Definition
Radiation nephropathy is the kidney parenchymal injury and loss of function caused by radiation exposure to the kidneys. Its typical form is caused by external beam ionizing radiation, by x-rays or gamma-rays. It may also be caused by radioisotope therapies that irradiate kidneys internally. It is not common in current clinical practice but remains a risk of accidental or belligerent radiation exposures. The term nephropathy is preferred instead of nephritis, because radiation nephropathy does not have major inflammatory features.
Historical recognition
Radiation nephropathy was first recognized in 1927. Earlier descriptions of kidney injury in irradiated subjects may have been caused by tumor lysis syndromes rather than true radiation injury to kidneys. The best cohort studies are those of Luxton and colleagues, in which radiation nephropathy is described in men who had undergone external beam x-irradiation for treatment of seminoma. , After delivery of 20 Gy or more x-irradiation in fractionated doses, over a period of 4 weeks, approximately 20% of thus-treated subjects developed radiation nephropathy of varying severity. Similar presentations were reported in case reports and smaller series over the next 25 years, in both adults and children. Structural and ultrastructural features were well-described.
Epidemiology
There are two modern congeners of radiation nephropathy. The first occurs in subjects that have undergone hematopoietic stem cell transplantation (HSCT) that is preceded by total body irradiation, as part of the conditioning regimen. , This has been called bone marrow transplant nephropathy ( BMT nephropathy ). The second may complicate the use of internal radioisotope therapies.
The 2017 Annual Data Report of the United States Renal Data System reports that of 700,000 prevalent patients on chronic dialysis in the USA, 159 have radiation nephropathy as their indicated cause of end-stage renal disease (ESRD). Eighty-nine patients on chronic dialysis are reported as a complication of HSCT. It is likely that these are underestimates, because the 2728 forms that indicate the diagnosis of ESRD are not reliable.
Clinical features
Radiation nephropathy presents typically at 3 or more months after sufficient irradiation, with azotemia and hypertension. There is nonnephrotic proteinuria. The more severe variants may develop thrombocytopenia and even microangiopathic hemolytic anemia, reminiscent of hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP).
Urinalysis shows proteinuria and microhematuria. The proteinuria is generally below the nephrotic range.
Radiation nephropathy may occur in children and in adults, in men and in women. No racial predisposition is known. But Judele et al. have reported complement regulatory defects in subjects who developed thrombotic microangiopathy after radiation-based HSCT, defects that are the same ones that are associated with HUS. It is not known whether these complement regulatory defects predispose to usual radiation nephropathy.
Previous or concurrent use of chemotherapy, such as cyclophosphamide or cis-platinum, may predispose to radiation nephropathy, much as some chemotherapies predispose to normal tissue radiation injury generally. It is likely, but not proven, that underlying kidney disease predisposes to radiation nephropathy.
Dose considerations
External beam
The dose of radiation required to predictably cause noncancerous normal tissue radiation injury is well above that used in diagnostic radiology. Thus a computed tomography scan of the abdomen delivers 1 centiGray (or “rad”) to both kidneys, which is 1000-fold lower than the single fraction dose of 10 Gy that may cause radiation nephropathy. Because there is tissue repair in between fractions, a total radiation dose of 10 Gy, given in multiple fractions over a week or more, is not likely to cause kidney injury. But a higher total dose, for example, 20 Gy, given over 4 weeks, may well cause radiation nephropathy, as described by Luxton and others (vide supra).
The aforementioned dose considerations are valid for radiation fields that only expose the kidneys, and for partial or total body irradiation.
Irradiation of a single kidney and not the other may cause unilateral kidney arterial and or parenchymal injury, scarring, and renin-dependent hypertension, but not radiation nephropathy per se. , Despite improvements in treatment planning, this remains a current clinical issue for people undergoing radiotherapy of the upper abdomen. When the irradiation fields include the kidneys, kidney scarring ensues.
Radioisotope
Administration of therapeutic radioisotope, for instance yttrium 90 attached to octreotide, may cause kidney injury by glomerular filtration of the radioisotope conjugate and its reabsorption by the kidney tubules. , The radiation injury is then local, with damage to tubules and glomeruli. It is difficult to calculate the exact irradiation dose, because it is delivered continuously, over days to weeks.
Use of radioisotope therapies may increase in the future, for instance with delivery of antibodies conjugated to beta- or gamma-emitting radioisotopes. The antibody provides the specificity and the isotope damages the targeted cancer cells. The pharmacokinetics of the conjugate will determine its potential kidney toxicity. Dose-finding studies should be done to identify the potential kidney doses, which will define whether a conjugate is safe for use.
As for diagnostic x-ray, use of diagnostic nuclear medicine isotope scanning poses no kidney risk because the doses are well below those that may cause injury to the kidneys.
Histology
The light microscopic appearance of radiation nephropathy is characteristic, with decreased glomerular cellularity, increased mesangial matrix, and mesangiolysis ( Fig. 20.1 ).
There is no evidence for an immunopathogenesis of radiation nephropathy, which makes immunofluorescence studies unhelpful.
Electron microscopy often shows glomerular endothelial injury and dramatic expansion of the subendothelial space with a somewhat electron-lucent material ( Fig. 20.2 ).
There is tubulointerstitial scarring, as is expected for any chronic kidney disease.
Testing
There is no specific blood test that is diagnostic of radiation nephropathy. There is also no specific imaging feature, although kidney parenchymal volume loss may be more marked than is typical for other chronic kidney diseases. Palestro et al. did report a transient kidney positivity after bone scanning of two subjects that had been irradiated 9 months before, but neither developed signs of radiation nephropathy.
The serum lactate dehydrogenase may be elevated in the more severe variants that occur after HSCT. Assays that indicate TTP are negative, such as those for ADAMSTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) level or activity. But abnormalities of complement regulatory components have been reported in the thrombotic microangiopathy that can complicate HSCT.
Differential diagnosis
Acute kidney injury (AKI) in total or partial-body-irradiated subjects has been described, but does not have the features as described earlier. In addition, AKI has not been reported in subjects that have undergone local kidney irradiation. Thus the AKI in subjects that have undergone partial or total body irradiation appears more related to the multiorgan injury, volume depletion, and sepsis that such subjects may develop.
In a subject who develops kidney disease after HSCT, there are multiple causes of both acute and chronic kidney disease. AKI within several weeks of irradiation is not likely to be caused by radiation nephropathy. Other causes of AKI should be sought, especially if the irradiation dose was below the usual thresholds. These include volume depletion, sepsis, and use of nephrotoxic therapies.
Medication use after allogeneic HSCT may include cyclosporine, tacrolimus, or sirolimus to prevent graft-versus-host disease (GVHD). Each is potentially nephrotoxic, and the effects of the first two calcineurin inhibitors (CNIs) may be similar to radiation nephropathy. But withdrawal of the CNI should at least stabilize the loss of kidney function in cases of clear-cut CNI toxicity, whereas CNI withdrawal will not benefit radiation nephropathy. Sirolimus nephrotoxicity is less apt to cause hypertension, and more apt to cause significant proteinuria, and thus can be distinguished from radiation nephropathy.
GVHD after allogeneic HSCT can be complicated by kidney injury, in particular nephrotic syndrome. Kidney biopsy in these cases shows minimal change nephropathy, focal glomerulosclerosis, and even membranous nephropathy. These features are not those of radiation nephropathy.
In a patient who has cancer, nephrotoxicities of chemotherapy must also be considered. Their cause and expression may be easy to recognize, as in the hypomagnesemic nephropathy caused by cis-platinum, or may be less specific, as in the interstitial nephritis caused by immunomodulators. Other chemotherapies, such as gemcitabine, may cause HUS-like syndromes that have clinical features similar to those of radiation nephropathy. The key differential feature is whether the patient has had kidney radiation exposure in a dose sufficient to cause injury.
Evolution
Luxton included milder forms of radiation nephropathy in his reports, and it is possible that some kidney-irradiated patients merely develop proteinuria or hypertension without subsequent loss of kidney function. The modern congener of radiation nephropathy, “BMT nephropathy,” appears however to be progressive, with loss of kidney function. We have described a biphasic loss of kidney function in such cases, with an initial rapid then a slower phase ( Fig. 20.3 ). It is possible, but not established, that medical intervention causes the loss of function to become slower.
Pathophysiology: Experimental models
There are well-established local kidney and total body irradiation models of radiation nephropathy. Mice, rats, dogs, pigs, and monkeys have been used. The radiosensitivity of these species is not very different, although mice can show a longer latency to expression of injury than do rats, pigs, and monkeys. The rat models are very useful because they show a similar radiation dose response, latency, and histopathology to the radiation nephropathy in humans. In addition to external beam models, there are also models of internal radioisotope radiation nephropathy in mice.
Time course and histology
In laboratory animals, single fraction local kidney or total body irradiation of 9 to 11 Gy causes a similar chronology of kidney injury. Proteinuria occurs within 1 to 2 months after irradiation, followed by azotemia and hypertension. Histopathology studies show injury of all kidney tissues, including vasculature, glomeruli, tubular epithelium, and interstitium. The mesangiolysis of human radiation nephropathy is very evident in the rat model, less so in pigs or monkeys.
The role of fibrosis
Progressive fibrosis of glomeruli and interstitium occurs in all models. An accentuation of peritubular fibrosis occurs at the origin of the proximal tubule in the rat, porcine, and monkey models of radiation nephropathy, and is called glomerulotubular neck stenosis , ( Fig. 20.4 ). This feature has also been seen in BMT nephropathy, a modern congener of radiation nephropathy. It also occurs in other chronic progressive human kidney diseases. It is likely to evolve to an atubular glomerulus, which is a clear mechanism for how fibrosis itself can cause kidney function loss.
The renin angiotensin system
The rat model has been used to test whether radiation itself activates the renin-angiotensin system. There is thus far only scant evidence that the renin-angiotensin system is activated in radiation nephropathy. The benefit of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) to treat, prevent, and mitigate experimental radiation nephropathy may be via other mechanistic pathways.
Nonetheless, suppression of the renin-angiotensin system by a temporary high salt diet is associated with the significant mitigation benefit of the temporary high salt diet, when the latter is used in a rat model starting at 3 weeks after irradiation and ending at 10 weeks.
Oxidative stress
Although the initial effect of tissue irradiation is to cause double strand deoxyribonucleic acid breaks via immediate oxidative stress, the role of persistent chronic oxidative stress in radiation nephropathy is doubtful. The antioxidants apocynin and genestein do not mitigate experimental radiation nephropathy.
Endothelial injury
Vascular injury has long been implicated in normal tissue radiation injury, including the kidneys. Human studies show reduction in kidney blood flow at doses as low as 400 rads (cGy) and similar features are seen in laboratory animals. , Occlusion of blood vessels ranging from 10 to 100 microns in diameter occurs as a late effect in lung or kidney in rat models. A high-dose 30 Gy local irradiation model in rats showed endothelial dysfunction with impaired endothelial dependent vasodilation. More recently, we showed impaired endothelial-dependent vasodilation of preglomerular arterioles after an 11 Gy partial body irradiation single fraction exposure, also in a rat model. This vascular effect was first evident at 3 weeks after irradiation and its severity increased at 6 then 12 weeks after irradiation. Impaired endothelial generation of epoxyeicosatrienoic acid (EET) metabolites correlates with this microvascular effect. Moreover, studies in the rat model of radiation nephropathy show the benefit of EET mimetics as mitigators.
Treatment, prevention, and mitigation
Use of the radiation nephropathy model has enabled differentiation of treatment, prevention, and mitigation of normal tissue radiation injuries ( Fig. 20.5 ). Although prevention of normal tissue radiation injuries may be possible with agents, such as amifostine, these are generally too toxic for human use. They would also not be useful for nonanticipated exposures, such as those caused by accident or terrorist events.
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