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Clinical radiation nephropathy
Int. I. Radiation
Oncology
Biol.
Pergamon
Phys.,
Vol. 3 I, No. 5, pp. 1249- 1256, 1995 Copyright 0 1995 Elsevier Science Ltd Printed in the USA. All rights reserved 0360.3016/95 $9.50 + DO
0360-3016(94)00428-5
l
Special Feature -Late
Effects Consensus Conference
CLINICAL
RADIATION J.
NEPHROPATHY
ROBERT CASSADY,
M.D.
Professorand Head,Departmentof RadiationOncology, University of Arizona Health SciencesCenter, 1501N. CampbellAvenue, Tucson,AZ 85724 An analysis of the normal tissue effects of irradiation of the kidney is presented. Various clinical syndromes resulting from treatment are described as well as the potential cellular basis for these findings. Effects of concurrent and/or sequential treatment with irradiation and various chemotherapeutic agents are discussed and the impact of these agents on toxicity presented. Adverse consequences of renal treatment in the child is described and possible radiation effects on so-called compensatory hypertrophy following nephrectomy presented. Renal consequences described to date of bone marrow transplantation programs utilizing irradiation are also presented. The necessity of a dose-volume histogram analysis approach to analyzing renal toxic effects in patients followed for long (> 10 year) periods is essential in developing accurate guidelines of renal tolerance. Radiation nephropathy, Radiation nephritis, Hyperrenninemic tograms, Pediatric radiation renal tolerance, Growth arrest, Chemo/radiation interactions.
INTRODUCTION
difficult. Theseinclude variations in equipment usedproducing x-rays of differing RBE (orthovoltage vs. megavoltage), variations in radiation fraction size used, and overall time of treatment, unclear descriptionsof treatment volumes, and radiation fields making assessment of total renal masstreated to various dosesimpossible,limited descriptionsof prior or coexisting renal disease,and finally, and perhapsof greatest importance, variability in duration of follow-up after treatment combined with the small number of instancesof toxicity described. Although clinically relevant toxicity is clearly avoidable by exclusion of an adequatevolume of renal tissue treated to more than a modest dose, the kidneys’ central location frequently makes this difficult or impossible when tumors of the abdomen or retroperitoneum are treated.
Clinical radiation damage to the kidney represents an uncommonly described toxicity of radiation that can result in considerable morbidity and/or death. First described nearly 90 years ago (2, 49), the papers of Luxton and Kunkler and Farr and Luxton in 1952 first clearly described clinical manifestations and consequences (21,24-26). Maier noted only 151 casesas having been described in the literature in his review article in 1972 (27).
ANATOMICAL
hypertension, Tolerance, Dose-volume hisHypertrophy, Bone marrow transplantation,
PHYSIOLOGY
The kidneys are paired organscomposedof large numbers of nephronsfunctioning in a parallel fashion to permit “constancy of the internal environment” by selective waste/toxic substanceremoval from the blood plasma and also aid in electrolyte and fluid balance regulation (53). They also produce the active derivative of vitamin D, the enzyme rennin, and erythropoietin. As with the lung, toxicity scoring systemsmust have the capacity to separateeffects on a limited renal massfrom overall functional effects. As these latter, clinically more relevant toxicities are usually related to the total volume of renal mass treated, dose-volume histograms are essential to permit prediction of likely toxicity. However, in addition to an absenceof literature describing renal dose-volume histograms correlated with clinical outcome, a variety of other problems make development of accurate dose-response curves for radiation nephropathy
PATHOPHYSIOLOGY OF RADIATION DAMAGE TO THE KIDNEY A functional model of the kidney proposes that this paired organ consists of a number of functional units arranged in parallel. This functional unit, the nephron, consists of a glomerulus with its capillary network and a proximal and distal convoluted tubule arrangement. Variation exists within the kidney and cortical nephrons have a short loop of Henle, whereas juxtamedullary nephrons have a long loop of Henle and are thought to be primarily responsible for baseline renal function in fasting individuals. Although the nephron might be considered a miniature 1249
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I. J. Radiation Oncology l Biology 0 Physics
organ composed of a number of cells in series, damage to anyone of which may prove functionally damaging, the parallel arrangement of many such units compiled with redundancy in the system permits significant cumulative damage to occur without obvious functional or clinical significance. The kidney also plays a feedback/control role in red blood cell formation and also plays a role in blood pressure regulation. The role of irradiation in primary (vs. indirect) effects on these two functions is very controversial and poorly studied. Almost all morphologic information regarding the initial site(s) of radiation damage occurring days to weeks or even months following irradiation is based on murine studies, as human data is almost entirely limited to late or end stage renal disease many months or years following treatment. Interpretation of these murine studies varies considerably. Studies reported by Phillips and colleagues suggested that tubular cell damage was primarily responsible for renal toxicity from radiation (35). Subsequently, Glatstein, Fajardo, and Brown demonstrated early damage to glomerular and juxtaglomerular cells with glomerular thrombosis and suggested this site as an important site of toxicity (12). They also noted that the term “radiation nephritis” was a misnomer as inflammatory exudates were rarely noted and proposed ‘ ‘radiation nephropathy” as a more suitable descriptive term. More recently, Hoopes and colleagues have suggested that multiple target sites exist for radiation damage to the kidney that have different times of expression (14, 15). Their studies suggested that initial functional survival depend on the extent/repair of parenchymal damage and also demonstrated extensive tubular cell repopulation in surviving animals. Early blood vessel wall changes were temporary, whereas perivascular fibrosis from damage to perivascular connective tissue was the dose-limiting toxicity for late effects. Such a multiple target explanation, which include secondary effects from hypertension, anemia, etc., seem to best explain clinical and laboratory studies that have been performed. Similarly, White has described early and late changes following significant renal irradiation (50). Early changes include atypism and tubular cell necrosis as well as endothelial microvascular damage especially in the subendothelial space separating the endothelium from the basement membrane. Characteristic late changes include a total renal mass reduction with prominent and sclerosed interlobular and arcuate arteries. Significant occlusion of glomerular capillary loops and glomerular hyalinization is seen with progressive atrophy of tubules. Associated with all these changes are significant degrees of interstitial fibrosis. CLINICAL SYNDROMES Although first described early in this century, clinical toxic effects of bilateral renal irradiation were first well
Volume 31, Number 5, 1995 Table I. Clinical syndromes following renal irradiation Type
Latent period
Acute radiation nephropathy (nephritis) Chronic radiation nephropathy Benign hypertension Malignant hypertension Hyperreninemic hypertension (Goldblatt kidney)
6- 12 months 2 18 months 2 18 months 12-18 months 2 18 months
described and categorized by Luxton and Kunkler, Fart-, and Luxton who described four primary clinical syndromes that were separated both by extent of symptoms and their initial time of appearance following irradiation (Table 1) (21, 24). Thus, “acute radiation nephritis” was first clinically apparent 6- 12 months following exposure of both kidneys to moderate doses of radiation whereas, “chronic radiation nephritis” appeared 18 months to years following treatment. Similarly hypertension, either “benign” or “malignant” was categorized and appeared 18 months to years after treatment. They also identified asymptomatic proteinuria as a manifestation of radiation damage. More recently, hyperrenninemic hypertension following unilateral renal irradiation has been described as a clinical syndrome as has the nephrotic syndrome (11, 16). Overlap of these clinical groupings is common and progression of “acute” symptoms to a chronic phase, often with hypertension, is common. One or more months following bilateral renal irradiation of 20.0-25.0 Gy, symptoms of headache, vomiting, hypertension, edema, and fatigue may be noted. Clinically, funduscopic findings of arteriolar-venous nicking, normochromic normocytic anemia, urinary findings of microscopic hematuria, proteinuria, urinary casts with elevated B-2 microglobulin levels, decreased creatinine clearance, and elevated blood urea nitrogen levels may accompany these symptoms (20). These findings are rarely seen in the first 6 months following treatment and may resolve with medical management with little or no residual or may progress to a mild or severe chronic phase or the patient may develop malignant hypertension, which is often fatal (Table 2). Table 2. Clinical svmotoms/signs of radiation nephropathv Symptoms Edema Dyspnea Headache/hypertension Nocturia Lassitude Signs Proteinuria Anemia Hypertension Cardiac enlargement Note that these are in no way unique from other causes of renal damage
Clinical
CUYuLAllVt RAOIATION RAOS
radiation
nephropathy
0
J. R. CASSADY
4000 1 3ooo 2000 1 IO00 0b I3OF
-hPAH M H M 6--d
p,
1251
Renat Plasma Flaw Glamcru~aar Filtratran ROM Bloodurea Nitrogen Yawnal Urine ConcmhOllOn
1 i
Tm PAH mp/Min
GFR ml. / Yin.
BUN m9. % SC.
1
150 140 I30 I20 I+ II0 c :;f ZJi
-J ---
I
y-y;-, /&,b&Mj
’
1
LlddL&.:
5
1,
-i’
Fig. 1. Typical data from Avioli et al. (1) measuring renal function parameters during and after irradiation. Note the initial rise in elomerularfiltratin rate and renal nlasmaflow followed by a late decreasein both parameters.
In contrast, tubular function appearedto recover. Avioli et aZ.and othershave describedtruly acutechanges in renal function parametersafter irradiation (Fig. 1) (1, 20). After treatment of 20.0 + Gy, an initial rise (15-20%) is seen in glomerular filtration rate (GFR) during the course of treatment. In the months following treatment, GFR decreased an average of 20-25% from baseline in 8 of 10 patients studied. Renal plasmaflow consistently decreased; however, tubular function appearedto recover in the latter half of the first year following an initial decrease.In contrast, more conventional measureof renal function (BUN, creatinine clearance,and serumcreatinine) rarely show abnormalities in the initial 6 months following irradiation; however, may then show progressive abnormalities in patients destined to develop radiation nephropathy. Serum and urine B-2 microglobulin levels correlate well with glomerular and tubular function, respectively, whereas serum levels correlate very well with inulin clearance (Fig. 2) (51). Unfortunately, it is not uncommon for patients to show no acute or subacute signs or symptoms and, many years following treatment, present with chronic nephropathy and/or hypertension with proteinuria (vide infra). Death has occurred
in nearly half the reported
patients
in 3-5 weeks time using reduced daily fractions (37). Clinical studies by Dewit et al. support this contention (8). However, the duration of follow-up is critical to development of “safe’ ’ levels of treatment and, as noted above, signs and symptoms of late radiation damage to the kidneys may not develop for years (46). The studies of Thompson et al. and Stewart et al. are of importance in this respect (41, 45).
who have
manifested acute changes; however, most of these patients were seen in the predialysis and prerenal transplant era. 5L
RADIATION: TOLERANCE DOSES AND TOLERANCE VOLUMES Renal tolerance (TD 515) has been stated to be 20.0 Gy when irradiation has been delivered to both kidneys
, 1
Serum
,
I
I,
I
I
I
2
3
45
10
20
30
PZ-microglobulin
(lug/ml)
Fig. 2. Nearly linear correlation of inulin clearance with serum levels of BZ-macroglobulin [data of Wibell ef al. (51)].
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Volume
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Correlation of Dose with Symptomatic Radiation Nephropathy 100
Thompson, et al. Dewit, et al. A Avioli, et al.
-
l
80-
n
80-
+ Luxton + LeBourgeois; x Kim, et al.
Dewit;
Kim
70$ 5
60-
;
50-
5
40302010 -
L.ilmt
period
(years)
0
Fig. 3. Data of Thompson et al. (45) demonstrating an extremely long latent period following irradiation prior to development of symptomatic (black bars) radiation nephropathy. Black and white bars depict patients in whom any renal-related abnormality was found. Thompson et al. assessed the incidence of clinically symptomatic nephropathy after delivery of radiation (-20.0 Gy) to suppress gastric acid formation in patients with postgastrectomy peptic ulcer disease (45). A 17% (11 out of 67) incidence of “symptomatic” renal disease was found with nine deaths related to renal problems. A total of 31 (46%) renal-related abnormalities were noted. The minimum follow-up period in this study was 8 years, with a range of 8- 19 years. The latent period in nearly half of the patients developing renal abnormalities was greater than 10 years (Fig. 3). In contrast, a maximum followup period of 5 years was available in the Dewit et al. study (17- 18 Gy) (8), and only 12 months in the study of Avioli (20-24 Gy) (1). Longer follow-up was also available in the study of Willett et al. (minimum dose 26.0 Gy); however, most of their patients received irradiation to only one kidney or a portion of one kidney (52). Willett’s study suggests that radiation doses of 26.0-30.0 Gy probably eliminates renal function in that kidney when unilateral treatment is given (Table 3). As less accurate dosimetry may flaw the study of Thompson, it will be of considerable importance in the future to obtain long-term follow-up in patients receiving more than 15 Gy to one or both kidneys. Dose-volume histograms of renal radiation treatment levels correlated with such long-term followup information will ultimately be necessary for accurate Table 3. Evidence of a plateau in radiation effect on renal function decrease A. Percent Decrease in Mean Creatinine Clearance as a Function of % Kidney irradiated # pts 38 17 31
# Observations
Mean % decrease in creatinine clearance
50%
48
10
60-85% 90- 100%
21
19 24
% Kidney irradiated
41
0
I 500
I 1000
I 1500
I
I
I
I
2500 2000 Dose kGy)
3000
3500
4000
1
Fig. 4. Dose-responsecurve generatedfrom data presentedin severalseriesin the literature. An approximatethresholddose of 15.0 Gy (conventionalfractionation) is seenand a plateauis noted beyond dosesof 30.0 + Gy.
predictions of renal “tolerance” to irradiation. However, for the present, a threshold dose of - 15.0 Gy delivered with conventional fractionation (in the absence of interactive drugs and underlying renal disease)appearsreasonable while radiation dosesof more than 25.0-30.0 Gy to the total renal mass are likely to eliminate useful renal function in patients followed for sufficiently long periods of time (Fig. 4). Treatment of one kidney and ipsilateral renal artery may produce renal artery narrowing with increasedrennin secretion from the juxtaglomerular apparatus (6, 11, 29). This phenomenon has been noted most often following treatment of infants or children and should be distinguished from other types of renal radiation-related hypertension. Although great caution should be exercised, vascular surgical approachesor nephrectomy may be curative (19, 36).
SPECIAL
CLINICAL
SETTINGS
Pediatric radiation renal tolerance In general, the tolerance of the kidneys in the child to radiation is similar to that of the adult. There is one possible exception. Peschel et al. has reported chemical alterations in renal function in three infants given 12- 14 Gy to reduce massive hepatomegaly from neuroblastoma (34). Although not definitive, this suggests that the infantile kidney may be subject to developmental toxicity from irradiation and, like other infantile tissues (i.e., brain, bone) may be transiently more sensitive to developmental arrest. Some experimental animal data exists to support this contention (48). Sagerman et aZ. demonstrated that moderate doses of unilateral irradiation (20.0-30.0 Gy) causedgrowth arrest and/or atrophy in the developing kidney(s) of children with neuroblastoma (38). Moskowitz and Donaldson and
Clinical
Table 4. Pediatric Radiation dose GY)
Renal Radiation
nephropathy
Tolerance
# pts
Follow up Interval (months)
16 1 4
48- 148 175 12-121
11.0-13.0 13.01-14.0 14.01-15.0
radiation
in engrafted patients. Guinan et al. and Tarbell et al. have reported the development of hemolytic anemia and renal insufficiency in 16 out of 39 children with acute lymphoblastic leukemia (ALL) or neuroblastoma (NB) who had undergone allogeneic or autologous bone marrow transplantation (9, 32) (Table 5) (13, 43). The median time to development of this complication was 5 months posttransplant. Biopsies done on two patients were consistent with “radiation nephropathy.” Nine of 28 children with autologous transplants for ALL developed this complication after intensive preparatory therapy consisting of VM 26, cytosine arabinoside, and cyclophosphamide, and 12- 14 Gy in 6-8 fractions at 0.09-o. 11 Gy/min total body irradiation. Seven of the 11 children receiving allogeneic transplantation for neuroblastoma (NB) were affected. The preparatory regimen for these children included cisplatinum, VM 26, melphalan, and cyclophosphamide, and similar total body irradiation. The authors speculate that this complication is related to both the intensive chemotherapy and total body irradiation. Lawton et al. have noted renal dysfunction in 14 out of 103 adults transplanted primarily for leukemias and lymphomas (10) (Fig. 5) (22). A wide variety of chemotherapeutic agents/regimens were used for this group of patients. Radiation parameters were similar to the pediat-
Nephropathy 0 0 1
The presence of only one case of nephropathy at the dose levels cited suggest that most pediatric patientsdo not differ substan-
tively from adults. Cassady et al. have presented data that suggestthat moderate dosesof irradiation (14.5-20.0 Gy) may reduce or eliminate the ability of a remaining kidney to hypertrophy after nephrectomy (3, 30). Cassady et al. and Malcolm et al. have also provided some long-term data on clinical radiation tolerance by studying children with Wilms’ tumor who received moderate dosesof renal irradiation becauseof prior peritoneal tumor spill (11 patients) or bilateral renal involvement (10 patients) (3, 28) (Table 4). All 21 children had survived their Wilms’ tumor and were followed for periods of 12 months to 175 months. All but one child was followed for a minimum of 48 months after treatment. Of 16 children receiving 11.0-13.0 Gy (follow-up 48- 148 months), no child experienced clinical renal toxicity. One child received 13.62 Gy (follow-up 175 months) and has demonstrated no renal toxicity, whereas one of four children receiving 14.0 1- 15.00 Gy demonstrated transient radiation nephropathy. This is consistent with data from National Wilms’ Tumor Study where only one child has reportedly developed nephropathy (44). It must also be remembered that all these children also received actinomycin-D (AmD) + vincristine although the effect of AmD on enhancing radiation nephropathy is controversial (4,5,7, l&39). Thus, by extrapolation from these pediatric data to adults, a fractionated dose of 1400 rad appears to be relatively safe even on a long-term basiswhen delivered without chemotherapy (Fig. 4).
ric reports.
Author Guinan, Tarbell
Lawton
following
et al.
bone marrow
Primary disease
Radiation
Children
ALL
ibid
Neuroblastoma
12-144 Gy/6-8 9- 11 cGy/min Ibid
Adults
Leukemia and Lymphoma
autologous
Almost all of these children platinum.
and adults had been extensively
in these settings
with low-dose
rate
Chemo/radiation interactions A number of chemotherapeutic agents are recognized as potentiating the effect of x-irradiation and/or contribute with or without irradiation to renal toxicity. Actinomycin D (AmD) has been shown in experimental in vivo and in vitro systemsas well as in clinical situations to potentiate the effect of irradiation on many normal tissuesincluding the gut, lung, and skin (5, 7). Its potentiating effect on the kidney is controversial. Keidan and Sagerman have reported clinical cases of radiation nephropathy and invoked AmD potentiation (18, 39). However, renal radiation dosesin both instances (23.70 and 25.0 Gy) are also consistent with radiation effect alone. Concannon et al.
Age group et al.
Treatment
irradiation may improve renal radiation tolerance significantly (33).
Bone marrow transplantation Several groups have by now reported on “radiation” nephropathy occurring after bone marrow transplantation Table 5. Nephropathy
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transplantation
technique Fx
12-13 Gy/8-9 Fx tid (1.56 Gy/Fx) 14 pt-7.2 Gyf4Fx (bid X 2d.) pretreated
Preparatory chemotherapy
No. Affected/ No. treated
VM-26, Ara-C Cyclophosphamide VM 26, Melphalan Cis-platinum Cyclophosphamide Various
9128
with several chemotherapeutic
7/l 1 14/103
agents including
cis-
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Volume 3 I, Number 5, 1995
40-
0
90
160
270
360
460
540
630
720
610
900
Fig. 5. Late renal dysfunction in adult receiving bone marrow transplantation with total body irradiation as a conditioning agent correlated with time after transplant (Reprinted, with permission, from Lawton et al. (22)).
have presented in viva laboratory data (dog), which fails to demonstrate enhancement by AmD with follow-up of 5 months (4). At this time, no clear evidence of potentiation is available; however, caution is urged. Moulder and Fish have demonstrated increasedtoxicity in a rat model when cisplatinum or BCNU were combined with irradiation (32). Toxicity with platinum was greatest when radiation preceded cisplatinum use (Fig. 6) (31).
All sequenceswere equally toxic with BCNU. A minimal effect was seen with mitomycin. Using an immature rat model, Donaldson et al. demonstrated that doxorubicin apparently enhanced renal radiation toxicity (9). Iphosphamide may produce significant nephrotoxicity; however, it is unclear if it potentiates or is potentiated by concurrent or prior radiation treatment. MANAGEMENT
I
I:1
100 80
g ;
60
z 2 40 L9
5 Months
i ............. 3 MO”,hS 0’ 0
f 2
I I I I I 4 6 8 10 12 Months After Renal lrradlatlon
I 14
-1
16
Fig. 6. Data from Moulder and Fish (32) demonstrating influence of cis-platinum on radiation renal toxicity using a rat model. Timing was also of importance in this interaction with the greatest toxicity noted when radiation preceded cis-platinum usage.
Efforts to reduce the work load of the kidney(s) should be undertaken including bed rest, low protein diet, and fluid and salt restriction. Peripheral and pulmonary edema should be treated vigorously, as should hypertension with appropriate medications. Anemia, when present should be corrected especially when it contributes to an already compromised cardiovascular state. In general, transfusionshave proven most effective, although newer biologic response modifiers, erythropoietin, etc., remain largely untested. As an under production of erythropoietin has been postulated as contributing to this anemia, this possibility is intriguing (10). Although little evidence is available that improvements in renal plasma flow or glomerular filtration rates occur with time, tubular function does appear to undergo some recovery and, therefore, efforts to support and treat the patient actively until such recovery can transpire is both logical and important. The advent of effective dialysis and transplantation
Clinical radiation nephropathy
programs has undoubtedly changed the outlook for patients suffering moderate or severe degrees of nephropathy. However, prevention of significant damage through effective treatment planning and sophisticated external radiation approaches remain the best technique to minimize morbidity (47). Biochemical approaches using renal
0 J. R. CASSADY
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artery infusion of vasoconstricting agentsand altered fractionation approaches have also been suggested as techniques to reduce renal effects of irradiation (17, 23, 40, 42, 47). Careful long-term studies incorporating a dosevolume histogram approach need to be performed and should be actively promoted.
REFERENCES 1. Avioli, L. V.; Lazor, M. Z.; Cotlove, E.; Brace, K. C.; Andrews, J. R. Early effects of radiation on renal function in man. Am. J. Med. 34:329-337; 1963. 2. Baerman, G.; Linser, P. Uber die locale und allgemeine Wirkung der Rontgenstrahlen. Mtinchen Med. Worchenschr. 7:996; 1904. 3. Cassady, J. R.; Lebowitz, R. L.; Jaffe, N.; Hoffman, A. Effect of low dose irradiation on renal enlargement in children following nephrectomy for Wilms’ tumor. Acta Radiol. Oncol. 20:5-8; 1981. 4. Concannon, J. P.; Summers, R. E.; Cole, C.; Weil, C. Effects on renal function. X-radiation combined with systemic actinomycin-D. Am. J. Roentgenol. 108: 141- 148; 1970. 5. Concannon, J. P.; Summers, R. E.; King, J.; Tcherkow, G.; Cole, C.; Rogow, E. Enhancement of x-ray effects on the small intestinal epithelium of dogs by actinomycin-D. Am. J. Roentgenol. Rad. Ther. Nucl. Med. 105: 126- 136; 1969. 6. Crummy, A. B., Jr.; Hellman, S.; Stansel, H. C., Jr.; H&ill, P. B. Renal hypertension secondary to unilateral radiation damage relieved by nephrectomy. Radiology 84: 108; 1965. 7. D’ Angio, G. J.; Farber, S.; Maddock, C. L. Potentiation of x-ray effects of actinomycin-D. Radiology 73:175-177; 1959. 8. Dewit, L.; Anninga, J. K.; Hoefnagel, C. A.; Nooyen, W. J. Radiation injury in the human kidney: A prospective analysis using specific scintigraphic and biochemical endpoints. Int. J. Radiat. Oncol. Biol. Phys. 19:977-983; 1990. 9. Donaldson, S.; Moskowitz, P.; Canty, E.; Fajardo, L. Combination radiation-adriamycin therapy: Renoprival growth, functional and structural effects in the immature mouse. Int. J. Radiat. Oncol. Biol. Phys. 6:851-859; 1980. 10. Gerber, B. B.; Altman, K. J. Radiation biochemistry. vol. II. New York: Academic Press; 1970:29-30. 11. Gerlock, A. J.; Goncharenko, V. A.; Ekelund, I. Radiationinduced stenosis of the renal artery causing hypertension: Case report. J. Urol. 1181064-1065; 1977. 12. Glatstein, E.; Fajardo, L. F.; Brown, J. M. Radiation Injury in the mouse kidney-I Sequential light microscopic study. Int. J. Radiat. Oncol. Biol. Phys. 2:933-943; 1977. 13. Guinan, E. C.; Tarbell, N. J.; Niemeyer, C. M.; Sallan, S. E.; Weinstein, H. J. Intravascular hemolysis and renal insufficiency after bone marrow transplantation. Blood 72(2):45 l-455; 1988. 14. Hoopes, P. J.; Gillette, E. L.; Benjamin, S. A. The pathogenesis of radiation nephropathy in the dog. Radiat. Res. 104:406-419; 1985. 1.5. Hoopes, P. J.; Gillette, E. L.; Cloran, J. A.; Benjamin, S. A. Radiation nephropathy in the dog. Br. J. Cancer Suppl. 7:273-276; 1986. 16. Hulbert, W. C., Jr.; Ettinger, L. J.; Wood, B. P.; Anderson, V. M.; Putnam, T. C.; Rabinowitz, R. Hyperreninemic hypertension secondary to radiation nephritis in a child. Urology 26:153-156; 1985. 17. Johnson, R. E.; Doppman, J. L.; Harbert, J. C.; Steckel, R. J.; MacLowry. J. D. Prevention of radiation nephritis
18. 19. 20. 21. 22.
23.
24. 25. 26. 27. 28. 29. 30. 31. 32.
33. 34. 35.
36.
with renal artery infusion of vasoconstrictors. Radiology 91:103-108; 1968. Keidan, S. E. Actinomycin-D in treatment of cancer in children. Br. J. Surg. 53:614-618; 1966. Kim, T. H.; Somerville, P. J.; Freeman, C. R. Unilteral radiation nephropathy-The long-term significance. Int. J. Radiat. Oncol. Biol. Phys. 10:2053-2059; 1984. Krochak, R. J.; Baker, D. G. Radiation nephritis. Clinical manifestations and pathophysiologic mechanisms. Urology 27:389-393; 1986. Kunkler, P. B.; Farr, R. F.; lxton, R. W. The limit of renal tolerance to x-rays. Br. J. Radio]. 25:190-201; 1952. Lawton, C. A.; Cohen, E. P.; Cohen, E. P.; Barber-Derus, S. W.; Murray, K. J.; Ash, R. C.; Casper, J. T.; Moulder, J. E. Late renal dysfunction in adult survivors of bone marrow transplantation. Cancer 67:2795-2800; 1991. Lebesque, J. V.; Stewart, F. A.; Hart, A. A. M. Analysis of the rate of expression of radiation-induced renal damage and the effects of hyperfractionation. Radiother. Oncol. 5: 147- 157; 1986. Luxton, R. W. Radiation nephritis. Q. J. Med. 22:215-242: 1953. Luxton, R. W. Radiation nephritis. A long-term study of 54 patients. Lancet 2: 122 1- 1224; 196 1. Luxton, R. W.; Kunkler, P. B. Radiation nephritis. Acta Radiol. 2: 169- 178; 1964. Maier, J. G. Effects of radiations on kidney, bladder and prostate. Front. Radiat. Ther. Oncol. 6:196-227; Base]: Karger; Baltimore: University Park Press; 1972. Malcolm, A. W.; Jaffe, N.; Folkman, J.; Cassady, J. R. Bilateral Wilms’ tumor. Int. J. Radiat. Oncol. Biol. Phys. 6:167- 174; 1980. McGill, C. W.; Holder, T. M.; Smith, T. H.; Ashcraft, K. W. Postradiation renovascular hypertension. J. Pediatr. Surg. 14:831-833; 1979. Moskowitz, P. S.; Donaldson, S. S. Chemotherapy-induced inhibition of compensatory renal growth in the immature mouse. Am. J. Roentgenol. 132:306; 1979. Moulder, J. E.; Fish, B. L. Effect of sequencing on combined toxicity of renal irradiation and cisplatin. NC1 Monogr. 6:35-39; 1988. Moulder, J. E.; Fish, B. L. Influence of nephrotoxic drugs on the late renal toxicity associated with bone marrow transplant conditioning regimens. Int. J. Radiat. Oncol. Biol. Phys. 20:333-337; 1991. Moulder, J. E.; Fish, B. L.; Wilson, J. F. Tumor and normal tissue tolerance for fractionated low-dose-rate radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 19:341-345; 1990. Peschel, R. E.; Chen, M.; Seashore, J. The treatment of massive hepatomegaly in Stage IV-S neuroblastoma. Int. J. Radiat. Oncol. Biol. Phys. 7:549-553; 1981. Phillips, T. L.; Benak, S.; Ross, G. Ultrastructural and cellular effects of ionizing radiation. In: Vaeth, M., ed. Frontiers of radiation therapy and oncology. Baltimore: University Park Press; 1972:21. Robbins, M. E. C.; Hopewell, J. W.; Golding, S. J. Func-
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38. 39. 40. 41.
42.
43.
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tional recovery in the irradiated kidney following removal of the contralateral unirradiated kidney. Radiother. Oncol. 6:309-316; 1986. Rubin, P.; Casarett, G. W. Concepts of clinical radiation pathology. In: Dahymple, G.; Gaulden, M.; Kallomorgen, G.; Vogel, H., eds. Medical radiation biology. vol. 8. Philadelphia: W. B. Saunders; 1973:160-189. Sagerman, R. H.; Berdon, W. E.; Baker, D. H. Renal atrophy without hypertension following abdominal irradiation in infants and children. Ann. Radiol. 12:278-284; 1969. Sagerman, R. H. Radiation nephritis. J. Urol. 91:332-336; 1964. Steckel, R. J.; Tobin, P. L.; Stein, J. J.; Bennett, R. L. Intraarterial epinephrine protection against radiation nephritis. A progress report. Radiology 92:1341-1345; 1969. Stewart, F. A.; Lebesque, J. V.; Hart, A. A. M. Progressive development of radiation damage in mouse kidneys and the consequences for reirradiation tolerence. Int. J. Radiat. Biol. 53:405-415; 1988. Stewart, F. A.; Soranson, J. A.; Alpen, E. L.; Williams, M. V.; Denekamp, J. Radiation-induced renal damage: The effects of hyperfractionation. Radiat. Res. 98:407-420; 1984. Tarbell, N.; Guinan, E.; Niemeyer, C.; Mauch, P.; Sallan, S. E.; Weinstein, H. J. Late onset of renal dysfunction in survivors of bone marrow transplantation. Int. J. Radiat. Oncol. Biol. Phys. 15:99-104; 1988.
Volume 3 1, Number 5, 1995 44. Tefft, M. Radiation related toxicities in National Wilms’ Tumor Study Number 1. Int. J. Radiat. Oncol. Biol. Phys. 2:455-463; 1977. 45. Thompson, P. L.; Mackay, I. R.; Robson, G. S. M.; Wall, A. J. Late radiation nephritis after gastric x-irradiation for peptic ulcer. Q. J. Med. New Series 40: 145- 157; 1971. 46. Turesson, I. The progression rate of late radiation effects in normal tissue and its impact on dose-response relationships. Radiother. Oncol. 15:217-226; 1989. 47. Vigneri, P.; Arger, P.; Pollack, H.; Kligerman, M. M. Localization and protection of kidneys in radiation treatment planning using computed tomagraphy. Int. J. Radiat. Oncol. Biol. Phys. 11:1209-1213; 1985. 48. Wachtel, L. W.; Cole, L. J.; Rosen, V. X-ray-induced glomerulosclerosis in rats: Modification of lesion by food restriction, uninephrectomy and age. J. Geront. 21442; 1966. 49. Warthin, A. S. Am. J. Med. Sci. 133:737; 1907. 50. White, D. C. The histo pathologic basis for functional cecrements in late radiation injury in devise organs. Cancer 37:1126-1143; 1976. 51. Wibell, L.; Evrin, P. E.; Berggard, I. Serum B,-Microglobulin in renal disease. Nephron 10:320-331; 1973. 52. Willett, C. G.; Tepper, J. E.; Orlow, E. L.; Shipley, W. U. Renal complications secondary to radiation treatment of upper abdominal malignancies. Int. J. Radiat. Oncol. Biol. Phys. 12:1601-1604; 1986. 53. Williams, M. V. The cellular basis of renal injury by radiation. Br. J. Cancer Suppl. 7:257-264; 1986.
Oncology
Biol.
Pergamon
Phys.,
Vol. 3 I, No. 5, pp. 1249- 1256, 1995 Copyright 0 1995 Elsevier Science Ltd Printed in the USA. All rights reserved 0360.3016/95 $9.50 + DO
0360-3016(94)00428-5
l
Special Feature -Late
Effects Consensus Conference
CLINICAL
RADIATION J.
NEPHROPATHY
ROBERT CASSADY,
M.D.
Professorand Head,Departmentof RadiationOncology, University of Arizona Health SciencesCenter, 1501N. CampbellAvenue, Tucson,AZ 85724 An analysis of the normal tissue effects of irradiation of the kidney is presented. Various clinical syndromes resulting from treatment are described as well as the potential cellular basis for these findings. Effects of concurrent and/or sequential treatment with irradiation and various chemotherapeutic agents are discussed and the impact of these agents on toxicity presented. Adverse consequences of renal treatment in the child is described and possible radiation effects on so-called compensatory hypertrophy following nephrectomy presented. Renal consequences described to date of bone marrow transplantation programs utilizing irradiation are also presented. The necessity of a dose-volume histogram analysis approach to analyzing renal toxic effects in patients followed for long (> 10 year) periods is essential in developing accurate guidelines of renal tolerance. Radiation nephropathy, Radiation nephritis, Hyperrenninemic tograms, Pediatric radiation renal tolerance, Growth arrest, Chemo/radiation interactions.
INTRODUCTION
difficult. Theseinclude variations in equipment usedproducing x-rays of differing RBE (orthovoltage vs. megavoltage), variations in radiation fraction size used, and overall time of treatment, unclear descriptionsof treatment volumes, and radiation fields making assessment of total renal masstreated to various dosesimpossible,limited descriptionsof prior or coexisting renal disease,and finally, and perhapsof greatest importance, variability in duration of follow-up after treatment combined with the small number of instancesof toxicity described. Although clinically relevant toxicity is clearly avoidable by exclusion of an adequatevolume of renal tissue treated to more than a modest dose, the kidneys’ central location frequently makes this difficult or impossible when tumors of the abdomen or retroperitoneum are treated.
Clinical radiation damage to the kidney represents an uncommonly described toxicity of radiation that can result in considerable morbidity and/or death. First described nearly 90 years ago (2, 49), the papers of Luxton and Kunkler and Farr and Luxton in 1952 first clearly described clinical manifestations and consequences (21,24-26). Maier noted only 151 casesas having been described in the literature in his review article in 1972 (27).
ANATOMICAL
hypertension, Tolerance, Dose-volume hisHypertrophy, Bone marrow transplantation,
PHYSIOLOGY
The kidneys are paired organscomposedof large numbers of nephronsfunctioning in a parallel fashion to permit “constancy of the internal environment” by selective waste/toxic substanceremoval from the blood plasma and also aid in electrolyte and fluid balance regulation (53). They also produce the active derivative of vitamin D, the enzyme rennin, and erythropoietin. As with the lung, toxicity scoring systemsmust have the capacity to separateeffects on a limited renal massfrom overall functional effects. As these latter, clinically more relevant toxicities are usually related to the total volume of renal mass treated, dose-volume histograms are essential to permit prediction of likely toxicity. However, in addition to an absenceof literature describing renal dose-volume histograms correlated with clinical outcome, a variety of other problems make development of accurate dose-response curves for radiation nephropathy
PATHOPHYSIOLOGY OF RADIATION DAMAGE TO THE KIDNEY A functional model of the kidney proposes that this paired organ consists of a number of functional units arranged in parallel. This functional unit, the nephron, consists of a glomerulus with its capillary network and a proximal and distal convoluted tubule arrangement. Variation exists within the kidney and cortical nephrons have a short loop of Henle, whereas juxtamedullary nephrons have a long loop of Henle and are thought to be primarily responsible for baseline renal function in fasting individuals. Although the nephron might be considered a miniature 1249
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organ composed of a number of cells in series, damage to anyone of which may prove functionally damaging, the parallel arrangement of many such units compiled with redundancy in the system permits significant cumulative damage to occur without obvious functional or clinical significance. The kidney also plays a feedback/control role in red blood cell formation and also plays a role in blood pressure regulation. The role of irradiation in primary (vs. indirect) effects on these two functions is very controversial and poorly studied. Almost all morphologic information regarding the initial site(s) of radiation damage occurring days to weeks or even months following irradiation is based on murine studies, as human data is almost entirely limited to late or end stage renal disease many months or years following treatment. Interpretation of these murine studies varies considerably. Studies reported by Phillips and colleagues suggested that tubular cell damage was primarily responsible for renal toxicity from radiation (35). Subsequently, Glatstein, Fajardo, and Brown demonstrated early damage to glomerular and juxtaglomerular cells with glomerular thrombosis and suggested this site as an important site of toxicity (12). They also noted that the term “radiation nephritis” was a misnomer as inflammatory exudates were rarely noted and proposed ‘ ‘radiation nephropathy” as a more suitable descriptive term. More recently, Hoopes and colleagues have suggested that multiple target sites exist for radiation damage to the kidney that have different times of expression (14, 15). Their studies suggested that initial functional survival depend on the extent/repair of parenchymal damage and also demonstrated extensive tubular cell repopulation in surviving animals. Early blood vessel wall changes were temporary, whereas perivascular fibrosis from damage to perivascular connective tissue was the dose-limiting toxicity for late effects. Such a multiple target explanation, which include secondary effects from hypertension, anemia, etc., seem to best explain clinical and laboratory studies that have been performed. Similarly, White has described early and late changes following significant renal irradiation (50). Early changes include atypism and tubular cell necrosis as well as endothelial microvascular damage especially in the subendothelial space separating the endothelium from the basement membrane. Characteristic late changes include a total renal mass reduction with prominent and sclerosed interlobular and arcuate arteries. Significant occlusion of glomerular capillary loops and glomerular hyalinization is seen with progressive atrophy of tubules. Associated with all these changes are significant degrees of interstitial fibrosis. CLINICAL SYNDROMES Although first described early in this century, clinical toxic effects of bilateral renal irradiation were first well
Volume 31, Number 5, 1995 Table I. Clinical syndromes following renal irradiation Type
Latent period
Acute radiation nephropathy (nephritis) Chronic radiation nephropathy Benign hypertension Malignant hypertension Hyperreninemic hypertension (Goldblatt kidney)
6- 12 months 2 18 months 2 18 months 12-18 months 2 18 months
described and categorized by Luxton and Kunkler, Fart-, and Luxton who described four primary clinical syndromes that were separated both by extent of symptoms and their initial time of appearance following irradiation (Table 1) (21, 24). Thus, “acute radiation nephritis” was first clinically apparent 6- 12 months following exposure of both kidneys to moderate doses of radiation whereas, “chronic radiation nephritis” appeared 18 months to years following treatment. Similarly hypertension, either “benign” or “malignant” was categorized and appeared 18 months to years after treatment. They also identified asymptomatic proteinuria as a manifestation of radiation damage. More recently, hyperrenninemic hypertension following unilateral renal irradiation has been described as a clinical syndrome as has the nephrotic syndrome (11, 16). Overlap of these clinical groupings is common and progression of “acute” symptoms to a chronic phase, often with hypertension, is common. One or more months following bilateral renal irradiation of 20.0-25.0 Gy, symptoms of headache, vomiting, hypertension, edema, and fatigue may be noted. Clinically, funduscopic findings of arteriolar-venous nicking, normochromic normocytic anemia, urinary findings of microscopic hematuria, proteinuria, urinary casts with elevated B-2 microglobulin levels, decreased creatinine clearance, and elevated blood urea nitrogen levels may accompany these symptoms (20). These findings are rarely seen in the first 6 months following treatment and may resolve with medical management with little or no residual or may progress to a mild or severe chronic phase or the patient may develop malignant hypertension, which is often fatal (Table 2). Table 2. Clinical svmotoms/signs of radiation nephropathv Symptoms Edema Dyspnea Headache/hypertension Nocturia Lassitude Signs Proteinuria Anemia Hypertension Cardiac enlargement Note that these are in no way unique from other causes of renal damage
Clinical
CUYuLAllVt RAOIATION RAOS
radiation
nephropathy
0
J. R. CASSADY
4000 1 3ooo 2000 1 IO00 0b I3OF
-hPAH M H M 6--d
p,
1251
Renat Plasma Flaw Glamcru~aar Filtratran ROM Bloodurea Nitrogen Yawnal Urine ConcmhOllOn
1 i
Tm PAH mp/Min
GFR ml. / Yin.
BUN m9. % SC.
1
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-J ---
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Fig. 1. Typical data from Avioli et al. (1) measuring renal function parameters during and after irradiation. Note the initial rise in elomerularfiltratin rate and renal nlasmaflow followed by a late decreasein both parameters.
In contrast, tubular function appearedto recover. Avioli et aZ.and othershave describedtruly acutechanges in renal function parametersafter irradiation (Fig. 1) (1, 20). After treatment of 20.0 + Gy, an initial rise (15-20%) is seen in glomerular filtration rate (GFR) during the course of treatment. In the months following treatment, GFR decreased an average of 20-25% from baseline in 8 of 10 patients studied. Renal plasmaflow consistently decreased; however, tubular function appearedto recover in the latter half of the first year following an initial decrease.In contrast, more conventional measureof renal function (BUN, creatinine clearance,and serumcreatinine) rarely show abnormalities in the initial 6 months following irradiation; however, may then show progressive abnormalities in patients destined to develop radiation nephropathy. Serum and urine B-2 microglobulin levels correlate well with glomerular and tubular function, respectively, whereas serum levels correlate very well with inulin clearance (Fig. 2) (51). Unfortunately, it is not uncommon for patients to show no acute or subacute signs or symptoms and, many years following treatment, present with chronic nephropathy and/or hypertension with proteinuria (vide infra). Death has occurred
in nearly half the reported
patients
in 3-5 weeks time using reduced daily fractions (37). Clinical studies by Dewit et al. support this contention (8). However, the duration of follow-up is critical to development of “safe’ ’ levels of treatment and, as noted above, signs and symptoms of late radiation damage to the kidneys may not develop for years (46). The studies of Thompson et al. and Stewart et al. are of importance in this respect (41, 45).
who have
manifested acute changes; however, most of these patients were seen in the predialysis and prerenal transplant era. 5L
RADIATION: TOLERANCE DOSES AND TOLERANCE VOLUMES Renal tolerance (TD 515) has been stated to be 20.0 Gy when irradiation has been delivered to both kidneys
, 1
Serum
,
I
I,
I
I
I
2
3
45
10
20
30
PZ-microglobulin
(lug/ml)
Fig. 2. Nearly linear correlation of inulin clearance with serum levels of BZ-macroglobulin [data of Wibell ef al. (51)].
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Correlation of Dose with Symptomatic Radiation Nephropathy 100
Thompson, et al. Dewit, et al. A Avioli, et al.
-
l
80-
n
80-
+ Luxton + LeBourgeois; x Kim, et al.
Dewit;
Kim
70$ 5
60-
;
50-
5
40302010 -
L.ilmt
period
(years)
0
Fig. 3. Data of Thompson et al. (45) demonstrating an extremely long latent period following irradiation prior to development of symptomatic (black bars) radiation nephropathy. Black and white bars depict patients in whom any renal-related abnormality was found. Thompson et al. assessed the incidence of clinically symptomatic nephropathy after delivery of radiation (-20.0 Gy) to suppress gastric acid formation in patients with postgastrectomy peptic ulcer disease (45). A 17% (11 out of 67) incidence of “symptomatic” renal disease was found with nine deaths related to renal problems. A total of 31 (46%) renal-related abnormalities were noted. The minimum follow-up period in this study was 8 years, with a range of 8- 19 years. The latent period in nearly half of the patients developing renal abnormalities was greater than 10 years (Fig. 3). In contrast, a maximum followup period of 5 years was available in the Dewit et al. study (17- 18 Gy) (8), and only 12 months in the study of Avioli (20-24 Gy) (1). Longer follow-up was also available in the study of Willett et al. (minimum dose 26.0 Gy); however, most of their patients received irradiation to only one kidney or a portion of one kidney (52). Willett’s study suggests that radiation doses of 26.0-30.0 Gy probably eliminates renal function in that kidney when unilateral treatment is given (Table 3). As less accurate dosimetry may flaw the study of Thompson, it will be of considerable importance in the future to obtain long-term follow-up in patients receiving more than 15 Gy to one or both kidneys. Dose-volume histograms of renal radiation treatment levels correlated with such long-term followup information will ultimately be necessary for accurate Table 3. Evidence of a plateau in radiation effect on renal function decrease A. Percent Decrease in Mean Creatinine Clearance as a Function of % Kidney irradiated # pts 38 17 31
# Observations
Mean % decrease in creatinine clearance
50%
48
10
60-85% 90- 100%
21
19 24
% Kidney irradiated
41
0
I 500
I 1000
I 1500
I
I
I
I
2500 2000 Dose kGy)
3000
3500
4000
1
Fig. 4. Dose-responsecurve generatedfrom data presentedin severalseriesin the literature. An approximatethresholddose of 15.0 Gy (conventionalfractionation) is seenand a plateauis noted beyond dosesof 30.0 + Gy.
predictions of renal “tolerance” to irradiation. However, for the present, a threshold dose of - 15.0 Gy delivered with conventional fractionation (in the absence of interactive drugs and underlying renal disease)appearsreasonable while radiation dosesof more than 25.0-30.0 Gy to the total renal mass are likely to eliminate useful renal function in patients followed for sufficiently long periods of time (Fig. 4). Treatment of one kidney and ipsilateral renal artery may produce renal artery narrowing with increasedrennin secretion from the juxtaglomerular apparatus (6, 11, 29). This phenomenon has been noted most often following treatment of infants or children and should be distinguished from other types of renal radiation-related hypertension. Although great caution should be exercised, vascular surgical approachesor nephrectomy may be curative (19, 36).
SPECIAL
CLINICAL
SETTINGS
Pediatric radiation renal tolerance In general, the tolerance of the kidneys in the child to radiation is similar to that of the adult. There is one possible exception. Peschel et al. has reported chemical alterations in renal function in three infants given 12- 14 Gy to reduce massive hepatomegaly from neuroblastoma (34). Although not definitive, this suggests that the infantile kidney may be subject to developmental toxicity from irradiation and, like other infantile tissues (i.e., brain, bone) may be transiently more sensitive to developmental arrest. Some experimental animal data exists to support this contention (48). Sagerman et aZ. demonstrated that moderate doses of unilateral irradiation (20.0-30.0 Gy) causedgrowth arrest and/or atrophy in the developing kidney(s) of children with neuroblastoma (38). Moskowitz and Donaldson and
Clinical
Table 4. Pediatric Radiation dose GY)
Renal Radiation
nephropathy
Tolerance
# pts
Follow up Interval (months)
16 1 4
48- 148 175 12-121
11.0-13.0 13.01-14.0 14.01-15.0
radiation
in engrafted patients. Guinan et al. and Tarbell et al. have reported the development of hemolytic anemia and renal insufficiency in 16 out of 39 children with acute lymphoblastic leukemia (ALL) or neuroblastoma (NB) who had undergone allogeneic or autologous bone marrow transplantation (9, 32) (Table 5) (13, 43). The median time to development of this complication was 5 months posttransplant. Biopsies done on two patients were consistent with “radiation nephropathy.” Nine of 28 children with autologous transplants for ALL developed this complication after intensive preparatory therapy consisting of VM 26, cytosine arabinoside, and cyclophosphamide, and 12- 14 Gy in 6-8 fractions at 0.09-o. 11 Gy/min total body irradiation. Seven of the 11 children receiving allogeneic transplantation for neuroblastoma (NB) were affected. The preparatory regimen for these children included cisplatinum, VM 26, melphalan, and cyclophosphamide, and similar total body irradiation. The authors speculate that this complication is related to both the intensive chemotherapy and total body irradiation. Lawton et al. have noted renal dysfunction in 14 out of 103 adults transplanted primarily for leukemias and lymphomas (10) (Fig. 5) (22). A wide variety of chemotherapeutic agents/regimens were used for this group of patients. Radiation parameters were similar to the pediat-
Nephropathy 0 0 1
The presence of only one case of nephropathy at the dose levels cited suggest that most pediatric patientsdo not differ substan-
tively from adults. Cassady et al. have presented data that suggestthat moderate dosesof irradiation (14.5-20.0 Gy) may reduce or eliminate the ability of a remaining kidney to hypertrophy after nephrectomy (3, 30). Cassady et al. and Malcolm et al. have also provided some long-term data on clinical radiation tolerance by studying children with Wilms’ tumor who received moderate dosesof renal irradiation becauseof prior peritoneal tumor spill (11 patients) or bilateral renal involvement (10 patients) (3, 28) (Table 4). All 21 children had survived their Wilms’ tumor and were followed for periods of 12 months to 175 months. All but one child was followed for a minimum of 48 months after treatment. Of 16 children receiving 11.0-13.0 Gy (follow-up 48- 148 months), no child experienced clinical renal toxicity. One child received 13.62 Gy (follow-up 175 months) and has demonstrated no renal toxicity, whereas one of four children receiving 14.0 1- 15.00 Gy demonstrated transient radiation nephropathy. This is consistent with data from National Wilms’ Tumor Study where only one child has reportedly developed nephropathy (44). It must also be remembered that all these children also received actinomycin-D (AmD) + vincristine although the effect of AmD on enhancing radiation nephropathy is controversial (4,5,7, l&39). Thus, by extrapolation from these pediatric data to adults, a fractionated dose of 1400 rad appears to be relatively safe even on a long-term basiswhen delivered without chemotherapy (Fig. 4).
ric reports.
Author Guinan, Tarbell
Lawton
following
et al.
bone marrow
Primary disease
Radiation
Children
ALL
ibid
Neuroblastoma
12-144 Gy/6-8 9- 11 cGy/min Ibid
Adults
Leukemia and Lymphoma
autologous
Almost all of these children platinum.
and adults had been extensively
in these settings
with low-dose
rate
Chemo/radiation interactions A number of chemotherapeutic agents are recognized as potentiating the effect of x-irradiation and/or contribute with or without irradiation to renal toxicity. Actinomycin D (AmD) has been shown in experimental in vivo and in vitro systemsas well as in clinical situations to potentiate the effect of irradiation on many normal tissuesincluding the gut, lung, and skin (5, 7). Its potentiating effect on the kidney is controversial. Keidan and Sagerman have reported clinical cases of radiation nephropathy and invoked AmD potentiation (18, 39). However, renal radiation dosesin both instances (23.70 and 25.0 Gy) are also consistent with radiation effect alone. Concannon et al.
Age group et al.
Treatment
irradiation may improve renal radiation tolerance significantly (33).
Bone marrow transplantation Several groups have by now reported on “radiation” nephropathy occurring after bone marrow transplantation Table 5. Nephropathy
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transplantation
technique Fx
12-13 Gy/8-9 Fx tid (1.56 Gy/Fx) 14 pt-7.2 Gyf4Fx (bid X 2d.) pretreated
Preparatory chemotherapy
No. Affected/ No. treated
VM-26, Ara-C Cyclophosphamide VM 26, Melphalan Cis-platinum Cyclophosphamide Various
9128
with several chemotherapeutic
7/l 1 14/103
agents including
cis-
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Volume 3 I, Number 5, 1995
40-
0
90
160
270
360
460
540
630
720
610
900
Fig. 5. Late renal dysfunction in adult receiving bone marrow transplantation with total body irradiation as a conditioning agent correlated with time after transplant (Reprinted, with permission, from Lawton et al. (22)).
have presented in viva laboratory data (dog), which fails to demonstrate enhancement by AmD with follow-up of 5 months (4). At this time, no clear evidence of potentiation is available; however, caution is urged. Moulder and Fish have demonstrated increasedtoxicity in a rat model when cisplatinum or BCNU were combined with irradiation (32). Toxicity with platinum was greatest when radiation preceded cisplatinum use (Fig. 6) (31).
All sequenceswere equally toxic with BCNU. A minimal effect was seen with mitomycin. Using an immature rat model, Donaldson et al. demonstrated that doxorubicin apparently enhanced renal radiation toxicity (9). Iphosphamide may produce significant nephrotoxicity; however, it is unclear if it potentiates or is potentiated by concurrent or prior radiation treatment. MANAGEMENT
I
I:1
100 80
g ;
60
z 2 40 L9
5 Months
i ............. 3 MO”,hS 0’ 0
f 2
I I I I I 4 6 8 10 12 Months After Renal lrradlatlon
I 14
-1
16
Fig. 6. Data from Moulder and Fish (32) demonstrating influence of cis-platinum on radiation renal toxicity using a rat model. Timing was also of importance in this interaction with the greatest toxicity noted when radiation preceded cis-platinum usage.
Efforts to reduce the work load of the kidney(s) should be undertaken including bed rest, low protein diet, and fluid and salt restriction. Peripheral and pulmonary edema should be treated vigorously, as should hypertension with appropriate medications. Anemia, when present should be corrected especially when it contributes to an already compromised cardiovascular state. In general, transfusionshave proven most effective, although newer biologic response modifiers, erythropoietin, etc., remain largely untested. As an under production of erythropoietin has been postulated as contributing to this anemia, this possibility is intriguing (10). Although little evidence is available that improvements in renal plasma flow or glomerular filtration rates occur with time, tubular function does appear to undergo some recovery and, therefore, efforts to support and treat the patient actively until such recovery can transpire is both logical and important. The advent of effective dialysis and transplantation
Clinical radiation nephropathy
programs has undoubtedly changed the outlook for patients suffering moderate or severe degrees of nephropathy. However, prevention of significant damage through effective treatment planning and sophisticated external radiation approaches remain the best technique to minimize morbidity (47). Biochemical approaches using renal
0 J. R. CASSADY
1255
artery infusion of vasoconstricting agentsand altered fractionation approaches have also been suggested as techniques to reduce renal effects of irradiation (17, 23, 40, 42, 47). Careful long-term studies incorporating a dosevolume histogram approach need to be performed and should be actively promoted.
REFERENCES 1. Avioli, L. V.; Lazor, M. Z.; Cotlove, E.; Brace, K. C.; Andrews, J. R. Early effects of radiation on renal function in man. Am. J. Med. 34:329-337; 1963. 2. Baerman, G.; Linser, P. Uber die locale und allgemeine Wirkung der Rontgenstrahlen. Mtinchen Med. Worchenschr. 7:996; 1904. 3. Cassady, J. R.; Lebowitz, R. L.; Jaffe, N.; Hoffman, A. Effect of low dose irradiation on renal enlargement in children following nephrectomy for Wilms’ tumor. Acta Radiol. Oncol. 20:5-8; 1981. 4. Concannon, J. P.; Summers, R. E.; Cole, C.; Weil, C. Effects on renal function. X-radiation combined with systemic actinomycin-D. Am. J. Roentgenol. 108: 141- 148; 1970. 5. Concannon, J. P.; Summers, R. E.; King, J.; Tcherkow, G.; Cole, C.; Rogow, E. Enhancement of x-ray effects on the small intestinal epithelium of dogs by actinomycin-D. Am. J. Roentgenol. Rad. Ther. Nucl. Med. 105: 126- 136; 1969. 6. Crummy, A. B., Jr.; Hellman, S.; Stansel, H. C., Jr.; H&ill, P. B. Renal hypertension secondary to unilateral radiation damage relieved by nephrectomy. Radiology 84: 108; 1965. 7. D’ Angio, G. J.; Farber, S.; Maddock, C. L. Potentiation of x-ray effects of actinomycin-D. Radiology 73:175-177; 1959. 8. Dewit, L.; Anninga, J. K.; Hoefnagel, C. A.; Nooyen, W. J. Radiation injury in the human kidney: A prospective analysis using specific scintigraphic and biochemical endpoints. Int. J. Radiat. Oncol. Biol. Phys. 19:977-983; 1990. 9. Donaldson, S.; Moskowitz, P.; Canty, E.; Fajardo, L. Combination radiation-adriamycin therapy: Renoprival growth, functional and structural effects in the immature mouse. Int. J. Radiat. Oncol. Biol. Phys. 6:851-859; 1980. 10. Gerber, B. B.; Altman, K. J. Radiation biochemistry. vol. II. New York: Academic Press; 1970:29-30. 11. Gerlock, A. J.; Goncharenko, V. A.; Ekelund, I. Radiationinduced stenosis of the renal artery causing hypertension: Case report. J. Urol. 1181064-1065; 1977. 12. Glatstein, E.; Fajardo, L. F.; Brown, J. M. Radiation Injury in the mouse kidney-I Sequential light microscopic study. Int. J. Radiat. Oncol. Biol. Phys. 2:933-943; 1977. 13. Guinan, E. C.; Tarbell, N. J.; Niemeyer, C. M.; Sallan, S. E.; Weinstein, H. J. Intravascular hemolysis and renal insufficiency after bone marrow transplantation. Blood 72(2):45 l-455; 1988. 14. Hoopes, P. J.; Gillette, E. L.; Benjamin, S. A. The pathogenesis of radiation nephropathy in the dog. Radiat. Res. 104:406-419; 1985. 1.5. Hoopes, P. J.; Gillette, E. L.; Cloran, J. A.; Benjamin, S. A. Radiation nephropathy in the dog. Br. J. Cancer Suppl. 7:273-276; 1986. 16. Hulbert, W. C., Jr.; Ettinger, L. J.; Wood, B. P.; Anderson, V. M.; Putnam, T. C.; Rabinowitz, R. Hyperreninemic hypertension secondary to radiation nephritis in a child. Urology 26:153-156; 1985. 17. Johnson, R. E.; Doppman, J. L.; Harbert, J. C.; Steckel, R. J.; MacLowry. J. D. Prevention of radiation nephritis
18. 19. 20. 21. 22.
23.
24. 25. 26. 27. 28. 29. 30. 31. 32.
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