Radiation nephropathy☆
Section snippets
Clinical occurrence
Radiation nephropathy was well documented in a large case series published by Kunkler et al2 over 50 years ago. These were men who had undergone therapeutic irradiation for seminomas. Radiation nephropathy occurred in about 20% of sufficiently irradiated subjects, and could take various clinical forms (Fig 1). The most common was acute radiation nephritis, which presented clinically as azotemia, hypertension, and anemia starting at 6 to 12 months after irradiation. Nephritis appears to be a
Radiation tolerance of the kidney
The kidney is a radiosensitive organ. Clinically, the tolerance dose (for 5% complications in 5 years) for the kidney is approximately 20 Gy, as compared with values of 50 and 60 Gy for the bladder and brain, respectively16, 17; doses of approximately 25 to 30 Gy given in conventional 2-Gy fractions to the total renal mass are likely to lead to chronic renal failure.18 Experimental studies indicate that the kidney has an extensive capacity for repair of sublethal radiation damage. The size of
Morphologic changes
The progressive reduction in renal function observed after kidney irradiation is associated with concomitant time- and dose-dependent alterations in all components of the nephron leading to glomerulosclerosis and/or tubulointerstitial fibrosis.26 Serial determinations of morphologic changes indicate that primarily glomerular but also tubular alterations occur in the early stages of radiation nephropathy. Irradiated glomeruli show lesions that appear to develop regardless of the examined species
Functional changes
There is a wealth of experimental data on functional changes in radiation nephropathy.26 Studies in the monkey,41 pig,45, 46 and rat47 have reported pronounced changes in GFR and effective renal plasma flow within several weeks of irradiation. There is evidence for an initial hyperemic response in GFR and effective renal plasma flow followed by a dose-dependent decline in GFR and effective renal plasma flow within 6 to 8 weeks of irradiation.45 Measurements of renal function assessed as blood
Cellular radiation injury
Renal tubular epithelial cells clearly are radiosensitive; a D0 (radiation dose that reduces the surviving fraction to 37% of initial value) of 1.5 Gy, similar to that found for other mammalian cells, has been reported.65 Similar values also have been noted for endothelial cells irradiated in vitro.66 Moreover, radiation-induced increases in glomerular and tubular cell proliferation, likely in response to radiation-induced cell kill, have been noted within several weeks of irradiation.67, 68, 69
Mesangial cell
Irradiating rat mesangial cells with single doses of 5 to 20 Gy γ rays led to isoform-specific alterations in gene expression of the profibrogenic cytokine transforming growth factor β (TGF-β). TGF-β1 messenger RNA (mRNA) levels showed a dose-independent increase 24 to 48 hours postirradiation. In contrast TGF-β3 mRNA levels showed a progressive dose-independent decrease over the same time period.75 These changes were associated with a concomitant increase in gene expression for several
In vivo mediators and mechanisms
In recent years the characterization of radiation-induced normal tissue injury has undergone a paradigmatic shift. Pathophysiologic data from a variety of late responding tissues indicate that the expression of radiation-induced normal tissue injury involves complex and dynamic interactions between several cell types within a particular organ.28, 80, 81, 82 These now are viewed not as passive bystanders, merely dying as they attempt to divide, but as active participants in an orchestrated, yet
RAS
The role of the RAS in radiation nephropathy is supported by multiple studies that show that antagonism of the RAS is beneficial, and also by evidence that AII excess exacerbates radiation nephropathy. Captopril was used successfully to treat established experimental radiation nephropathy, and this benefit is shared by the AII blocker L-158,809.48, 103 Prevention studies, in which drug is started at or just before irradiation, confirm the benefits of RAS antagonism, by ACE inhibitors or AII
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Supported in part by grants from the National Institutes of Health, CA24652 (E.P.C.) and DK51612 (M.E.C.R.), and the American Cancer Society ROG# 00–350–01. (E.P.C.)