We found evidence that radiation dose is associated with increasing chronic renal disease mortality even though estimated exposure in all individuals was less than 4 Gy and the median dose was 7.81 mGy. The strongest evidence for a radiation effect came from the subsample of the LSS cohort who also answered survey questions. Their ERR/Gy based on the linear model prior to adjusting for known chronic renal disease risk factors equaled 0.237 (95% CI: 0.02, 0.49) compared to 0.135 (95% CI: −0.008, 0.30) in the LSS as a whole. A quadratic dose model fit the data as well, if not minimally better, in both the subsample and the LSS as a whole and gave statistically significant ERR/Gy2 estimates of 0.15 (95% CI: 0.02, 0.32) and 0.09 (95% CI: 0.005, 0.20), respectively.
A dose-associated increased risk of kidney failure mortality has not been reported previously in the LSS cohort. However, a significant radiation-associated increase in kidney and ureteral stones was first observed in men but not women with the follow-up of the AHS ending in 1998 (19
). Frequent stone formation may be a sign of decreased kidney function and may also increase the risk of kidney failure, as shown by Gillen et al.
). Yamada et al.
also noted a significant quadratic dose relationship for hypertension and for myocardial infarction incidence in those less than 40 years of age at the time of the bombing (19
). In fact, Sasaki et al.
first reported significant relationships between radiation dose and rise in both systolic and diastolic blood pressure, potentially quadratic in nature, even after accounting for aging and smoking (20
). There is an interesting similarity between our finding of a quadratic dose relationship between radiation and kidney disease and their findings. Our study results and prior results from the RERF cited above suggest that there truly is a relationship between radiation dose and kidney function and that part of the effect of radiation on cardiovascular health is via kidney function. Although we attempted to validate that by looking at the radiation dose relationship with deaths caused by both cardiovascular and renal failure, there were far too few events to do this (n
We are aware of only a limited number of studies that attempted to evaluate the association between radiation dose and kidney health, and none that analyzed the association between dose and chronic renal failure mortality. A recent review of 14 studies, including all the studies we found independently, evaluating bone marrow transplant (BMT) survivors treated with total-body irradiation and renal failure as measured by serum creatinine, proteinuria, anemia and hypertension found a significant linear relationship between biologically effective radiation doses above 16 Gy and kidney failure (20
). Unfortunately, it is difficult to compare the BMT population to atomic bomb survivors. First, biologically effective doses are used to measure radiation exposure in cancer patients while weighted doses were used in the atomic bomb survivors. Cancer patients also receive a cumulative dose that is usually at least 10 times greater than those of the atomic bomb survivors, and the dose received is fractionated over multiple treatments. In addition, cancer survivors are often treated with various other therapies toxic to the kidneys, which may confound the association between radiation and renal failure.
Admittedly, the evidence for an association between radiation dose and kidney disease mortality is limited to the least specific definition of possible CRF listed anywhere on the death certificate. This most sensitive category of possible CRF actually includes kidney disease and renal failure of unspecified length (but not acute conditions) as well as a variety of chronic kidney conditions, only one of which is chronic renal failure. However, the ability to detect renal failure, especially chronic renal failure, has changed drastically over the years this cohort has been followed. In fact, a consensus definition of CKD and its diagnosis was not reached until 2002 (23
). Thus the use of CKD or CRF as a cause of death on the death certificate in our cohort was likely not consistent throughout time and does not correspond with this current consensus definition. Nevertheless, it is unlikely that there is bias associated with exposure level since personal physicians diagnosing this condition, or others filing out the death certificate, were unlikely to have known an individual’s dose from the atomic bomb.
The finding that ERR/Gy estimates increased when we adjusted for hypertension and diabetes was somewhat surprising and should be interpreted in light of the large confidence intervals around these estimates. We would have expected that as independent risk factors for kidney disease they would have explained some of the absolute risk in this population. In addition, prior findings from atomic bomb survivors between radiation dose and increased risk of hypertension, hypertensive heart disease mortality, CVD incidence and mortality, and known associations in the general public between blood pressure, kidney failure and heart disease suggest that hypertension is part of the mechanism between radiation and kidney disease mortality. For both reasons, we would have expected that adjusting for hypertension would have decreased the size of association between radiation and kidney disease mortality as it would reflect only that part truly independent of blood pressure.
One limitation of our study that could possibly explain this odd finding is that we relied on self-report. However, when we evaluated the association between hypertension and diabetes on kidney disease mortality, they each increased the risk as expected. Furthermore, when we validated the self-reported conditions against the most recent clinic visits in those who participated in both the clinically followed AHS and the questionnaires, the positive predictive value of self-reported hypertension for truly having diastolic blood pressure and/or systolic blood pressure in the hypertensive range was 82.5% and the negative predictive value was 72%. Data were not available to validate self-reported diabetes. Another limitation of our study is the reliance on death certificate data that may not be accurate, especially for contributing causes of death and diseases that tend to be asymptomatic like kidney disease until their end stages. And as mentioned previously, the definitions and diagnosis of CKD and CRF have changed over time, although they were likely to be similar amongst physicians within each community at a particular time. All of these limitations would have likely affected all survivors the same regardless of dose, which would have led to non-differential bias and decreased our ability to find a significant association when one was truly present rather than increase the risk of finding an association when one was not really present.
In conclusion, our results suggest, but do not prove, that there is a positive association between radiation dose and kidney disease mortality at doses under 3 Gy. The relationship is likely mediated through blood pressure, but there also appears to be a component independent of blood pressure. While our study cannot address this independent component, it may be related to inflammation, which is one of the mechanisms of atherosclerotic cardiovascular in the general population (33
) and has been noted to be elevated in a dose-dependent manner among atomic bomb survivors (34
). As relationships between radiation dose and blood pressure, presence of hypertension, cardiovascular disease mortality and incidence of myocardial infarction in those <40 years old at exposure have already been reported, our findings further suggest that part of the risk of cardiovascular disease, particularly myocardial infarction risk, is mediated by renal dysfunction. Given the importance of cardiovascular disease as a cause of mortality in those exposed to whole-body radiation and therapeutic radiation to the chest, our results suggest that future studies should seek to better measure kidney function over time and evaluate its association with the incidence and mortality of cardiovascular events, especially myocardial infarction.