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The time factor in the radiation response of the kidney
Radiotherapy and Oncology, 5 (1986) 75 78 Elsevier
75
RTO00174
Editorial
The time factor in the radiation response of the kidney
Key words." Kidney, radiation response
The recent paper by Williams et al. [20] and other publications by members of this group [17,18,19] is of considerable interest, providing valuable information on the effects of fractionated radiation on the mouse kidney. The reaction of the kidney to radiation is complex and the assessment of isoeffect doses following fractionated exposure is difficult in a tissue system where the severity of damage was found to increase with time. This is particularly true in the most recent studies, where long treatment times of up to 80 days presented difficulties in the interpretation of time zero with respect to the timing of subsequent measurements. While the authors were aware of this problem and sought to overcome it by the "latency assays" it is still not surprising that the iso-effect doses and hence the assessment of dose recovered varies as a function of the endpoint selected. A similar problem was seen in the experimental studies by Glatstein et al. [6]. The rubidium-86 extraction assay, when used to assess the effects of treatments given in 9 fractions, showed a large increment ( ~ 10 Gy) in the iso-effect dose between a 4 and an 18 day regime. However, an alternative parameter, renal weight, did not produce the same result. Other authors [13,18] also reported renal weight to be a less sensitive indicator o f radiation damage. One group [13] selected an histological grading system in preference to either weight changes or a functional assay of renal damage for establishing iso-effect data. Williams et al. [20] provide iso-effect data for several endpoints using two precise assay techniques,
urine output and sTCr-EDTA clearance. The recovered dose between 20 and 80 days, excluding one result where a negative value was obtained, varied between 1.5 and 8.7 Gy (3-18%). While these differences do not exceed accepted levels of significance, the time exponents obtained from these data do depend on the way the results are expressed. The recovered dose is largely a feature of the difference in iso-effect dose between 20 and 40 days, with no significant increase in iso-effect dose being seen between 40 and 80 days. The authors claim that these findings, with respect to a time factor, were consistent with a "slow repair" process [20]. Examination of their earlier two fraction data suggests that the pattern of recovery recorded, on the basis of results obtained using the two functional assays, was not consistent with that originally described in the lung [4]. The phenomenon termed "slow repair" in the lung was found to be initiated shortly after irradiation with a recovery half time o f approximately 10 days. No evidence for any significant recovery was seen in the kidney within this time scale, iso-effect doses remaining fairly constant with intervals between fractions of 1-25 days. The pattern of recovery in the kidney is more akin to that reported in the spinal cord [9]. Here the iso-effect dose, in a two fraction study, remained constant with a 1-16 day interval between fractions; a significant increase in recovery was seen when the interval was extended to 32 days. It then remained stable at this higher level with interfraction intervals o f between 32 and 60 days. This would appear to
0167-8140/86/$03.50 9 1986 ElsevierSciencePublishers B.V. (BiomedicalDivision)
76 be in very good agreement with the two fraction data for the kidney [18] which showed a rise in isoeffect dose between 25 and 40 days with no significant change between 40 and 80 days. Results from the 16 fraction experiments [20] would also appear to be consistent with this pattern. In the spinal cord the time-dependent recovery was associated with unstimulated cell proliferation, which coincided with the release and division of neuroglial cells from a G1/S block [9]. In their paper Williams et al. [20] also suggested that the results of studies with pigs [8] c o n t r a s t with those in rodents in that there was a considerable increase in iso-effect dose with time in the pig studies. This statement would seem difficult to justify if approximately comparable pig and mouse data are compared (Table I). For a small number of fractions (5-6) the change in iso-effect dose between 4~40 days was consistent with a time exponent of 0.055-0.095 in the mouse and m i n u s 0.03 in the pig. However, when the 14 fraction pig and 16 fraction mouse results were compared the time exponent was greater in the pig. Thus pig and mouse data would apparently appear to be different but not in any consistent way. The previous suggestion made on the basis of pig results alone [8], that the value of the time exponent increased with fraction number, can no longer be justified on the basis of this new data. Moreover, since the mouse/pig differences are not consistently in one direction they cannot be explained simply by a process related to continued renal growth, inferring greater proliferation in the pig kidney model. The lack of a general pattern in the iso-effect data between pig and mouse with respect to time is further illustrated in Fig. 1. This graph also illustrates the recovery in both the pig and mouse kidney between 3 and 6 weeks seen by most investigators. The value of the time exponent over this period varies by a factor o f 5-8 in the mouse and by 4 in the pig. In an Annual Report from this Institute a comparison was made between the results o f split dose studies in the pig, where a single kidney was irradiated and those of similar investigations in the mouse [15] where the remaining hypertrophied kid-
TABLE I Iso-effect data in pig and mouse kidney for selected numbers of fractions given in different overall times. Species
Fraction no.
Iso-effect dose (Gy)
Mouse [18]
5 5 6 16 16 14
24.5" (4) 30.5 23.6 b (4) 26.8 19.0 a (5) 18.1 52.9" (20) 54.5 48.0 ~ (20) 55.3 20.4 (18) 27.5
Pig [8] Mouse [20] Pig [8]
Time exponent (40) 0.095 (40) 0.055 (39) - 0 . 0 3 * (40) 0.043 (40) 0.204 (39) 0.39
The overall treatment time associated with a specified iso-effect dose is given in parenthesis. The assay techniques used are as follows: s 7Cr_EDTA clearance; b 25% reduction in renal weight; r urine output; d 131i_hippuran renogram. * Best fit to 6F in 4, 18 and 39-day data, includes previous unpublished data.
ney h a d b e e n treated after unilateral nephrectomy. On the basis of this comparison it was suggested that the recovery seen in the pig between 18 and 39 days, but not in the mouse, was possibly related to stimulated repopulation. It was argued that a hypertrophied kidney would have expressed its full proliferative potential prior to irradiation and could not respond further. However, the concept of stimulated or perhaps unstimulated proliferation 7060" 50-
. ~ r/-[o2o[ ~.L3:::=~._..::.{~. 16 ~[oo4:
~ou~
5F [032) lZ.F 1039)
30-
o CD
. . . .
~
~
~
~ /
:
F
\'2~ [046[
ir~
9
10
2 /
f
Ib
S
410
610 80
Time {days]
Fig. 1. Log-log graph showing the relationship between iso-effect dose and overall treatment time for studies involving either mouse (broken lines) or pig (solid lines). The number of fractions used by various investigators is given with the associated slope (time exponent) of the lines between 3 and 4 weeks. [[~---/x, ref. 20; *---/~*, <>--~i,, ref. 18; O - - O , re[ 15; I I - - A - - O , ref. 8 plus unpublished data from Hopewelt et al.]. * 5 Fraction data has been redrawn to show the same time related change as for 2 fractions in the mouse [t8].
77 [9] in the kidney is unproven and is perhaps difficult to fully justify in an organ where the majority of renal growth following a variety of insults, is mainly the result of cell enlargement, hypertrophy not proliferation. For example, 75% of the compensatory growth seen following unilateral nephrectomy was by cell enlargement [12]. Hypertrophy and hence improved total renal function was also found in a situation where DNA synthesis was partly blocked I11]. A cell cycle block may well occur in any irradiated tissue. Hypertrophy was also seen in a situation where the normal low level of [aH]thymidine incorporation in the kidney was decreased [10]. However, with some forms of renal injury hyperplasia may predominate [2,14]. In the normal rat kidney both cell division and cell enlargement play a part in normal renal growth. Between 7 and 95 days cell enlargement was found to be at least twice as important as cell proliferation [3]. Comparable data for the pig does not exist but is clearly worthy of study. However, if proliferation is important it does not influence the fraction response in the pig with respect to the mouse in any specific way. An alternative explanation of the increase in isoeffect dose between 3 and 6 weeks is the possibility of an induced radiobiological hypoxia in an organ confined by a fibrous capsule. Reduced blood flow [5], impaired ERPF [1] and oedema [7] have been reported shortly after the commencement of a fractionated radiation treatment. In this respect the pig kidney may be different from the mouse in the sense that the renal capsule is a significantly more robust structure in the pig. There would appear to be no completely satisfactory explanation of the time factor in the response of the kidney to fractionated irradiation. The radiation tolerance of the kidney is influenced by complex radiobiological and physiological factors and functional assays of damage cannot necessarily be equated with reproductive cell survival. No one animal model or assay system can provide a complete understanding of the problems involved. A complete understanding can only come from the study of a variety of assay techniques in several animal models with a frank interchange of
views of the different findings likely to be obtained. It is worth concluding by pointing out that the relationship between iso-effect dose and fraction number produced remarkably good agreement when the different model systems and assay techniques were compared [16]. J. W. Hopewell and M. E. C. Robbins
CRC Normal Tissue Radiobiology Research Group Research Institute (University of Oxford) Churchill Hospital Oxford, U.K.
References 1 Avioli, L. V., Lazor, M. Z., Cotlove, E., Brace, K. C. and Andrews, J. W. Early effects of radiation on renal function in man. Am. J. Med. 34: 329-337, 1963. 2 Castle, W. N. and McDougal, W. S. Coutralateral renal hyperplasia and increase renal function after relief of chronic unilateral ureteral obstruction. J. Urol. 132: 1016-1020, 1984. 3 Enesco, M. and Leblond, C. P. Increases in cell number as a factor in the growth of organs and tissue in the young male rat. J. Embryol. Exp. Morphol. 10: 530-562, 1962. 4 Field, S. B., Hornsey, S. and Kutsani, Y. Effects of fractionated irradiation on mouse lung and on phenomenon of slow repair. Brit. J. Radiol. 49: 700-707, 1976. 5 Glatstein, E. Alterations in rubidium-86 extraction in normal mouse tissues after irradiation. Radiat. Res. 53: 88-101, 1973. 6 Glatstein, E., Brown, R. C., Zanelli, G. D. and Fowler, J. F. The uptake of rubidium-86 in mouse kidneys irradiated with fractionated doses of X-rays. Radiat. Res. 61: 417-426, 1975. 7 Glatstein, E., Fajardo, L. F. and Brown, J. M. Radiation injury in the mouse kidney. I. Sequential light microscopic study. Int. J. Radiat. Oncol. Biol. Phys. 2: 933-943, 1977. 8 Hopewell, J. W. and Wiernik, G. Tolerance of the pig kidney to fractionated X-irradiation. In: Radiobiological Research and Radiotherapy, pp. 65-73. I.A.E.A., Vienna, 1977. 9 Hornsey, S., Myers, R., Coultas, P. G., Rogers, M. A. and White, A. Turnover of proliferative cells in the spinal cord after X-irradiation and its relation to time-dependent repair of radiation damage. Brit. J. Radiol. 54: 1081-1085, 1981. 10 Janicki, R. H. Renal adaptation during chronic NH4C1 acidosis in the rat: no role for hyperplasia. Am. J. Physiol. 219: 613-617, 1970.
78 11 Janicki, R. H. and Lingas, J. Unabated renal hypertrophy in uninephrectomised rats treated with hyproxyurea. Am J. Phys. 219: 1188-1191, 1970. 12 Johnson, H. A. and Roman; J. M. vera. Compensatory renal enlargement. Hypertrophy versus hyperplasia. Am. J. Path. 39: 1-13, 1966. 13 Jordon, S. W., Yahas, J. N., Butler, J. L. B. and Kligerman, M . M . Dependence of fraction size for negative pi-meson induced renal injury. Int. J. Radial. Oncol. Biol. Phys. 7: 223-227, 1981. 14 McCreight, C. E. and Witcofski, R. L. Sequence of morphlogical and functional changes in renal epithelium following heavy metal poisoning. In: Compensatory Renal Hypertrophy, pp. 251-269. Editors: N. W. Nowinski and R. J. Gross. Academic Press, New York, 1969. 15 Phillips, T. and Fu, K. Derivation of time-dose factors for normal tissues using experimental endpoints in the mouse. In: Proc. of Conference on Time-Dose Relationships in Clin-
16
17
18
19
20
ical Radiotherapy, pp. 42-47. Editors: W. L. Caldwell and D. D. Tolbert, University of Wisconsin, 1974. Robbins, M. E. C. and Hopewell, J. W. Radiation related renal damage. In: Renal Toxicity in the Experimental and Clinical Situation. Editors: P. H. Bach and E. A. Lock. CRC Press Inc., Boca Raton, Florida, 1985 (in press). Stewart, F. A., Soranson, J. A., Alpen, E. L., Williams, M. V. and Denekamp, J. Radiation-induced renal damage. The effects of hyperfractionation. Radial. Res. 98: 407-420, I984. Williams, M. V. and Denekamp, J. Radiation induced renal damage in mice: Influence of overall treatment time. Radiother. Oncol. 1: 355-369, 1984. Williams, M. V. and Denekamp, J. Radiation induced renal damage in mice: Influence of fraction size. Int. J. Radiat. Oncol. Biol. Phys. 10: 885-893, 1984. Williams, M. V., Stewart, F. A., Soranson, J. A. and Denekamp, J. The influence of overall treatment time on renal injury after multifraction irradiation. Radiother. Oncol.: in press.
75
RTO00174
Editorial
The time factor in the radiation response of the kidney
Key words." Kidney, radiation response
The recent paper by Williams et al. [20] and other publications by members of this group [17,18,19] is of considerable interest, providing valuable information on the effects of fractionated radiation on the mouse kidney. The reaction of the kidney to radiation is complex and the assessment of isoeffect doses following fractionated exposure is difficult in a tissue system where the severity of damage was found to increase with time. This is particularly true in the most recent studies, where long treatment times of up to 80 days presented difficulties in the interpretation of time zero with respect to the timing of subsequent measurements. While the authors were aware of this problem and sought to overcome it by the "latency assays" it is still not surprising that the iso-effect doses and hence the assessment of dose recovered varies as a function of the endpoint selected. A similar problem was seen in the experimental studies by Glatstein et al. [6]. The rubidium-86 extraction assay, when used to assess the effects of treatments given in 9 fractions, showed a large increment ( ~ 10 Gy) in the iso-effect dose between a 4 and an 18 day regime. However, an alternative parameter, renal weight, did not produce the same result. Other authors [13,18] also reported renal weight to be a less sensitive indicator o f radiation damage. One group [13] selected an histological grading system in preference to either weight changes or a functional assay of renal damage for establishing iso-effect data. Williams et al. [20] provide iso-effect data for several endpoints using two precise assay techniques,
urine output and sTCr-EDTA clearance. The recovered dose between 20 and 80 days, excluding one result where a negative value was obtained, varied between 1.5 and 8.7 Gy (3-18%). While these differences do not exceed accepted levels of significance, the time exponents obtained from these data do depend on the way the results are expressed. The recovered dose is largely a feature of the difference in iso-effect dose between 20 and 40 days, with no significant increase in iso-effect dose being seen between 40 and 80 days. The authors claim that these findings, with respect to a time factor, were consistent with a "slow repair" process [20]. Examination of their earlier two fraction data suggests that the pattern of recovery recorded, on the basis of results obtained using the two functional assays, was not consistent with that originally described in the lung [4]. The phenomenon termed "slow repair" in the lung was found to be initiated shortly after irradiation with a recovery half time o f approximately 10 days. No evidence for any significant recovery was seen in the kidney within this time scale, iso-effect doses remaining fairly constant with intervals between fractions of 1-25 days. The pattern of recovery in the kidney is more akin to that reported in the spinal cord [9]. Here the iso-effect dose, in a two fraction study, remained constant with a 1-16 day interval between fractions; a significant increase in recovery was seen when the interval was extended to 32 days. It then remained stable at this higher level with interfraction intervals o f between 32 and 60 days. This would appear to
0167-8140/86/$03.50 9 1986 ElsevierSciencePublishers B.V. (BiomedicalDivision)
76 be in very good agreement with the two fraction data for the kidney [18] which showed a rise in isoeffect dose between 25 and 40 days with no significant change between 40 and 80 days. Results from the 16 fraction experiments [20] would also appear to be consistent with this pattern. In the spinal cord the time-dependent recovery was associated with unstimulated cell proliferation, which coincided with the release and division of neuroglial cells from a G1/S block [9]. In their paper Williams et al. [20] also suggested that the results of studies with pigs [8] c o n t r a s t with those in rodents in that there was a considerable increase in iso-effect dose with time in the pig studies. This statement would seem difficult to justify if approximately comparable pig and mouse data are compared (Table I). For a small number of fractions (5-6) the change in iso-effect dose between 4~40 days was consistent with a time exponent of 0.055-0.095 in the mouse and m i n u s 0.03 in the pig. However, when the 14 fraction pig and 16 fraction mouse results were compared the time exponent was greater in the pig. Thus pig and mouse data would apparently appear to be different but not in any consistent way. The previous suggestion made on the basis of pig results alone [8], that the value of the time exponent increased with fraction number, can no longer be justified on the basis of this new data. Moreover, since the mouse/pig differences are not consistently in one direction they cannot be explained simply by a process related to continued renal growth, inferring greater proliferation in the pig kidney model. The lack of a general pattern in the iso-effect data between pig and mouse with respect to time is further illustrated in Fig. 1. This graph also illustrates the recovery in both the pig and mouse kidney between 3 and 6 weeks seen by most investigators. The value of the time exponent over this period varies by a factor o f 5-8 in the mouse and by 4 in the pig. In an Annual Report from this Institute a comparison was made between the results o f split dose studies in the pig, where a single kidney was irradiated and those of similar investigations in the mouse [15] where the remaining hypertrophied kid-
TABLE I Iso-effect data in pig and mouse kidney for selected numbers of fractions given in different overall times. Species
Fraction no.
Iso-effect dose (Gy)
Mouse [18]
5 5 6 16 16 14
24.5" (4) 30.5 23.6 b (4) 26.8 19.0 a (5) 18.1 52.9" (20) 54.5 48.0 ~ (20) 55.3 20.4 (18) 27.5
Pig [8] Mouse [20] Pig [8]
Time exponent (40) 0.095 (40) 0.055 (39) - 0 . 0 3 * (40) 0.043 (40) 0.204 (39) 0.39
The overall treatment time associated with a specified iso-effect dose is given in parenthesis. The assay techniques used are as follows: s 7Cr_EDTA clearance; b 25% reduction in renal weight; r urine output; d 131i_hippuran renogram. * Best fit to 6F in 4, 18 and 39-day data, includes previous unpublished data.
ney h a d b e e n treated after unilateral nephrectomy. On the basis of this comparison it was suggested that the recovery seen in the pig between 18 and 39 days, but not in the mouse, was possibly related to stimulated repopulation. It was argued that a hypertrophied kidney would have expressed its full proliferative potential prior to irradiation and could not respond further. However, the concept of stimulated or perhaps unstimulated proliferation 7060" 50-
. ~ r/-[o2o[ ~.L3:::=~._..::.{~. 16 ~[oo4:
~ou~
5F [032) lZ.F 1039)
30-
o CD
. . . .
~
~
~
~ /
:
F
\'2~ [046[
ir~
9
10
2 /
f
Ib
S
410
610 80
Time {days]
Fig. 1. Log-log graph showing the relationship between iso-effect dose and overall treatment time for studies involving either mouse (broken lines) or pig (solid lines). The number of fractions used by various investigators is given with the associated slope (time exponent) of the lines between 3 and 4 weeks. [[~---/x, ref. 20; *---/~*, <>--~i,, ref. 18; O - - O , re[ 15; I I - - A - - O , ref. 8 plus unpublished data from Hopewelt et al.]. * 5 Fraction data has been redrawn to show the same time related change as for 2 fractions in the mouse [t8].
77 [9] in the kidney is unproven and is perhaps difficult to fully justify in an organ where the majority of renal growth following a variety of insults, is mainly the result of cell enlargement, hypertrophy not proliferation. For example, 75% of the compensatory growth seen following unilateral nephrectomy was by cell enlargement [12]. Hypertrophy and hence improved total renal function was also found in a situation where DNA synthesis was partly blocked I11]. A cell cycle block may well occur in any irradiated tissue. Hypertrophy was also seen in a situation where the normal low level of [aH]thymidine incorporation in the kidney was decreased [10]. However, with some forms of renal injury hyperplasia may predominate [2,14]. In the normal rat kidney both cell division and cell enlargement play a part in normal renal growth. Between 7 and 95 days cell enlargement was found to be at least twice as important as cell proliferation [3]. Comparable data for the pig does not exist but is clearly worthy of study. However, if proliferation is important it does not influence the fraction response in the pig with respect to the mouse in any specific way. An alternative explanation of the increase in isoeffect dose between 3 and 6 weeks is the possibility of an induced radiobiological hypoxia in an organ confined by a fibrous capsule. Reduced blood flow [5], impaired ERPF [1] and oedema [7] have been reported shortly after the commencement of a fractionated radiation treatment. In this respect the pig kidney may be different from the mouse in the sense that the renal capsule is a significantly more robust structure in the pig. There would appear to be no completely satisfactory explanation of the time factor in the response of the kidney to fractionated irradiation. The radiation tolerance of the kidney is influenced by complex radiobiological and physiological factors and functional assays of damage cannot necessarily be equated with reproductive cell survival. No one animal model or assay system can provide a complete understanding of the problems involved. A complete understanding can only come from the study of a variety of assay techniques in several animal models with a frank interchange of
views of the different findings likely to be obtained. It is worth concluding by pointing out that the relationship between iso-effect dose and fraction number produced remarkably good agreement when the different model systems and assay techniques were compared [16]. J. W. Hopewell and M. E. C. Robbins
CRC Normal Tissue Radiobiology Research Group Research Institute (University of Oxford) Churchill Hospital Oxford, U.K.
References 1 Avioli, L. V., Lazor, M. Z., Cotlove, E., Brace, K. C. and Andrews, J. W. Early effects of radiation on renal function in man. Am. J. Med. 34: 329-337, 1963. 2 Castle, W. N. and McDougal, W. S. Coutralateral renal hyperplasia and increase renal function after relief of chronic unilateral ureteral obstruction. J. Urol. 132: 1016-1020, 1984. 3 Enesco, M. and Leblond, C. P. Increases in cell number as a factor in the growth of organs and tissue in the young male rat. J. Embryol. Exp. Morphol. 10: 530-562, 1962. 4 Field, S. B., Hornsey, S. and Kutsani, Y. Effects of fractionated irradiation on mouse lung and on phenomenon of slow repair. Brit. J. Radiol. 49: 700-707, 1976. 5 Glatstein, E. Alterations in rubidium-86 extraction in normal mouse tissues after irradiation. Radiat. Res. 53: 88-101, 1973. 6 Glatstein, E., Brown, R. C., Zanelli, G. D. and Fowler, J. F. The uptake of rubidium-86 in mouse kidneys irradiated with fractionated doses of X-rays. Radiat. Res. 61: 417-426, 1975. 7 Glatstein, E., Fajardo, L. F. and Brown, J. M. Radiation injury in the mouse kidney. I. Sequential light microscopic study. Int. J. Radiat. Oncol. Biol. Phys. 2: 933-943, 1977. 8 Hopewell, J. W. and Wiernik, G. Tolerance of the pig kidney to fractionated X-irradiation. In: Radiobiological Research and Radiotherapy, pp. 65-73. I.A.E.A., Vienna, 1977. 9 Hornsey, S., Myers, R., Coultas, P. G., Rogers, M. A. and White, A. Turnover of proliferative cells in the spinal cord after X-irradiation and its relation to time-dependent repair of radiation damage. Brit. J. Radiol. 54: 1081-1085, 1981. 10 Janicki, R. H. Renal adaptation during chronic NH4C1 acidosis in the rat: no role for hyperplasia. Am. J. Physiol. 219: 613-617, 1970.
78 11 Janicki, R. H. and Lingas, J. Unabated renal hypertrophy in uninephrectomised rats treated with hyproxyurea. Am J. Phys. 219: 1188-1191, 1970. 12 Johnson, H. A. and Roman; J. M. vera. Compensatory renal enlargement. Hypertrophy versus hyperplasia. Am. J. Path. 39: 1-13, 1966. 13 Jordon, S. W., Yahas, J. N., Butler, J. L. B. and Kligerman, M . M . Dependence of fraction size for negative pi-meson induced renal injury. Int. J. Radial. Oncol. Biol. Phys. 7: 223-227, 1981. 14 McCreight, C. E. and Witcofski, R. L. Sequence of morphlogical and functional changes in renal epithelium following heavy metal poisoning. In: Compensatory Renal Hypertrophy, pp. 251-269. Editors: N. W. Nowinski and R. J. Gross. Academic Press, New York, 1969. 15 Phillips, T. and Fu, K. Derivation of time-dose factors for normal tissues using experimental endpoints in the mouse. In: Proc. of Conference on Time-Dose Relationships in Clin-
16
17
18
19
20
ical Radiotherapy, pp. 42-47. Editors: W. L. Caldwell and D. D. Tolbert, University of Wisconsin, 1974. Robbins, M. E. C. and Hopewell, J. W. Radiation related renal damage. In: Renal Toxicity in the Experimental and Clinical Situation. Editors: P. H. Bach and E. A. Lock. CRC Press Inc., Boca Raton, Florida, 1985 (in press). Stewart, F. A., Soranson, J. A., Alpen, E. L., Williams, M. V. and Denekamp, J. Radiation-induced renal damage. The effects of hyperfractionation. Radial. Res. 98: 407-420, I984. Williams, M. V. and Denekamp, J. Radiation induced renal damage in mice: Influence of overall treatment time. Radiother. Oncol. 1: 355-369, 1984. Williams, M. V. and Denekamp, J. Radiation induced renal damage in mice: Influence of fraction size. Int. J. Radiat. Oncol. Biol. Phys. 10: 885-893, 1984. Williams, M. V., Stewart, F. A., Soranson, J. A. and Denekamp, J. The influence of overall treatment time on renal injury after multifraction irradiation. Radiother. Oncol.: in press.