Radiation Nephropathy Research Articles

A 5-Year-Old Girl With Impaired Renal Function After Autologous Bone Marrow Transplantation

ONE MARROW TRANSPLANTATION(BMT) increasingly is used for the treatmentof patients with hematologic malignancies, somemetabolic and immunologic diseases, and de-pressed bone marrow after cancer treatment. Renalinsufficiency after BMT is common and related tomanycauses.Wepresentthecaseofagirlwhohadrenalinsufficiency4monthsafterautologousBMT.

Long-term toxicity of [177Lu-DOTA0,Tyr3]octreotate in rats

Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models. Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2x278 MBq groups. Three doses of 185 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469+/-18, 134+/-70 and 65+/-15 micromol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria. Injection of high doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.

Role of free radicals on mechanism of radiation nephropathy

In our study, after applying a single dose of 612 cGy irradiation, we aimed to observe the role of free radicals on tissue damage in the kidney caused by radiation by measuring NO level, Na/K-ATPase activity and TBARS amount which is an indicator of free radical damage. On the other hand we investigated whether the tissue damage can be prevented by vitamin A or not. This study was performed on three groups: 1. Control group 2. The group to which irradiation was administrated 3. The group which was given radiation + vitamin A. The irradiation group of animals were given a single dose of gamma irradiation at a sublethal dose. In the group which was administrated both irradiation + vitamin A, vitamin A was given for two days prior to irradiation. The amount of NO was measured by ESR spectroscopy, Na/K-ATPase and TBARS were measured by spectrophotometry. As a result of radiation mediated tissue damage in the kidney, we observed a NO loss, a decrease in Na/K-ATPase activity and an increase in TBARS amount. Although the administration of vitamin A before radiation, did not have any effect on NO loss and decrease in Na/K-ATPase.

Mitigation of Radiation Nephropathy

Restricted accessAbstractFirst published March 2006Mitigation of Radiation NephropathyE.P. Cohen, B.L. Fish, and J.E. MoulderView all authors and affiliationsVolume 54, Issue 2_supplhttps://doi.org/10.1177/108155890605402s57

Mitigation of radiation nephropathy after internal α-particle irradiation of kidneys

Internal irradiation of kidneys as a consequence of radioimmunotherapy, radiation accidents, or nuclear terrorism can result in radiation nephropathy. We attempted to modify pharmacologically, the functional and morphologic changes in mouse kidneys after injection with the actinium ((225)Ac) nanogenerator, an in vivo generator of alpha- and beta-particle emitting elements. The animals were injected with 0.35 muCi of the (225)Ac nanogenerator, which delivers a dose of 27.6 Gy to the kidneys. Then, they were randomized to receive captopril (angiotensin-converting enzyme inhibitor), L-158,809 (angiotensin II receptor-1 blocker), spironolactone (aldosterone receptor antagonist), or a placebo. Forty weeks after the (225)Ac injection, the placebo-control mice showed a significant increase in blood urea nitrogen (BUN) (87.6 +/- 6.9 mg/dL), dilated Bowman spaces, and tubulolysis with basement membrane thickening. Captopril treatment accentuated the functional (BUN 119.0 +/- 4.0 mg/dL; p <0.01 vs. placebo controls) and histopathologic damage. In contrast, L-158,809 offered moderate protection (BUN 66.6 +/- 3.9 mg/dL; p = 0.02 vs. placebo controls). Spironolactone treatment, however, significantly prevented the development of histopathologic and functional changes (BUN 31.2 +/- 2.5 mg/dL; p <0.001 vs. placebo controls). Low-dose spironolactone and, to a lesser extent, angiotensin receptor-1 blockade can offer renal protection in a mouse model of internal alpha-particle irradiation.

Expression of alpha-smooth muscle actin on experimental radiation nephropathy

一、材料和方法 1. 实验模型建立:按文献[1]的方法制作放射性肾病动物模型.6周雄性Wistar大鼠(日本SLC公司,n=32)被随机分成对照组(n=12)和照射组(n=20),全麻后开腹将右肾切除,暴露左肾,给予X线25 Gy单次照射.照射后1、3、6、9个月4个时间点分别处死各组动物。

Role of Angiotensin Converting Enzyme Inhibitor on the Functional Changes in Irradiated Rates

Background: Kidney irradiation clearly leads to a progressive reduction in function associated with concomitant glomerulosclerosis and/or tubulointerstitial fibrosis. Administration of Angiotensin-converting enzyme [ACE] inhibitor markedly abrogates the severity of radiation nephropathy and can prevent the functional changes that occur after irradiation. Objective: The present study was designed to test the efficacy of converting enzyme inhibition [enalapril] and its possible mechanistic basis in preventing functional changes in irradiated rates. Method: Prior to irradiation, rats were randomized to groups receiving enalapril or no treatment, in addition to a control group of non-irradiated, non-treated rates. Enalapril was administered intraperitoneally [0.1 mg/kg body weight/day], 4 weeks before and 12 weeks after irradiation. Both groups were exposed to a single dose of 7Gy gamma radiation. Results: Irradiation induced significant elevations in the levels of blood urea nitrogen, serum creatinine, and serum activities of lactate dehydrogenase [LDH]; creatine kinase [CK]; alanine amino transferase [ALT]; and aspartate amino transferase [AST] compare to control values, indicative of renal, cardiac, and hepatic injury. Also there was an increase in the serum levels of triglycerides, total cholesterol, and LDL-cholesterol. On the contrary, HDL-cholesterol level was decrease. The heart, kidney and liver antioxidant enzymes including total glutathione peroxidase [total-GPX], glutathione reductase [GR], and superoxide dismutase [SOD] activities were inhibited, while malondialdehyde [MDA] level in these organs was elevated, indicative of increased lipid peroxidation. These data confirm the role of oxidative stress in radiation injury. It can be concluded that enalapril treatment of rats prior to irradiation was able to diminish the functional changes that occur after irradiation as evidenced by a beneficial decrease in all parameters determined in the sera of these rats, with an increase in the level of HDL-cholesterol and an amelioration of inhibition of antioxidant enzymes activities in the organs of these rats.

Renal involvement in bone marrow transplantation

Bone marrow transplantation (BMT) is an effective therapeutic strategy for leukaemic malignancies and depressed bone marrow following cancer. However, its side effects on kidneys have been reported. Some drugs and irradiation are also suggested to be nephrotoxic. It is well known that haemolytic uraemic syndrome (HUS) after BMT develops as late-onset BMT nephropathy. Cyclosporine A (CsA) is a possible cause. Radiation nephropathy shows changes that are similar to the histology of HUS. These findings suggest that endothelial damage is closely associated with the pathogenesis of post-BMT nephropathy. Recently, some patients have developed glomerulonephritis accompanied by graft-versus-host disease (GVHD) after BMT. In these patients immune deposits are found mainly in subepithelium and mesangium equal to those of secondary membranous glomerulonephritis. A murine experimental model of GVHD manifests similar symptoms and histological changes to those of actual patients and may suggest the pathogenesis of glomerulonephritis.

Renal Tubulointerstitial Changes after Internal Irradiation with α-Particle–Emitting Actinium Daughters

The effect of external gamma irradiation on the kidneys is well described. However, the mechanisms of radiation nephropathy as a consequence of targeted radionuclide therapies are poorly understood. The functional and morphologic changes were studied chronologically (from 10 to 40 wk) in mouse kidneys after injection with an actinium-225 (225Ac) nanogenerator, a molecular-sized, antibody-targeted, in vivo generator of alpha-particle-emitting elements. Renal irradiation from free, radioactive daughters of 225Ac led to time-dependent reduction in renal function manifesting as increase in blood urea nitrogen. The histopathologic changes corresponded with the decline in renal function. Glomerular, tubular, and endothelial cell nuclear pleomorphism and focal tubular cell injury, lysis, and karyorrhexis were observed as early as 10 wk. Progressive thinning of the cortex as a result of widespread tubulolysis, collapsed tubules, glomerular crowding, decrease in glomerular cellularity, interstitial inflammation, and an elevated juxtaglomerular cell count were noted at 20 to 30 wk after treatment. By 35 to 40 wk, regeneration of simplified tubules with tubular atrophy and loss with focal, mild interstitial fibrosis had occurred. A lower juxtaglomerular cell count with focal cytoplasmic vacuolization, suggesting increased degranulation, was also observed in this period. A focal increase in tubular and interstitial cell TGF-beta1 expression starting at 20 wk, peaking at 25 wk, and later declining in intensity with mild increase in the extracellular matrix deposition was noticed. These findings suggest that internally delivered alpha-particle irradiation-induced loss of tubular epithelial cells triggers a chain of adaptive changes that result in progressive renal parenchymal damage accompanied by a loss of renal function. These findings are dissimilar to those seen after gamma or beta irradiation of kidneys.

Extraosseous accumulation of99mTc-HMDP to radiation nephropathy, mimicking recurrent neuroblastoma

The aim of this study is to clarify the period of extraosseous accumulation of (99m)Tc-hydroxymethylenediphosphonate (HMDP) to radiation nephropathy mimicking recurrent or remnant neuroblastoma in the pararenal region. We reviewed five neuroblastoma and one ganglioneuroblastoma patients (2 boys and 4 girls aged 1-9 years) who underwent (99m)Tc-HMDP bone scintigraphies periodically before and after radiation therapy. Increased renal uptake coincident with the radiation port appeared in 5 of 6 patients from 0 to 3 months (mean 1.7 months), and persisted up to 7 months after the completion of radiotherapy. Renal uptake of (99m)Tc-HMDP was gradually decreased, and eventually became accumulation defects in 5 of 6 patients from 6 to 17 months (mean 8.9 months) after radiotherapy. When extraosseous accumulation is found after radiation therapy in neuroblastoma patients, radiation nephropathy would be a candidate in the differential diagnosis besides recurrent or remnant tumor.

The Importance of Age, Fludarabine and Total Body Irradiation in the Incidence and Severity of Chronic Renal Failure Following Allogeneic Hematopoietic Stem Cell Transplantation.

Nonmalignant late effects significantly impair the quality of life of long-term survivors following hematopoietic stem cell transplantation (HSCT), the major risk factors being chronic graft-versus-host disease (GVHD) and the use of total body irradiation (TBI) in the preparative regime. There has been a shift towards the use of fractionated, as opposed to single-dose TBI, in an attempt to reduce toxicity. Few reports exist on the renal consequences of HSCT, although many warn about the potential toxicity that eventually leads to chronic renal failure (CRF). However, the exact incidence of HSCT nephropathy is unknown, as there is a lack of well-designed analyses to provide cumulative incidence rates and descriptions of risk factors. The aim of this study was to assess retrospectively the risk and severity of CRF following TBI-based preparative regimes and the contribution of other patient, disease and post-transplant factors. From February 1996 to April 2004, 274 patients had TBI-based preparative regimes for allogeneic HSCT at our institution. Chemotherapy mainly consisted of cyclophosphamide (120 mg/kg) alone or in combination with fludarabine (90 mg/m2). TBI was started the day after completion of chemotherapy and was delivered as a single dose of 7.5 Gy (7.5S), 12 Gy in 6 fractions (12F), or 14.4 Gy in 8 fractions (14.4F). Fludarabine and high-dose TBI (14.4 Gy) were administered preferentially to those patients receiving T-cell depleted (TCD) grafts. GVHD prophylaxis was with a combination of cyclosporin (CSA) + methotrexate in unmanipulated transplants and with CSA alone or nothing in case of TCD grafts. CRF was defined as a persistent increase of serum creatinine (SCr) to greater than 120 μmol/l in males and 97 μmol/l in females (upper limits at our institution) over a period of at least six months. The cumulative incidence of CRF was 11% for the whole group. Renal tissue was available for review in 9 patients. All except one had histologic features suggestive of thrombotic microangiopathy ± radiation nephropathy. Kaplan-Meier analysis revealed a significant association between the incidence of CRF and older age at transplantation (>30 years; P = 0.0043), administration of fludarabine (P = 0.0014), high-dose/unfractionated TBI (14.4F > 7.5S > 12F; P = 0.0005) and TCD (P = 0.0031). Since fludarabine was usually associated to TCD grafts and high-dose TBI, we investigated whether the use of fludarabine was masking the effect of these other factors. Only older age at transplant (HR = 2.97; 95% CI, 1.32–6.68; P = 0.008) and fludarabine administration (HR = 3.22; 95% CI, 1.47–7.04; P = 0.003) remained significant in a multivariate Cox regression analysis. Of note, although TBI dose/fractionation did not fit in the multivariate model, CRF severity was significantly different as 38% of the patients in the 7.5S group currently require or have required permanent dialysis as opposed to 7% in both 12F and 14.4F groups combined. In conclusion, the incidence and severity of CRF post-transplant is associated with age, fludarabine administration and TBI dose/fractionation and, therefore, these factors should be kept in mind in order to prevent this late effect and devise new preparative regimens for HSCT.

Peptide receptor radiotherapy (PRRT) with [Y-90-DOTA,Tyr3]octreotide: Toxicity and efficacy of 4-cycle and single-cycle regimens

3046 Background: PRRT with [Y-90-DOTA,Tyr3]octreotide (Y-90-SMT487, OctreoTher) has potential benefit in patients with somatostatin receptor positive tumors. We investigated whether toxicity (tox), mainly renal and red marrow (RM), and effects on tumor size are different when the total radioactivity (RA) is given in 4 equal cycles (4-cy) or in fewer cycles (cy), but with higher activity per cy (Hi-cy). Methods: 60 patients (pts) with neuroendocrine tumors were treated with 1 or more cy of Y-90-SMT487 escalating from 4 x 25 to 4 x 100 mCi/m2 (4-cy, n=34; 32 completed 1, 28 completed 4 cy) or 1 to 3 x 100 to 250 mCi/m2, up to a renal limit of 27 Gy (Hi-cy, n=26). The individual RA for a renal dose of 27 Gy had been determined prior to entry by PET using Y-86-SMT487. All pts received concomitant infusion of amino acids for renal protection. The first dose of RA was 60 ± 27 mCi/m2 (mean ± SD) in the 4-cy group, and 164 ± 41 mCi/m2 in the Hi-cy group (P<0.001). The cumulative RA was 219 ± 108 mCi/m2 (4-cy) and 224 ± 58 mCi/m2 (Hi-cy), similar in both groups, as were other baseline parameters. Results: Overall, 9 pts had transient WHO grade 3 and 1 pt grade 4 RM tox; 1 pt had myelodyplasia after 2 years. During the first cy, nadir platelets (Hi-cy: 111 ± 45 x 10E9/L, 28% ± 29% less than baseline) and nadir leukocytes (Hi-cy: 3.2 ± 1.2 x 10E9/L, 38% ± 27% less than baseline) were lower in the Hi-cy than in the 4-cy group (P<0.01), but differences were NS between groups after full dose. Renal tox included 2 pts with radiation nephropathy (late grade 3) and 2 with suspected radiation nephropathy; no pts required dialysis. Pts with follow-up of >30 months (n=13) showed a mean decrease in calculated creatinine clearance of 10.9 ± 4.1 mL/min, or 13.0 ± 4.9% from baseline. Differences between 4-cy and Hi-cy groups were NS. 5 pts had PR, 7 minor response, and 30 SD. In 12 4-cy pts with measurable tumor shrinkage, the smallest size occurred after 17 ± 11 months; in 10 Hi-cy pts after 13 ± 8 months (NS). Conclusions: PRRT with Y-90-SMT487 after individual dosimetry is well tolerated. Except for reversible early RM tox, we did not observe major differences in tox or efficacy between the 4-cy and Hi-cy groups. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp.

Clinical aspects of radiation nephropathy.

Small radiolabeled molecules are finding increasing clinical use for targeted radionuclide therapy. With the administration of radiolabeled small molecules, the bone marrow is not necessarily the first organ to show radiation toxicity. Rapid excretion of radioactivity through the urinary tract and the retention of radiolabeled small-protein molecules in the kidneys may expose the kidneys to radiation sufficient enough to cause toxicity--and in clinical trials, radiation toxicity of the urinary tract has become clinically relevant. The cells of the kidneys are slowly repairing cells; thus, the radiation toxicity may not be manifest for several months. The clinical and pathological features associated with radiation nephropathy, and issues particular to radiation nephropathy following targeted radionuclide therapy, are described here.

Low-dose radiation modifies the progression of chronic renal failure

Previous studies have indicated that the application of low dose radiation to an arterial ligation has the potential to subsequently reduce or eliminate restenosis caused by smooth muscle cell proliferation. Sufficient kidney irradiation causes a radiation nephropathy and often leads to renal failure. In order to evaluate the effect of low-dose irradiation on the kidney we hypothesized that this particular therapy modifies renal injury in rats with renal ablation and subsequently slows the rate of the progression. For further clarification of the effect of irradiation at low doses, we determined proliferating cell nuclear antigen (PCNA) and monocyte chemoattractant protein-1 (MCP-1) expression in remnant kidneys after low-dose radiation. Adult Wistar rats (n = 10) were studied during the two weeks after renal ablation. The left kidney was irradiated 24 hours after an operation in anaesthetised animals with 3 Grey in a single dose. Ablated rats without irradiation (n = 9) served as nephrectomized animals group. Rats without surgery and without radiation (n = 10) served as healthy controls. Renal damage was assessed using the following parameters: urine protein excretion rate (UprotV, mg/day), awake systolic blood pressure (SBP, mm Hg), serum creatinine (SCr, micromol/l). The indirect immunofluorescence method was used for the detection of PCNA and MCP-1 expression. Glomerular and tubular immunostaining was scored semiquantitatively. Numerous PCNA positive cells and MCP-1 expression were present in the glomerulus and tubulointerstitium in nephrectomized rat kidneys. Low-dose radiation application was associated with a significant reduction in PCNA and low MCP-1 expression. This study shows that the application of low-dose irradiation has the potential to modify the progression of chronic renal failure in rats.

Relevance of external beam dose-response relationships to kidney toxicity associated with radionuclide therapy.

The importance of the kidney as a dose-limiting organ is likely to increase as smaller molecular vectors and radiometals become more commonly used in targeted radionuclide therapy. Data derived from kidney irradiation by external-beam therapy (XRT) indicate that the kidney is radiosensitive. The features of radiation nephropathy seen post-treatment appear similar between local XRT, total-body irradiation (TBI), and radionuclide therapy. For uniform kidney irradiation, tolerance doses appear to be approximately 15-17 Gy in 2 Gy fractions for local XRT and probably less than this (approximately 12 Gy in 2 Gy fractions) when radiation is delivered systemically as TBI in the context of bone marrow transplant protocols. Animal studies indicate that the linear quadratic (LQ) model with an alpha/beta parameter of 1.5-3 Gy seems to adequately describe the XRT fractionation sensitivity of kidney for doses per fraction down to approximately 1 Gy, but may underestimate the effectiveness of fraction sizes less than this. Animal studies have also clarified the dose-dependency of the time to expression of radiation nephropathy and have indicated that radiation nephropathy may be alleviated by pharmacological means.

Impact of angiotensin II type 2 receptor blockade on experimental radiation nephropathy.

In the rat, blockade of angiotensin II type 1 receptors diminishes the functional changes that occur after kidney irradiation. It has been hypothesized that some of the beneficial effects of angiotensin II type 1 blockers in renal disease are caused by a rise in angiotensin II that stimulates the angiotensin II type 2 receptor. If this hypothesis applied in this model, blockade of the type 2 receptor should exacerbate radiation nephropathy and/or counteract the beneficial effects of type 1 receptor blockade. To assess this hypothesis, rats were given total-body irradiation plus bone marrow transplantation and then treated for 12 weeks with a type 1 receptor blocker (L158,809), a type 2 blocker (PD123319), both blockers, or no blockers. Rats were assessed for renal function (proteinuria, hypertension, azotemia) and renal failure for up to 62 weeks. Contrary to the hypothesis, the type 2 blocker alone produced a temporary delay in the development of radiation nephropathy, and it substantially enhanced the efficacy of the type 1 blocker. This implies that both type 1 and type 2 angiotensin receptors need to be blocked to achieve the maximum level of prophylaxis of radiation nephropathy. We speculate that the beneficial effect of the angiotensin II type 2 receptor blocker is due to a reduction in radiation-induced renal cell proliferation or fibrosis.

Radiation nephropathy

The pronounced radiosensitivity of renal tissue limits the total radiotherapeutic dose that can be applied safely to treatment volumes that include the kidneys. The incidence of clinical radiation nephropathy has increased with the use of total-body irradiation (TBI) in preparation for bone marrow transplantation and as a consequence of radionuclide therapies. The clinical presentation is azotemia, hypertension, and, disproportionately, severe anemia seen several months to years after irradiation that, if untreated, leads to renal failure. Structural features include mesangiolysis, sclerosis, tubular atrophy, and tubulointerstitial scarring. Similar changes are seen in a variety of experimental animal models. The classic view of radiation nephropathy being inevitable, progressive, and untreatable because of DNA damage-mediated cell loss at division has been replaced by a new paradigm in which radiation-induced injury involves not only direct cell kill but also involves complex and dynamic interactions between glomerular, tubular, and interstitial cells. These serve both as autocrine and as paracrine, if not endocrine, targets of biologic mediators that mediate nephron injury and repair. The renin angiotensin system (RAS) clearly is involved; multiple experimental studies have shown that antagonism of the RAS is beneficial, even when not initiated until weeks after irradiation. Recent findings suggest a similar benefit in clinical radiation nephropathy.

Is the renal dosimetry for [90Y-DOTA0,Tyr3]octreotide accurate enough to predict thresholds for individual patients?

The accuracy in the dosimetry for radionuclide therapy shows a great contrast to that obtained in external beam radiotherapy. The dosimetry for [(90)Y-DOTA(0), Tyr(3)] octreotide is evaluated in patients to see whether the accuracy of the dosimetry is high enough to distinguish the probability for radiation nephropathy. The 5% threshold for late end-point nephropathy at 23 Gy with external beam radiotherapy becomes with (90)Y therapy at least 30-35 Gy, when it is given in three or more fractions. More accurate linear-quadratic (LQ) model parameters are, however, needed to predict a more precise threshold for renal damage in this dose rate region. The average MIRD-based dose to the kidneys was 27 +/- 4 Gy (N = 52) with no evidence for renal damage. The variance in the dose is only caused by the high variability in renal uptake kinetics of the compound. Using the actual kidney volumes instead of the phantom values lowered the kidney dose considerably, but the variance in the dose greatly increased. As the peptide specifically localizes in the kidney cortex, the dose to the cortex increased up to a factor 1.5 compared to the MIRD whole kidney dose. Both the sum of uncertainties of ? 40% in the actual dose to the kidneys and the unknown maximum tolerable kidney dose for internal therapy make that a fixed injected activity of 13.32 GBq together with a patient-averaged dosimetry is as good as patient-kinetics specific dosimetry using the MIRD method.

ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy.

Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway. Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy; an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

Proteinuria and Vascular Changes after Renal Irradiation: The Role of Reactive Oxygen Species (ROS) and Vascular Endothelial Growth Factor (Vegf)

Proteinuria occurs in all degrees of radiation nephropathy and can be present without other symptoms. In this study, radiation-induced proteinuria in C3H mice demonstrated a clear dose-response relationship and was apparent before the onset of significant structural vascular changes and decreases in renal function. This suggests that proteinuria is not a secondary event due to loss of the vascular structure. In an attempt to ameliorate radiation-induced proteinuria and progressive renal failure, two factors were studied. The influence of reactive oxygen species (ROS), which are generated by infiltrating neutrophils and mediate proteinuria in models of acute glomerular injury, was the first to be investigated. Short-term administration of the reactive oxygen scavengers superoxide dismutase (SOD) and catalase did not reverse an established radiation-induced proteinuria. Continuous administration of the antioxidant N-acetylcysteine (NAC) also failed to inhibit this proteinuria. However, since no direct assessment of the impact of these interventions on renal redox status was made, the putative role of ROS in radiation-induced proteinuria and nephropathy remains undefined. The second factor studied was vascular endothelial growth factor (Vegf), which is suggested to be involved in glomerular vessel permeability and the development of proteinuria in some models of renal disease. Northern blot analysis of mRNA from whole kidneys did not demonstrate any increased expression of Vegf after irradiation. There was also no change in the ratio of the different Vegf isoforms (PCR analysis), either in the whole kidney or in isolated glomeruli. No significant role for Vegf was identified for radiation-induced vascular changes or proteinuria, although post-transcriptional changes cannot be excluded.