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The effects of fractionated doses of fast neutrons (42 MeVd----Be) on the radiation response of the pig kidney have been assessed and compared with those observed after X irradiation. Following X irradiation there was a marked increase in the total dose at which renal function was preserved with decreasing fraction size. The rate of this increase was dependent on the overall treatment time; for fractionated irradiation given over 18 or 39 days the exponents related to fraction number, N, were 0.36 +/- 0.03 and 0.48 +/- 0.003, respectively. In contrast, there was no significant change in the iso-effect dose for renal injury following fractionated irradiation with fast neutrons where there was also little effect of varying the overall treatment time. Analysing these data by means of the linear-quadratic (LQ) model, using both an Fe-plot and the Tucker test, gave alpha/beta ratios of 2.42 +/- 0.06 Gy and 2.99 +/- 0.16 Gy, respectively, for X-ray doses given in 18 days. For fractionated doses of X rays given in 39 days the alpha/beta ratios were 0.40 +/- 0.01 Gy and 0.47 +/- 0.02 Gy, respectively. The alpha/beta ratios for renal tissue following fast neutron irradiation obtained by the two methods were also similar, i.e. 15.00 +/- 0.60 Gy and 15.72 +/- 3.76 Gy, respectively. The pronounced fractionation effect seen with X irradiation, particularly for doses administered over 39 days as opposed to 18 days, coupled with the absence of any such effect with fast neutrons, resulted in a marked increase in relative biological effectiveness (RBE) with decreasing X-ray dose/fraction. The slopes of the resulting regression lines were -0.73 +/- 0.05 and -0.33 +/- 0.02, respectively. The lack of dose sparing associated with fractionation, or variation of the overall treatment time for fast neutron irradiation, suggests that doses administered to tumours adjacent to the kidney can be given as a few relatively large dose/fractions in a short overall treatment time without an increased risk of complications related to renal tissue. This may be of therapeutic advantage in the treatment of rapidly proliferating tumours where dose may be wasted using more conventional protracted fractionated irradiation schedules.

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Groups of mature Large White female pigs, approximately 10 months of age, received single intravenous infusions of 1.5, 2 or 2.5 mg/kg body weight (equivalent to approximately 90, approximately 120 and approximately 150 mg/m2) cisplatin. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured before and at 4 weeks after cisplatin infusion by renography using [99 mTc]-DTPA (diethylenetriamminepentaacetic acid and iodohippurate sodium I 131, respectively. The left kidney of each cisplatin-treated animal plus that of four age-matched control pigs was then removed surgically, and GFR and ERPF were measured in the remaining kidney at 4 weekly intervals for up to 24 weeks after unilateral nephrectomy (UN). The pigs treated with cisplatin exhibited no consistent change in either GFR or ERPF at 4 weeks after treatment. A histological evaluation of kidneys from animals treated with greater than or equal to 2 mg/kg cisplatin that had been removed at UN revealed both tubular and glomerular lesions. The latter consisted of cell proliferation on the parietal surface of the urinary space; damage to the S1 portion of the proximal convolution was also noted. Following UN there was a pronounced dose-dependent reduction in the functional status of the remaining kidney such that the increase in GFR and ERPF in pigs initially receiving 2.5 mg/kg cisplatin was less than 50% of that seen in age-matched UN controls. Moreover, the glomerular lesions observed at 4 weeks after cisplatin infusion had apparently progressed to glomerular hyalinisation by 24 weeks after UN. Thus, prior treatment with cisplatin may cause a permanent reduction in renal functional reserve that may be clinically "silent" until exposure to an additional nephrotoxic insult.

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Both kidneys in mature female Large White pigs, ca. 45 weeks old were irradiated with single doses of 7.8-14.0 Gy of 60Co gamma-rays. Radiation-induced changes in renal function were assessed on the basis of sequential individual measurements of kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) for up to 24 weeks after irradiation. At the same time intervals blood samples were taken to determine plasma renin levels and the haematological status of each animal. Two weeks after irradiation the ERPF and in particular the GFR was increased. This was followed by a pronounced, dose-dependent, decline in renal haemodynamics. Minimal functional levels were observed 8-12 weeks after irradiation. Function then somewhat recovered. There was a significant (r greater than or equal to 0.98; p less than 0.001) inverse relationship between the mean values of GFR and ERPF, determined at 4-24 weeks after irradiation, and the radiation dose. After a dose of 7.8 Gy the reduction in ERPF was greater than that for GFR. However, at higher doses both parameters were reduced to an equal extent. The resulting slope of the dose-effect curve for impaired renal function versus dose was significantly steeper for GFR than that for ERPF (p less than 0.001). There was a significant reduction (p less than 0.002) in the erythrocyte count, the haematocrit and haemoglobin levels within 6-8 weeks of irradiation; this anaemia was characterized as a normochromic normocytic anaemia. There were no marked changes in plasma renin levels as a result of renal irradiation. The pathogenesis of late radiation-induced damage to the kidney is discussed in the light of these findings.

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In 14-week-old (immature) and 45-week-old (mature) pigs either the right kidney (unilateral irradiation, UI) or both kidneys (bilateral irradiation, BI) were irradiated. The kidneys of immature pigs received single doses of 7.0-12.6 Gy of 250 kV X-rays; mature pigs received single doses of 7.8-14.0 Gy of 60Co gamma-rays. These were assumed to be approximately equivalent to the X-ray doses using a RBE of 0.9 gamma-rays/X-rays. The glomerular filtration rates (GFR) and effective renal plasma flows (ERPF), were determined for up to 24 weeks after irradiation. From these data dose-effect curves were obtained by determining, at each dose level, the percentage of irradiated kidneys which exhibited a greater than or equal to 50 per cent reduction in GFR and ERPF. 60Co gamma-ray doses were normalised to approximately equivalent X-ray doses. The dose-effect curves were fitted by probit analysis, and ED50 values (+/- SE) calculated for both GFR and ERPF. Similar conclusions could be drawn from the results obtained following the determination of both GFR and ERPF. However, the ED50 values obtained for ERPF were significantly lower than those for GFR (p less than 0.05). In 14-week-old animals the kidney of UI animals was significantly more radiosensitive than that of BI animals, i.e. the ED50 values, in terms of GFR, were 8.74 +/- 0.31 Gy and 10.97 +/- 0.23 Gy, respectively (p less than 0.001). In 45-week-old pigs the reverse was true; the ED50 values were 12.67 +/- 0.34 Gy and 8.78 +/- 0.15 Gy (p less than 0.001) for unilateral- or bilateral-irradiated animals, respectively. The kidney of BI mature animals appeared to be as radiosensitive as the UI immature pigs. Thus the renal response to radiation was markedly influenced by the age of the animals and by the proportion of the renal tissue irradiated.

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The right kidney of 11 mature 10-month-old Large White female pigs was irradiated with single doses of 9.8-14.0 Gy of 60Co gamma rays. Individual kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured using 99mTc-DTPA and 131I-hippuran renography for periods up to 24 weeks after irradiation. Renal function was assessed either as a functional index, FI (FI = irradiated/unirradiated kidney function), or as the individual kidney GFR and ERPF. The radiation-induced changes after the irradiation of a single kidney (unilaterally irradiated--UI) of mature pigs were compared with those previously observed in 14-week-old immature pigs. Irradiation resulted in a dose-dependent reduction in the FI for both GFR and ERPF. However, these reductions were significantly less than those previously seen in immature pigs. Within 2 weeks of irradiation GFR increased in both the irradiated and the unirradiated kidneys in each animal, compared with unirradiated age-matched control kidneys. No marked changes in renal hemodynamics were seen in mature animals after a single dose of 9.8 Gy. This was in marked contrast to the pronounced reduction in the GFR and ERPF in the irradiated kidney previously observed in immature animals irradiated with an equivalent single dose of X rays. After higher doses, the irradiated kidney in mature pigs showed a dose-dependent reduction in GFR and ERPF. However, the extent of this reduction was significantly less than that seen in immature animals. There was no apparent difference in the response of the unirradiated kidneys in mature or immature pigs. The ED50 values, based on a probit fit to the data for the proportion of functional tests in which the irradiated kidney showed a greater than or equal to 50% reduction in GFR or ERPF, were higher in the mature animals; for example for ERPF the ED50 values were 11.76 +/- 0.28 Gy and 7.67 +/- 0.34 Gy for mature and immature animals, respectively. Thus, the UI kidney in mature pigs appears to be less radiosensitive than the UI kidney in immature animals.

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