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British Journal of Radiology (2005) Supplement_27, 82-88
© 2005 British Institute of Radiology
doi: 10.1259/bjr/18309193
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British Journal of Radiology Supplement_27 (2005),82-88 © 2005 The British Institute of Radiology

Full Paper

Radiation-induced multi-organ involvement and failure: the contribution of radiation effects on the renal system

J E Moulder, PhD1 and E P Cohen, MD2

1 Radiation Oncology and 2 Nephrology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA


   Abstract
Top
 Abstract
Introduction
 Renal injury after accidental...
 The therapeutic BMT experience...
 Experimental approaches to...
 Conclusions
 References
 
Clinical and experimental studies suggest that acute or chronic renal injury could occur after certain types of radiation accidents. Such renal injury could be life-threatening in its own right, could exacerbate other radiation injuries and could complicate the treatment of non-radiation injuries. The clinical experience with therapeutic bone marrow transplantation (BMT) indicates that acute renal failure is conceivable in radiation accident victims who receive BMT, and there are experimental data that suggest that radiation-induced bone marrow aplasia could exacerbate acute renal failure caused by other agents. Both the experimental data and the clinical experience with therapeutic BMT also suggest that chronic renal failure could occur after radiation accidents if the bilateral renal dose exceeded 4–5 Gy and if bone marrow toxicity was avoided by partial body shielding or therapeutic interventions. In addition, clinical experience using radiolabelled biologicals in cancer therapy shows that internal deposition of certain types of radioactive material can cause chronic renal failure. There is clinical evidence that the progression of established chronic radiation-induced renal injury can be attenuated by treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin II (AII) receptor antagonists. There is also pre-clinical evidence that the risk of radiation-induced chronic renal failure can be reduced through prophylactic use of ACE inhibitors or AII receptor antagonists, and a randomised clinical trial of this approach is in progress.


   Introduction
Top
 Abstract
 Introduction
Renal injury after accidental...
 The therapeutic BMT experience...
 Experimental approaches to...
 Conclusions
 References
 
Most of the biomedical concern about radiation accidents and radiological terrorism has focused on acute injuries to the central nervous system, haematopoietic system and gastrointestinal tract, as well as on late stochastic effects such as cancer and mutations. However, under certain circumstances late normal tissue injuries could also occur, including chronic renal failure [1, 2]. There may also be some circumstances in which acute renal failure could occur after a radiation accident, due not to the radiation itself but to therapeutic interventions (e.g. use of nephrotoxic antibiotics or cyclosporin). This review will summarise what is known about radiation-related acute and chronic renal injury from experimental and clinical studies, and then discuss approaches to the prophylaxis and treatment of such injuries.


   Renal injury after accidental or intentional radiation exposure
Top
 Abstract
 Introduction
 Renal injury after accidental...
The therapeutic BMT experience...
 Experimental approaches to...
 Conclusions
 References
 
Bilateral renal irradiation can produce chronic renal injury in many species of animals at relatively low doses. In the rat, radiation-induced renal failure can occur as early as 8 months after a single dose of 8.7 Gy, and renal dysfunction (e.g. elevated blood urea nitrogen) can be observed by 7 months after a single dose of 6.5 Gy [3]. In the pig, renal dysfunction has been demonstrated 3 months after a single dose of 7.8 Gy [4]. In dogs, detailed dose–response data are not available, but renal dysfunction has been shown at 6 months after a single dose of 10 Gy [5]. Mice appear to be the outliers, with single doses of 12 Gy and above being required to produce significant renal injury in less than approximately 9 months [6–8].

When animals are exposed to total body irradiation (TBI) and haematopoietic death is prevented by bone marrow transplantation (BMT), radiation nephropathy is a common late event. In the rat, radiation nephropathy is actually the dominant cause of chronic morbidity in pathogen-free rats given TBI plus BMT [3, 9]. Histopathological evidence of radiation nephropathy has been observed in Rhesus monkeys 6–8 years after BMT when the TBI dose was 7.2–8.5 Gy in a single fraction at 0.2 Gy min–1 [10].

Radiation nephropathy is also an acknowledged complication of clinical BMT when TBI is used as part of the preparative regimen [11–14]. This chronic BMT-associated nephropathy is characterised by a slow and progressive reduction of renal function that leads to renal failure. Histopathologically, there is glomerular and tubular injury and subsequent progressive scarring, and the more severe cases may present like haemolytic–uraemic syndrome [14–16]. 5–20% of long-term survivors of therapeutic BMT will develop chronic nephropathy (Figure 1Go), and many of these patients will require kidney transplants [17]. There is strong evidence that this nephropathy is radiation-induced, since local bilateral renal irradiation in humans produces radiation nephropathy at radiation doses only slightly above those used in clinical BMT [12], and renal shielding reduces the incidence of chronic nephropathy in a dose-dependent manner [13, 18] (Figures 1 and 2GoGo).



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  		Figure 1. Actual incidence of chronic nephropathy as a function of renal dose. Chronic nephropathy was defined as increased serum creatinine, increased blood urea nitrogen and decreased glomerular filtration rate accompanied by anaemia and hypertension, and without any obvious cause other than radiation [18]. The number of patients at risk are shown in parentheses, and the plots stop when there were fewer than six patients still at risk. Actuarial log rank analysis was done to compare the incidence of chronic nephropathy by renal dose. Trend analysis was done using the Cox proportional hazards model, and a statistically significant trend (p=0.012) exists for decreasing renal dose and decreasing incidence of chronic nephropathy. Adapted with permission from Lawton et al [18].

 


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  		Figure 2. Dose–response curve for chronic nephropathy after total body irradiation plus bone marrow transplantation from the clinical reports of Lawton et al [18] (•) and Miralbell et al [13] (O). The "equivalent single dose" is derived from the actual fractionated low dose rate regimen by assuming an {alpha}/{beta} ratio of 1.5–4.0 Gy [3, 20, 21] for the fractionation effect, and a dose rate reduction factor of 1.2–1.5 [3, 22] for the dose rate effect. The vertical error bars are standard deviations; the horizontal error bars reflect the biological uncertainty in the "equivalent single dose" calculation.

 
Radiation nephropathy after therapeutic BMT has been reported for renal doses as low as 11.8 Gy in 9 fractions at 0.08–0.20 Gy min–1 [18] and 12 Gy in 6 fractions at 0.12–0.20 Gy min–1 [13]. Chronic radiation nephropathy has also been observed to occur after the local renal irradiation (typically 7.5 Gy in 5 fractions at approximately 1.0 Gy min–1) that was formerly used to treat kidney transplant rejection [19]. Based on the known relationships between fraction size, dose rate and normal tissue tolerance [3, 20–22], it is likely that these fractionated doses are roughly equivalent (in terms of renal tolerance) to a high dose rate single dose of 4–5 Gy (Figure 2Go).

More recently, radiation nephropathy has also emerged as a complication of cancer therapy with radiolabelled biologicals [23–26]. The risk of such radiation nephropathy appears to depend on both the isotope used and the pharmacokinetics of the carrier molecule [23–25]. In one recent study, the median absorbed renal radiation dose for the patients with the most severe nephropathy was estimated to be 7.1 Gy (delivered at a decreasing dose rate over a period of several days) [25].

Clearly then, renal radiosensitivity is low enough that chronic renal injury would be anticipated to occur after radiation accidents if the bilateral renal dose exceeded 4–5 Gy and if bone marrow toxicity was avoided by partial body shielding, by BMT or by novel approaches to reducing the biological effects of bone marrow aplasia. However, actual reports of such chronic renal injury after radiation accidents are rare to non-existent, although two victims of the Tokai-mura criticality accident developed renal failure as part of multiple organ system failure [27].


   The therapeutic BMT experience as a guide to what to expect in radiation accidents
Top
 Abstract
 Introduction
 Renal injury after accidental...
 The therapeutic BMT experience...
Experimental approaches to...
 Conclusions
 References
 
While the renal injuries seen after therapeutic TBI/BMT may provide clues as to what types of injury might be seen in radiation accident victims who receive bilateral renal radiation, the therapeutic BMT data must be viewed with caution, as there is considerably more to the BMT procedure than just the TBI. First, the organ injuries seen after therapeutic BMT may be due to the pre-existing disease, or to prior attempts to treat the disease, rather than just to the TBI. Second, as part of therapeutic BMT, patients are treated with a wide range of drugs (e.g. antineoplastic drugs, antibiotics, immunosuppressive drugs) that may themselves cause delayed organ injuries. Finally, acute and chronic graft-versus-host disease (GVHD) is seen in 40–70% of clinical BMT patients, and GVHD can cause chronic normal tissue injury by itself (e.g. to skin, liver, gastrointestinal tract and lung). Note, however, that if BMT (or cord blood) is used to treat a radiation accident victim, it is likely that nephrotoxic antibiotics, immunosuppressive drugs and/or GVHD will be present [27, 28].

Acute renal failure after BMT
Acute renal failure (ARF) generally occurs within 30 days after BMT [29–31]. The incidence can be as high as 16% and outcomes are poor [29–31]. The occurrence of ARF after BMT largely corresponds with the period of post-BMT neutropenia. Aminoglycoside antibiotics [29], cyclosporin [32], red cell haemolysis [31] and elevated serum iron [33] have all been implicated in its pathogenesis. It is also possible that TBI is a contributor to ARF after BMT. This would be consistent with the higher incidence of ARF after allogeneic BMT (which usually uses TBI in the preparative regimen) than after autologous BMT (which rarely uses radiation) [31]. In addition, Gruss et al [30] have shown in a univariate analysis that the use of TBI is an independent risk factor for ARF after BMT. However, ARF would not appear to be caused solely by renal irradiation as it is not seen in experimental BMT models and it has not been reported after human bilateral renal irradiation [34]. Another intriguing connection of ARF to BMT and radiation is the hypothesis that bone marrow stem cells contribute to the healing of renal injuries [35], raising the possibility that bone marrow aplasia caused by radiation might exacerbate ARF induced by other agents.

Prevention and treatment of ARF after BMT requires the same attention to volume status and nephrotoxins (e.g. aminoglycoside antibiotics and cyclosporin) that ARF does in any setting [31]. The utility of dialysis is not well defined; that is, the role of intensive dialysis compared with conventional dialysis has not been studied [31]. Suppression of the renin–angiotensin system, for which there is pre-clinical and clinical evidence for efficacy against chronic nephropathy after BMT [36], has not been assessed for efficacy against ARF.

Chronic renal failure after BMT
In 1991 we reported 14 cases of chronic radiation nephropathy in adult allogeneic BMT patients [37], and since then over 100 cases have been reported [17]. There are multiple reports of the evolution of BMT nephropathy to renal failure and the requirement for dialysis [12, 15] or kidney transplantation [38, 39]. As illustrated in Figure 1Go, a cohort study of partial renal shielding [18] showed that renal dose reduction was associated with a reduction in the incidence of chronic radiation nephropathy. A similar phenomenon was observed by Miralbell et al [13] (Figure 2Go).

There is pre-clinical evidence (see below) that established BMT nephropathy can be treated with angiotensin converting enzyme (ACE) inhibitors [40, 41] or angiotensin II (AII) receptor antagonists [41, 42], and the clinical efficacy of these agents for the treatment of radiation nephropathy has now been established [19, 43] (Figure 3Go). There is also experimental evidence (see below) that these agents can be used prophylactically to prevent the development of radiation nephropathy [42, 44–49], but their clinical efficacy for this use has not yet been established.



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  		Figure 3. Treatment of clinical radiation nephropathy with the angiotensin converting enzyme (ACE) inhibitor, captopril. The patient received a bilateral renal dose of 9.8 Gy in 9 fractions at 0.08–0.20 Gy min–1 as part of the total body irradiation used in the preparatory regimen for bone marrow transplantation (BMT). After 7 months, the patient developed BMT nephropathy as confirmed by biopsy (see Figure 2Go in Cohen and Robbins [16]). At 12 months, captopril therapy was begun at a dose of 12.5 mg daily and has been continued at that dose. Renal function is shown as 100 x the reciprocal of the serum creatinine. Stabilisation of kidney function is evident from the significant (p<0.001) change in the slope.

 
In 1998, we began a randomised placebo-controlled trial of an ACE inhibitor, captopril, to prevent BMT nephropathy in patients undergoing TBI-based BMT. Captopril, or an identically appearing placebo, is started at the time of engraftment of the new marrow and is continued for 1 year. The major outcomes to be tested are kidney function and specifically BMT nephropathy syndrome [12, 43, 50]. The delay in starting captopril is to avoid any interference with marrow engraftment, and because experimental studies indicated that a several week delay in starting captopril does not materially reduce its long-term efficacy [48]. Captopril therapy stops at 1 year because the major period of risk for BMT nephropathy is the 8–12 months after BMT [12, 17, 43] and because experimental data indicated that stopping captopril after 1 year does not affect its long-term benefit [48].

As of October 2003, 53 subjects had been enrolled in this study. 24 enrolled subjects have died, which is not an unexpected rate for patients who undergo allogeneic BMT. 25 patients have now completed at least 2 months on the study drug. Although the planned study drug period is up to 1 year after BMT, the best duration of captopril therapy is not known. Our experimental data [49, 51] suggest that a 6-week duration of drug therapy exerts long-term benefit in attenuating the development of radiation nephropathy. Thus it is possible that even a 1–2 month period on captopril could exert long-term benefit in BMT patients. The most recent interim safety analysis (done in a masked fashion) has shown no statistically significant difference between the placebo and captopril groups for occurrence of renal failure, relapse (of original disease) or death. The original statistical calculations suggested that at least 50 subjects per arm would be needed to show the anticipated outcome differences.


   Experimental approaches to prophylaxis and treatment of chronic radiation-induced renal injury
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 Abstract
 Introduction
 Renal injury after accidental...
 The therapeutic BMT experience...
 Experimental approaches to...
Conclusions
 References
 
In the defined-flora, barrier-maintained rat, radiation nephropathy is the principal late toxicity seen after TBI when haematological death is prevented by BMT [3, 9]. Radiation nephropathy in the rat is characterised by proteinuria as early as 4–5 weeks after irradiation, azotemia by 8 weeks and hypertension by 9–10 weeks [3, 45, 52]. The injury is progressive and leads to renal failure (uraemia) as early as 22 weeks [3, 45]. This rat BMT model has been used to assess the effects of TBI fractionation and dose rate [3], interactions between TBI and other nephrotoxic drugs [3, 53], and possible treatment and prevention strategies [36].

Treatment and prophylaxis of radiation nephropathy with ACE inhibitors
In the early 1990s, we showed that established radiation nephropathy in the rat could be treated with a thiol-containing ACE inhibitor, captopril [40]. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective [40], and that captopril was effective even when given at a non-haemodynamic dose [41].

In other models of chronic renal failure, ACE inhibitors are most effective when started before renal injury is established, i.e. in a prophylactic approach. When ACE inhibitors were given in a prophylactic regimen, they were effective in reducing the incidence of renal failure after TBI, as illustrated in Figure 4Go [45]. The ACE inhibitors were not acting as "classical" radioprotectors, as they had no efficacy when given only during the radiation treatment [49]. A delay in the start of treatment until 3 weeks after TBI did not decrease the efficacy of captopril prophylaxis [48], and substantial preservation of renal function was sustained in animals treated with captopril for 6 months after TBI, and then taken off the drug [48]. Other types of antihypertensive drugs, as shown in Figure 4Go, did not prevent deterioration in renal function [45, 54]. The effectiveness of ACE inhibitors in the prophylaxis of radiation nephropathy was subsequently confirmed by Juncos et al [44] and Geraci et al [46].



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  		Figure 4. Effect of pharmacological interventions on the development of experimental radiation nephropathy after total body irradiation (TBI) plus bone marrow transplantation (BMT). Actual incidence curves are shown for animals that received 17 Gy TBI plus BMT and were treated with: angiotensin converting enzyme (ACE) inhibitors (low dose captopril, high dose captopril, or enalapril); an angiotensin II (AII) Type 1 receptor antagonist (L-158,809); or various other antihypertensives that act by mechanisms not directly related to AII activity (verapamil, hydralazine, hydrochlorothiazide and L-methyl-DOPA). Adapted with permission from Moulder et al [54].

 
Treatment and prophylaxis of radiation nephropathy with AII receptor antagonists
Since AII is a potent vasoconstrictor and hypertension plays a major role in radiation nephropathy, suppression of AII production by ACE inhibition provided an obvious explanation for the efficacy of captopril. However, ACE has substrates other than AII (e.g. bradykinin), and ACE inhibitors have actions that may not be the result of ACE inhibition (e.g. antimitotic activity). To determine whether captopril was functioning via inhibition of AII production, an AII Type 1 receptor antagonist (L-158,809) was tested against captopril [47]. When used for prophylaxis of radiation nephropathy, the AII receptor antagonist was markedly superior to captopril (Figure 4Go) [42, 47]. The efficacy of the AII blockers for prophylaxis of radiation nephropathy was confirmed by Oikawa et al [55]. Subsequent studies found that the superiority of the AII receptor antagonist over the ACE inhibitor seen in prophylaxis of radiation nephropathy was not seen in the treatment of established radiation nephropathy [41, 42].

Mechanistic studies of the treatment and prophylaxis of radiation nephropathy
The mechanistic basis for the efficacy of ACE inhibitors and AII receptor antagonists in chronic radiation nephropathy is not known, although it is known that both agents are also effective against radiation pneumonitis [56], and there are preliminary data suggesting that ACE inhibitors have efficacy against central nervous system injury [57]. The evidence for the efficacy of ACE inhibitors against acute injuries is very sparse; we found no evidence for efficacy against acute radiation-induced bone marrow [58] or gastrointestinal injury in rats [59], but Yoon et al [60] reported efficacy against radiation-induced gastrointestinal injury in mice. Mechanistic speculations include renin–angiotensin system suppression, suppression of radiation-induced proliferation, attenuation of a radiation-induced drop in nitric oxide (NO) synthesis, and inhibition of radiation-induced fibrosis via transforming growth factor-{beta}1 (TGF-{beta}1).

Renin–angiotensin system (RAS) suppression
An obvious explanation for the efficacy of RAS antagonism would be that radiation leads to RAS activation, and that such activation is detrimental. However, there is no physiological evidence for activation of the RAS during the post-radiation interval when RAS antagonism is most beneficial [52], and plasma renin levels [52], renal and whole blood AII levels [52] and AII receptor binding (JE Moulder, unpublished results) are unaffected by renal irradiation during the same post-radiation interval. This suggests an alternative explanation, namely that even the normal activity of the RAS is deleterious in the presence of radiation injury.

Radiation-induced proliferation
Some of the rat radiation nephropathy studies are consistent with the hypothesis that AII receptor antagonists attenuate radiation nephropathy by suppression of radiation-induced renal tubular cell proliferation. Irradiation induces proliferation of renal tubular cells within 4 weeks after irradiation, and treatment with an AII receptor antagonist delays this proliferation and decreases its magnitude [61]. This does not prove that radiation-induced proliferation is a mechanistically important step in the pathophysiology of injury, as an alternative hypothesis is that the proliferation is a result of some undefined event, and the AII receptor antagonist prevents that event and hence prevents the proliferation indirectly [61].

Suppression of NO synthesis
Radiation-induced endothelial injury could lead to a deficit of constitutive NO synthesis, with capillary thrombosis and hypertension, and this decrease could be opposed by ACE inhibitors and AII receptor antagonists. Renal radiation results in a deficit of urinary cyclic guanosine monophosphate (cGMP), a marker of renal NO activity [62], and a parallel drop in urinary nitrate/nitrite concentrations [54]; and the cGMP deficit is prevented by high dose captopril treatment [62]. Further suggestive evidence for a NO connection are a study which found that All-trans retinoic acid (ATRA) had a detrimental effect on radiation nephropathy that was accompanied by a drop in urinary cGMP [63], and the work by Verhagen et al [64] which suggests that normal levels of AII are detrimental to the kidney when NO synthesis is inhibited. Finally, studies have shown that chronic suppression of NO synthesis causes a syndrome that has some resemblance to radiation nephropathy, although it does not appear to produce mesangiolysis, which is a prominent feature of radiation nephropathy [65, 66].

Radiation-induced fibrosis
The mediators of fibrosis in radiation nephropathy have received little attention, and it is not clear whether fibrosis is a cause or an effect of injury [67]. Several studies argue that fibrosis is a critical step, and that ACE inhibitors and AII receptor antagonists may prevent this fibrosis. In particular, Datta et al [68] demonstrated that glomerular TGF-{beta}1 production is elevated in the course of radiation nephropathy, and that this elevation does not occur when an AII receptor antagonist is used.


   Conclusions
Top
 Abstract
 Introduction
 Renal injury after accidental...
 The therapeutic BMT experience...
 Experimental approaches to...
 Conclusions
References
 
Clinical and experimental data suggest that renal injury should occur after certain types of radiation accidents if fatal acute bone marrow damage is avoided by partial body shielding or therapeutic interventions. Acute renal failure could be caused or exacerbated by some of the therapies used to alleviate haematological and gastrointestinal injury (e.g. aminoglycoside antibiotics and cyclosporin), and chronic renal failure could be caused by bilateral renal irradiation at doses as low as 4–5 Gy. Radiation-induced chronic renal failure can be treated with clinically approved drugs (ACE inhibitors and AII Type 1 receptor antagonists), and there are pre-clinical data suggesting that these agents can be used prophylactically to decrease the probability and severity of chronic renal, lung and central nervous system injuries. Because the mechanistic basis for the efficacy of ACE inhibitors and AII receptor antagonists in chronic radiation nephropathy is not known, the applicability of these therapies to injuries such as radiation-induced multi-organ failure is difficult to evaluate.


   Footnotes
 
This work was supported by grant CA24652 from the US National Cancer Institute. Back


   References
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 Abstract
 Introduction
 Renal injury after accidental...
 The therapeutic BMT experience...
 Experimental approaches to...
 Conclusions
 References
 

  1. Moulder JE. Multiorgan problems associated with total and partial body irradiation. In: Ricks RC, Berger ME, O'Hara FM, editors. The medical basis for radiation-accident preparedness: the clinical care of victims. Boca Raton, FL: Parthenon Publishing Group, 2002:175–89.
  2. Coleman CN, Blakely WF, Fike JR, MacVittie TJ, Metting NF, Mitchell JB, et al. Molecular and cellular biology of moderate-dose (1–10 Gy) radiation and potential mechanisms of radiation protection. Report of a workshop at Bethesda, Maryland, December 17–18, 2001. Radiat Res 2003;159:812–34.[Medline]
  3. Moulder JE, Fish BL. Late toxicity of total body irradiation with bone marrow transplantation in a rat model. Int J Radiat Oncol Biol Phys 1989;16:1501–9.[Medline]
  4. Robbins MEC, Campling D, Rezvani M, Golding SJ, Hopewell JW. Radiation nephropathy in mature pigs following the irradiation of both kidneys. Int J Radiat Biol 1989;56:83–98.[Medline]
  5. Prescott DM, Hoopes PJ, Thrall DE. Modification of radiation damage in the canine kidney by hyperthermia: a histologic and functional study. Radiat Res 1990;124:317–25.[Medline]
  6. Stewart FA, Luts A, Lebesque JV. The lack of long-term recovery and reirradiation tolerance in the mouse kidney. Int J Radiat Biol 1989;56:449–62.[Medline]
  7. Williams MV, Denekamp J. Sequential functional testing of radiation-induced renal damage in the mouse. Radiat Res 1983;94:305–17.[Medline]
  8. Liao ZX, Travis EL. Unilateral nephrectomy 24 hours after bilateral kidney irradiation reduces damage to the function and structure of the remaining kidney. Radiat Res 1994;139:290–9.[Medline]
  9. Moulder JE, Fish BL, Abrams RA. Renal toxicity following total body irradiation and syngeneic bone marrow transplantation. Transplantation 1987;43:589–92.[Medline]
  10. van Kleef EM, Zurcher C, Oussoren YG, te Poele JAM, van der Valk M, Niemer-Tucker MMB, et al. Long-term effects of total body irradiation on the kidney of Rhesus monkeys. Int J Radiat Biol 2000;76:641–8.[Medline]
  11. Tarbell NJ, Guinan EC, Niemeyer C, Mauch P, Sallan SE, Weinstein HJ. Late onset of renal dysfunction in survivors of bone marrow transplantation. Int J Radiat Oncol Biol Phys 1988;15:99–104.[Medline]
  12. Cohen EP, Lawton CA, Moulder JE. Bone marrow transplant nephropathy: radiation nephritis revisited. Nephron 1995;70:217–22.[Medline]
  13. Miralbell R, Bieri S, Mermillod B, Helg C, Sancho G, Pastoors B, et al. Renal toxicity after allogeneic bone marrow transplantation: the combined effects of total-body irradiation and graft-versus-host disease. J Clin Oncol 1996;14:579–85.[Abstract/Free Full Text]
  14. Cohen EP. Renal failure after bone marrow transplantation. Lancet 2001;357:6–7.[Medline]
  15. Chappell ME, Keeling DM, Prentice HG, Sweny P. Haemolytic uraemic syndrome after bone marrow transplantation: an adverse effect of total body irradiation. Bone Marrow Transplant 1988;3:339–47.[Medline]
  16. Cohen EP, Robbins MEC. Radiation nephropathy. Semin Nephrol 2003;23:486–99.[Medline]
  17. Cohen EP. Radiation nephropathy after bone marrow transplantation. Kidney Int 2000;58:903–18.[Medline]
  18. Lawton CA, Cohen EP, Murray KJ, Derus SW, Moulder JE. Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplant 1997;12:1069–74.
  19. Cohen EP, Hussain S, Moulder JE. Successful treatment of radiation nephropathy with angiotensin II blockade. Int J Radiat Oncol Biol Phys 2003;55:190–3.[Medline]
  20. van Rongen E, Kuijpers WC, Madhuizen HT, van der Kogel AJ. Effects of multifraction irradiation on the rat kidney. Int J Radiat Oncol Biol Phys 1988;15:1161–70.[Medline]
  21. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:679–94.[Medline]
  22. Hall EJ. The dose-rate factor in radiation biology. Int J Radiat Biol 1991;59:595–610.[Medline]
  23. Cohen EP, Moulder JE, Robbins MEC. Radiation nephropathy caused by Yttrium 90. Lancet 2001;358:1102–3.[Medline]
  24. Lambert B, Cybulla M, Weiner SM, Van de Wiele C, Ham H, Dierckx RA, et al. Renal toxicity after radionuclide therapy. Radiat Res 2004;161:607–11.[Medline]
  25. Giralt S, Bensinger W, Goodman M, Podoloff D, Eary J, Wendt R, et al. 166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials. Blood 2003;102:2684–91.[Abstract/Free Full Text]
  26. Röttinger EM, Bartkowiak D, Bunjes D, Wennauer R, Bohr D. Enhanced renal toxicity of total body irradiation combined with radioimmunotherapy. Strahlenther Onkol 2003;179:702–7.[Medline]
  27. Maekawa K. Overview of medical care for highly exposed victims in the Tokaimura accident. In: Ricks RC, Berger ME, O'Hara FM, editors. The medical basis for radiation-accident preparedness: the clinical care of patients. Boca Raton, FL: Parthenon Publishing Group, 2002:313–8.
  28. Konchalovsky M. Multi-organ involvement and failure in selected Russian radiation accident cases. In: Fliedner TM, Meineke V, et al, editors. Radiation-induced multi-organ involvement and failure: a challenge for pathogenetic, diagnostic and therapeutic approaches and research, BJR Suppl. 27. London, UK: British Institute of Radiology, 2005:26–9.
  29. Zager RA, O'Quigley J, Zager BK, Alpers CE, Shulman HM, Gamelin LM, et al. Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients. Am J Kidney Dis 1989;13:210–6.[Medline]
  30. Gruss E, Bernis C, Tomas JF, Garcia-Canton C, Figuera A, Motellon JL, et al. Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome. Am J Nephrol 1995;15:473–9.[Medline]
  31. Cohen EP. Acute renal failure after bone marrow transplantation. In: Molitoris B, Finn W, editors. Acute renal failure. Philadelphia, PA: WB Saunders, 2001:344–8.
  32. Kennedy MS, Deeg HJ, Siegel M, Crowley JJ, Storb R, Thomas ED. Acute renal toxicity with combined use of amphotericin B and cyclosporine after marrow transplantation. Transplantation 1983;35:211–5.[Medline]
  33. Gordon LI, Brown SG, Tallman MS, Rademaker AW, Weitzman SA, Lazarus HM, et al. Sequential changes in serum iron and ferritin in patients undergoing high-dose chemotherapy and radiation with autologous bone marrow transplantation: possible implications for treatment related toxicity. Free Radic Biol Med 1995;18:383–9.[Medline]
  34. Robbins MEC, Bonsib SM. Radiation nephropathy: a review. Scanning Microsc 1995;9:535–60.[Medline]
  35. Kale S, Karihaloo A, Clark PR, Kashgarian M, Krause DS, Cantley LG. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J Clin Invest 2003;112:42–9.[Medline]
  36. Moulder JE, Fish BL, Cohen EP. ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy. Curr Pharm Des 2003;9:737–49.[Medline]
  37. Lawton CA, Cohen EP, Barber-Derus SW, Murray KJ, Ash RC, Casper JT, et al. Late renal dysfunction in adult survivors of bone marrow transplantation. Cancer 1991;67:2795–800.[Medline]
  38. Butcher JA, Hariharan S, Adams MB, Johnson CP, Roza AM, Cohen EP. Renal transplantation for end-stage renal disease following bone marrow transplantation: a report of six cases, with and without immunosuppression. Clin Transplant 1999;13:330–5.[Medline]
  39. Cohen EP, Piering WF, Kabler-Babbitt C, Moulder JE. End-stage renal disease (ESRD) after bone marrow transplantation: poor survival compared to other causes of ESRD. Nephron 1998;79:408–12.[Medline]
  40. Moulder JE, Fish BL, Cohen EP. Treatment of radiation nephropathy with ACE inhibitors. Int J Radiat Oncol Biol Phys 1993;27:93–9.[Medline]
  41. Moulder JE, Fish BL, Cohen EP. Radiation nephropathy is treatable with an angiotensin converting enzyme inhibitor or an angiotensin II type-1 (AT1) receptor antagonist. Radiother Oncol 1998;46:307–15.[Medline]
  42. Moulder JE, Fish BL, Cohen EP. Angiotensin II receptor antagonists in the treatment and prevention of radiation nephropathy. Int J Radiat Biol 1998;73:415–21.[Medline]
  43. Cohen EP, Lawton CA. Pathogenesis, prevention and management of radiation nephropathy. In: Tobias JS, Thomas PRM, editors. Current radiation oncology, Vol. 3. New York, NY: Oxford University Press, 1998:94–109.
  44. Juncos LI, Carrasco Dueñas S, Cornejo JC, Broglia CA, Cejas H. Long-term enalapril and hydrochlorothiazide in radiation nephritis. Nephron 1993;64:249–55.[Medline]
  45. Cohen EP, Moulder JE, Fish BL, Hill P. Prophylaxis of experimental bone marrow transplant nephropathy. J Lab Clin Med 1994;124:371–80.[Medline]
  46. Geraci JP, Sun MC, Mariano MS. Amelioration of radiation nephropathy in rats by postirradiation treatment with dexamethasone and/or captopril. Radiat Res 1995;143:58–68.[Medline]
  47. Moulder JE, Fish BL, Cohen EP, Bonsib SM. Angiotensin II receptor antagonists in the prevention of radiation nephropathy. Radiat Res 1996;146:106–10.[Medline]
  48. Moulder JE, Fish BL, Cohen EP. Noncontinuous use of angiotensin converting enzyme inhibitors in the treatment of experimental bone marrow transplant nephropathy. Bone Marrow Transplant 1997;19:729–36.[Medline]
  49. Moulder JE, Fish BL, Cohen EP. Brief pharmacologic intervention in experimental radiation nephropathy. Radiat Res 1998;150:535–41.[Medline]
  50. Cohen EP, Lawton CA, Moulder JE, Becker CG, Ash RC. Clinical course of late-onset bone marrow transplant nephropathy. Nephron 1993;64:626–35.[Medline]
  51. Cohen EP, Fish BL, Moulder JE. Successful brief captopril treatment in radiation nephropathy. J Lab Clin Med 1997;129:536–47.[Medline]
  52. Cohen EP, Fish BL, Moulder JE. The renin–angiotensin system in experimental radiation nephropathy. J Lab Clin Med 2002;139:251–7.[Medline]
  53. Lawton CA, Fish BL, Moulder JE. Effect of nephrotoxic drugs in the development of radiation nephropathy after bone marrow transplantation. Int J Radiat Oncol Biol Phys 1994;28:883–9.[Medline]
  54. Moulder JE, Robbins MEC, Cohen EP, Hopewell JW, Ward WF. Pharmacologic modification of radiation-induced late normal tissue injury. Cancer Treat Res 1998;93:129–51.[Medline]
  55. Oikawa T, Freeman M, Lo W, Vaughan DE, Fogo A. Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin–angiotensin inhibition. Kidney Int 1997;51:164–72.[Medline]
  56. Molteni A, Moulder JE, Cohen EP, Ward WF, Fish BL, Taylor JM, et al. Control of radiation-induced pneumopathy and lung fibrosis by angiotensin converting enzyme inhibitors and an angiotensin II type 1 receptor blocker. Int J Radiat Biol 2000;76:523–32.[Medline]
  57. Kim JH, Brown SL, Kolozsvary A, Jenrow KA, Ryu S, Rosenblum ML, et al. Modification of radiation injury by ramipril, inhibitor of angiotensin-converting enzyme, on optic neuropathy in the rat. Radiat Res 2004;161:137–42.[Medline]
  58. Moulder JE, Cohen EP, Fish BL, Hill P. Prophylaxis of bone marrow transplant nephropathy with captopril, an inhibitor of angiotensin-converting enzyme. Radiat Res 1993;136:404–7.[Medline]
  59. Moulder JE, Fish BL. Angiotensin converting enzyme inhibitor captopril does not prevent acute gastrointestinal radiation damage in the rat. Radiat Oncol Investig 1997;5:50–3.[Medline]
  60. Yoon SC, Park JM, Jang HS, Shinn KS, Bahk YW. Radioprotective effect of captopril on the mouse jejunal mucosa. Int J Radiat Oncol Biol Phys 1994;30:873–8.[Medline]
  61. Moulder JE, Fish BL, Regner KR, Cohen EP. Angiotensin II blockade reduces radiation-induced proliferation in experimental radiation nephropathy. Radiat Res 2002;157:393–401.[Medline]
  62. Cohen EP, Fish BL, Moulder JE. The role of nitric oxide in radiation nephropathy. Arch Physiol Biochem 1996;104:200–6.[Medline]
  63. Moulder JE, Fish BL, Regner KR, Cohen EP, Raife TJ. Retinoic acid exacerbates radiation nephropathy. Radiat Res 2002;57:199–203.
  64. Verhagen AM, Hohbach J, Joles JA, Braam B, Boer P, Koomans HA, et al. Unchanged cardiac angiotensin II levels accompany losartan-sensitive cardiac injury due to nitric oxide synthase inhibition. Eur J Pharmacol 2000;400:239–47.[Medline]
  65. Qiu C, Muchant D, Beierwaltes WH, Racusen L, Baylis C. Evolution of chronic nitric oxide inhibition hypertension: relationship to renal function. Hypertension 1998;31:21–6.[Abstract/Free Full Text]
  66. Verhagen AMG, Braam B, Boer P, Gröne JJ, Koomans HA, Joles JA. Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve renal angiotensin II concentrations. Kidney Int 1999;56:222–31.[Medline]
  67. Cohen EP, Bonsib SA, Whitehouse E, Hopewell JW, Robbins MEC. Mediators and mechanisms of radiation nephropathy. Proc Soc Exp Biol Med 2000;223:218–25.[Abstract/Free Full Text]
  68. Datta PK, Moulder JE, Fish BL, Cohen EP, Lianos EA. TGF-{beta}1 production in radiation nephropathy: role of angiotensin II. Int J Radiat Biol 1999;75:473–9.[Medline]




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