S.J. Golding

A morphological study of radiation nephropathy in the pig.

Both kidneys of mature pigs received a single dose of 9.8 Gy 60Co gamma rays. Pigs were killed between 2 and 24 weeks after irradiation and the kidneys examined histologically. Glomerular and tubular changes were observed within 2 weeks of irradiation. Neutrophils and other leukocytes were seen within glomerular capillary loops; mesangial matrix and cell number increased. A progressive increase in thickening of the basement membrane and a decrease in capillary lumina were then noted. Basement membrane duplication occurred within 12 weeks. By 24 weeks these lesions had increased in severity, sclerotic endstage glomeruli, predominantly subcapsular or juxtamedullary, being evident. Tubular lesions initially consisted of focal areas of tubular atrophy in the juxtamedullary region. By 6 weeks subcapsular foci of tubular degeneration, regeneration, and necrosis were found; these appeared to resolve 12 weeks after irradiation. At later times the severity of the tubular lesions varied between pigs, with some exhibiting interstitial fibrosis involving a complete band of subcapsular tissue, while others showed relatively mild changes. There was no apparent change in the vasculature. These findings indicate that (a) there is no one target or dose-limiting cell, and (b) the vasculature does not play a primary role in the development of radiation nephropathy.

Radiation nephropathy in mature pigs following the irradiation of both kidneys.

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.

Sequential evaluation of radiation-induced glomerular ultrastructural changes in the pig kidney

Both kidneys of 12 mature female pigs received either a single dose of 9.8 Gy 60Co gamma rays or sham irradiation. At intervals of 1-4 weeks serial renal biopsies were obtained, followed by sacrifice at 24 weeks after irradiation. Individual kidney glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and the hematocrit (Hct) were measured routinely. Renal irradiation resulted in a progressive decline in GFR, ERPF, and Hct, with minimal values being observed within 12 weeks of irradiation. No change in any of these parameters was noted in the sham-irradiated pigs. The initial morphological change in irradiated glomeruli was leukocyte attachment to capillary endothelial cells 3-6 weeks after irradiation followed by activation and swelling of the endothelial cells. This was followed by pronounced increases in capillary permeability with fluid and erythrocyte, leukocyte, and platelet exudation into the subendothelial/mesangial space. This resulted in compression of glomerular capillary lumina, which occurred concomitantly with the reduction in GFR. By 12 to 15 weeks after irradiation the changes in endothelial cells were less evident. However, mesangial cells exhibited evidence of activation and proliferation accompanied by progressive mesangial expansion and sclerosis. Thus the glomerular capillary endothelial and mesangial cells appear particularly important in the pathogenesis of radiation nephropathy.

CT evaluation of lymph node status at presentation of prostatic carcinoma

Computed tomographic (CT) studies performed within a general oncology service in 104 consecutive patients with prostatic carcinoma were reviewed retrospectively to assess the incidence and distribution of lymphadenopathy. All patients were staged with CT at initial presentation, had normal skeletal scintigrams and were candidates for radical radiotherapy. The likelihood of lymphadenopathy was associated with increasing T-stage. 57 of the 92 (62%) patients without lymph node enlargement had local disease confined to the prostate (T2 or less) compared with only two of the 12 (17%) patients with enlarged nodes. Lymph node enlargement was more likely with a primary tumour of poorly differentiated histology. 12 patients (11.5%) had lymphadenopathy by established CT criteria; six with pelvic nodal enlargement alone and six with enlargement of pelvic and retroperitoneal nodes. In all patients pelvic nodal enlargement predominated and no patient had isolated retroperitoneal lymphadenopathy. Our findings indicate that CT staging studies of prostatic cancer do not need to include the retroperitoneum if there is no lymphadenopathy at or below the aortic bifurcation.

Residual Radiation-induced Damage to the Kidney of the Pig as Assayed by Retreatment

The effect of re-irradiation on the previously irradiated kidney was studied in the Large White female pig. Both kidneys of 14-week-old pigs were initially irradiated with a single dose of 3-7 Gy of 250 kV X-rays. The individual kidney glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and the haematocrit (Hct) were serially measured up to 24 weeks after X-irradiation. Doses of 3 and 5 Gy of X-rays had little effect on the GFR. However, 7 Gy of X-rays caused a marked decline in the GFR up to 12 weeks after irradiation; the GFR then began to recover. A similar pattern of response was seen in the ERPF. In contrast, the Hct was reduced in all pigs 4 weeks after X-irradiation. The extent of the decline and subsequent recovery 24 weeks after irradiation appeared to be related to dose. Twenty-four weeks after X-irradiation both kidneys were re-irradiated with a single dose of 7.9 Gy of 60Co gamma-rays; both kidneys of four age-matched control pigs which had not previously received X-irradiation were similarly treated. Individual kidney GFR, ERPF and Hct were again serially measured up to 24 weeks after gamma-irradiation. Re-irradiation resulted in a significantly greater reduction in the GFR, ERPF and Hct compared with that seen after gamma-irradiation alone. Moreover, the severity of the reduction in the GFR and Hct observed after gamma-irradiation was related, in a dose-dependent manner, to the initial X-ray doses employed. These results indicate that the kidney fails to exhibit complete long-term recovery in function following irradiation. Re-irradiation of the kidney in patients should thus be viewed with extreme caution.

Nephropathy in the mature pig after the irradiation of a single kidney: A comparison with the immature pig

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.

Functional recovery in the irradiated kidney following removal of the contralateral unirradiated kidney

The right kidneys of seven Large White female pigs, approximately 14 weeks of age, were irradiated with single doses of 7-12.6 Gy of 250 kV X-rays. Sequential measurements of individual kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were carried out using 99mTc-DTPA and [131I]hippuran renography for time periods up to 24 weeks after irradiation. From this data, kidneys receiving a dose of 7 Gy were found to be functioning (F), while kidneys which received greater than or equal to 8.8 Gy were assessed as having no significant function (NF). When the pigs were approximately 10 months of age the contralateral unirradiated kidney was removed; the left kidney of three age-matched unirradiated pigs was also removed. The response of the right kidney to unilateral nephrectomy (UN) in these animals was assessed in terms of changes in haemodynamics (i.e. GFR and ERPF) for periods up to 24 weeks after UN. At post-mortem, the length and weight of the remaining kidney was measured. A marked increase in renal length was observed in irradiated kidneys following UN. In addition, the weights of irradiated kidneys following UN were greater than those of irradiated kidneys in age-matched pigs where the unirradiated kidney had not been removed. Four weeks after UN there was a pronounced increase in GFR and, in particular, ERPF in previously NF irradiated kidneys. The mean increase in these parameters, measured at the end of the follow-up period, when compared with the pre-surgery values, was 350.1 +/- 84.3 and 781.8 +/- 151.0% respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

‘Watch policy’ in patients with suspected stage I testicular seminoma: CT as a sole staging and surveillance technique

A study was undertaken to assess the role of computed tomography (CT) as the sole imaging technique for the staging and surveillance of patients with stage I testicular seminoma. Of the 15 patients studied, five (33%) relapsed. This relapse rate differs from other studies. The reasons for this are discussed.

The Effect of Unilateral Nephrectomy on the Subsequent Radiation Response of the Pig Kidney

The left kidney of 14 Large White female pigs, approximately 14 weeks of age, was surgically removed. Thirty weeks after unilateral nephrectomy (UN) the remaining kidney was irradiated with a single dose of between 11.9 and 15.6 Gy of 60Co gamma-rays; three pigs received sham irradiation. Following irradiation glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and haematocrit (Hct) were determined for up to 48 weeks after irradiation. Irradiation resulted in a dose-dependent decline in GFR, evident 8 weeks after irradiation. This was followed by a gradual improvement in GFR, although after doses of 14.0 Gy GFR remained below control values throughout the study. A similar pattern of response was seen in terms of ERPF, but this was not dose-related. Doses of greater than or equal to 14.0 Gy also caused a significant reduction (p less than 0.001) in Hct within 4-8 weeks. Minimal levels were evident 16 weeks after irradiation; Hct then increased, but remained below preirradiation values. Dose-effect curves were obtained by determining the percentage of irradiated kidneys which showed a greater than or equal to 50% reduction in GFR and ERPF, fitted by probit analysis, and ED50 values (+/- SE) were calculated for each parameter. The ED50 values for GFR and ERPF were 14.49 +/- 0.27 Gy and 12.56 +/- 0.98 Gy, respectively. These values were not significantly different from those obtained from intact age-matched pigs in which the right kidney alone was irradiated; UN did not compromise or alter the radiation response of the kidney to irradiation. However, the ED50 values obtained for the UN pigs were significantly greater (p less than 0.001) than the values of 9.76 +/- 0.17 Gy and 6.19 +/- 0.93 Gy, seen for GFR and ERPF in intact age-matched pigs in which both kidneys were irradiated. Thus although both experimental situations involved irradiating the entire renal tissue, the relative radiosensitivity of the kidneys varied considerably. These findings show that the radiosensitivity of the pig kidney can vary markedly, depending on the physiological status of the kidney at the time of irradiation.

The response of the pig kidney to the combined effects of cisplatin and unilateral renal irradiation

Seven mature Large White female pigs, approximately 10 months of age received a single dose of cis-dichlorodiammineplatinum(II), c-DDP (2.5 mg/kg body weight). Prior to, and 4 weeks after c-DDP administration, individual kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by [99mTc]DTPA and [131I]hippuran renography. Of the 5 pigs surviving the c-DDP treatment most exhibited a reduction in both GFR and ERPF; the mean reduction in GFR (36.2 +/- 18.9%) was more pronounced than that for ERPF (12.6 +/- 19.4%). However, the difference in the severity of the impairment in these two parameters was not significant (p greater than 0.55). Haematocrit, haemoglobin and red blood cell counts were markedly reduced 14 days after c-DDP infusion, and despite some recovery evident 21 days after treatment, all three haematological parameters were still reduced 28 days after c-DDP administration. The right kidneys of these 5 animals, plus 5 pigs which did not receive c-DDP, were irradiated with a single dose of 11.9 Gy of 60Co gamma-rays. Individual kidney GFR and ERPF was routinely measured up to 24 weeks after irradiation. Pigs in which only the right kidney was irradiated showed a marked increase in both GFR and ERPF values 2 weeks after irradiation. This was followed by a decline in function with a reduction of 50% in terms of ERPF 16 weeks after irradiation. Values then showed some evidence of a recovery in function. There was a concomitant compensatory response by the contralateral unirradiated kidney.(ABSTRACT TRUNCATED AT 250 WORDS)