 26) or high-dose (7-12 Gy) TBI (n = 11) and were sacrificed together with 8 age-matched controls after a post-irradiation interval of 5.9+/-1.5 years. Anthropometric data were collected: thyroid and pituitary glands were examined; serum levels of thyroid stimulating hormone (TSH), free thyroxin (FT4), insulin-like growth factor-I (IGF-I) and its binding protein-3 (IGFBP-3) were measured. RESULTS: Decrease in final height due to irradiation could not be demonstrated. There was a dose-dependent decrease in body weight, ponderal index, skinfold thickness and thyroid weight. The latter was not accompanied by elevation of TSH or decrease in FT4. Structural changes in the thyroid gland were found in 50% of the irradiated animals. Levels of IGF-I and IGFBP-3 did not differ between the dose groups, but the high-dose group had a lower IGF-1/IGFBP-3 ratio. CONCLUSION: Total body irradiation had a negative effect on body fat. There was no evidence of (compensated) hypothyroidism, but dose-dependent decrease in thyroid weight and changes in follicular structure suggest some effect of TBI on the thyroid gland. The decreased IGF-I/IGFBP-3 ratio in the high-dose group can indicate that the somatotrophic axis was mildly affected by TBI. These results show that TBI can have an effect on the physical build and thyroid gland of primates even in the absence of cytostatic agents or immunosuppressive drugs.

Long-term effects of X-irradiation on gastrointestinal function and regulatory peptides in monkeys.

PURPOSE: To investigate the long-term effects of X-irradiation on different aspects of gastrointestinal function in the non-human primate (Macaca mulatta). MATERIALS AND METHODS: Animals were exposed to X-radiation (5 or 6 Gy) or not (sham) and gastrointestinal function was investigated 4-6 years after exposure. Basal and agonist-stimulated short circuit current (Isc) responses were measured in isolated jejunum. Intestinal tissue was taken for histological analysis as well as for determination of mucosal marker enzyme activities and gastrointestinal regulatory peptide levels. Vasoactive intestinal peptide receptor characteristics were determined as well as VIP-stimulated Isc responses. GI peptides were also measured in plasma. RESULTS: Few differences were seen in basal electrical parameters or tissue morphology but there was a tendency for reduced basolateral membrane enzyme activity. VIP-stimulated Isc responses were reduced in irradiated animals as were VIP-stimulated adenylate cyclase responses. Plasma and tissue (ileal and colonic muscle layers) gastrin releasing peptide levels were increased in irradiated animals. In contrast circulating gastrin levels were lower. CONCLUSIONS: Late effects of total-body irradiation on GI function in monkeys showed altered circulating and tissue levels of some GI peptides. In addition the biological effects of vasoactive intestinal peptide were modified.

Late ophthalmological complications after total body irradiation in non-human primates.

PURPOSE: To investigate the long-term effects of total body irradiation (TBI) on the incidence and time course of ocular complications. MATERIALS AND METHODS: Rhesus monkeys treated with TBI photon doses up to 8.5 Gy and proton doses up to 7.5 Gy were studied at intervals up to 25 years post-irradiation. They were compared with control groups with a similar age distribution. Cataract formation and ocular fundus lesions were scored according to a standardized protocol. Fluorescein angiography and histopathology was performed in selected animals. RESULTS: Cataract formation occurred after a latent period of 3-5 years. Significant cataract induction was observed for photon-doses of 8 and 8.5 Gy and beyond 20 years after proton irradiation. The severity of the lesions represents significant impairment of vision and would require cataract surgery if similar results occurred in human bone marrow transplant patients. Fluorescein angiography demonstrated a normal pattern of retinal vessels in 13 out of 14 animals (93%) from the irradiated group and in eight out of nine animals (89%) from the control group. No additional lesions apart from age-related degenerative changes could be demonstrated. Histological evaluation revealed no radiation-associated vasculopathy. CONCLUSIONS: Radiation alone for doses up to 8.5 Gy of photons does not carry a potential risk for fundus pathology, whereas clinically important cataract induction should be anticipated within 5 years after photon doses of 8.0 and 8.5 Gy and proton doses in excess of 2.5 Gy.

Long-term consequences of high-dose total-body irradiation on hepatic and renal function in primates.

Radiation effects in non-human primates were studied in order to define the long-term risk of total-body irradiation (TBI) for bone marrow transplantation patients. The long-term effects of TBI could be investigated by keeping 84 monkeys of different ages, from an experiment on acute effects, under continuous observation for a period up to 25 years. The control group consisted of non-irradiated monkeys with a comparable age distribution and identical housing conditions. Since radiation was the common toxic agent, the different age groups provided the possibility to investigate the occurrence of deterministic effects after TBI. In the present study emphasis was placed on the assessment of hepatic and renal function and the associated histopathology. The values of the liver function parameters, such as alkaline phosphatase and gamma glutamyl transferase in the irradiated group were significantly increased after TBI (p < 0.05). Also the parameters of kidney dysfunction, e.g. haematocrit and blood urea nitrogen showed a significant change in the irradiated old-aged (post-irradiated interval > 15 years) cohort (p < 0.005). The impairment of the liver and renal functions, did not lead to clinical symptoms and were only associated with mild morphologic changes in the irradiated group of monkeys. In the population of bone marrow transplant patients treated with TBI, alterations in hepatic and renal function parameters after a post-irradiated interval of > 10 years can be anticipated. This could have consequences for the tolerance and toxicity of a broad range of drugs to be administered as additional medications.