These data extend our initial report of consistent trends for benefit of captopril to mitigate radiation injury after TBI-based HSCT. The occurrence of the BMT nephropathy syndrome or HUS is less in those subjects of the captopril arm compared to those of the placebo arm (). This positive result has occurred without increasing the relapse rate.
Patient survival is better in the captopril arm compared to the placebo arm (), and this appears to be influenced by less lung-related deaths in the captopril arm (). While neither of these differences reached statistical significance, the trend is favorable. In addition, although the present study shows only trends for benefit of captopril on the renal, pulmonary, and survival endpoints, it does show the safety of the use of captopril in irradiated patients.
The BMT nephropathy syndrome appears to be closely linked to use of TBI. Its mitigation by captopril is highly consistent with the mitigation benefit of captopril in experimental radiation nephropathy (9
). The benefit of captopril in this study occurred even though the median time of use of the study drug was only two months. That is also consistent with the experimental data that use of captopril only from 3 weeks to 10 weeks after TBI exerts a long-term mitigating benefit (5
). It is possible that a longer time of use of captopril would have increased its benefit in this study, but the treating physicians had a low threshold to stop the study drug. Further, the two subjects in the captopril cohort who developed the BMT nephropathy syndrome were on study drug for less than a week. Our pre-clinical data suggest that times-on-drug of less than six weeks are ineffective. If these two subjects are re-assigned to the placebo group, the difference in the BMT nephropathy endpoint between the captopril and placebo groups becomes highly significant (p< 0.01 by log rank test).
The trend towards mitigation of lung-related mortality is consistent with the benefit of angiotensin-converting-enzyme (ACE) inhibitors on radiation pneumopathy in rats (7
). The delivered mean mid lung radiation dose was less than 7 Gy in this study. At that dose, lung injury is usually held to be unlikely. Consistent with this, the pulmonary function tests were not different in the 2 groups. If anything the statistical trend was towards better preservation of DLCO in placebo rather than captopril treated subjects. Therefore, the potential pulmonary benefit does not appear to be attributable to protection of lung parenchyma by captopril.
The incidence of lung-related mortality was higher than one might have expected given that a single dose in excess of 8 Gy is generally required to produce radiation pneumonitis (13
). On the other hand, in radiation accident victims who had severe hematological toxicity, but who survived >10 days and probably received < 10 Gy exposures, Fliedner et al.
reported that 72% also had pulmonary injury (14
The subjects of our study had additional causes for lung injury, especially infection and or graft versus host disease. Those could add to the otherwise low risk of radiation injury. In that circumstance, mitigation of lung radiation injury could exert a general benefit to reduce the risk of lung-related deaths. In fact, the lung mortality benefit appears largely confined to the first 12 months after BMT, a time frame consistent with highest risks of infections as opposed to radiation associated fibrosis.
The delivered kidney radiation dose in these subjects was 9.8 Gy. In a parallel and contemporaneous cohort of subjects eligible for this study, but did not sign up for it, and who received the same renal radiation dose, cases of BMT nephropathy occurred at a rate of 10%. We estimate the equivalent single fraction dose of this regimen to be 6.5 Gy, at which one might expect some renal injury (15
). Concurrent or past chemotherapy is likely to increase that risk of injury.
The long term follow up of these subjects, over four years for all subjects, has yielded no additional cases of BMT nephropathy. Luxton identified radiation nephropathy as occurring acutely, within one year, or chronically, at up to five years after irradiation (16
). It is possible that longer follow-up may yield additional cases. Lesser degrees of injury could also occur, and be manifest as hypertension, without reduction in kidney function (17
). We do not have follow up information for the blood pressure to confirm or disprove that possibility.
Chronic kidney disease after HSCT is common, occurring in 20% or more of long term survivors (18
). Complete failure of kidneys leads to end-stage-renal disease(ESRD), the requirement for dialysis or transplant to sustain life; ESRD is up to sixteen times more common in subjects who have undergone HSCT, in comparison to the general population (20
). Chronic kidney disease appears to have an independent adverse effect on patient survival after HSCT (21
). Measures to mitigate its occurrence are thus of substantial importance.
Clinical application of our findings may be improved by identifying subjects at higher-than-average risk for radiation injury. At present, genetic markers for normal tissue radiation injury have limited value, other than for severe radiation sensitivity syndromes such as ataxia telangiectasia. It is possible that identification of biomarkers of radiation injury, such as proteinuria, could guide more focused clinical application of radiomitigators (22
). In the HSCT patient who undergoes radiation-based pre-HSCT conditioning, angiotensin-converting-enzyme inhibitors may be useful agents to mitigate the later occurrence of chronic kidney disease.
Finally, these results further support the concept that radiation-induced normal tissue injuries can be reduced in incidence and severity by post-irradiation pharmacologic interventions and should encourage clinical trials of this approach (23