Practice Essentials
Radiation nephropathy is kidney injury and impairment of function caused by ionizing radiation. It may occur after irradiation of one or both kidneys, and it may result in kidney failure. Exposure to ionizing radiation can cause tissue reactions depending on the absorbed dose.
Acute radiation nephropathy develops 6-12 months after irradiation, whereas chronic radiation nephropathy develops years later. Classic radiation nephropathy occurs after bilateral, local kidney irradiation and is characterized by chronic kidney disease occurring months or years after renal irradiation. [1] Nearly 7 million cancer patients were treated with radiation therapy in 2012, and the number of cancer survivors is increasing each year, highlighting the importance of addressing tissue toxicity and improving quality of life after radiation therapy. [2]
Radiation nephropathy with chronic kidney disease may also occur after hematopoietic stem cell transplantation (HSCT), also called bone marrow transplantation (BMT) nephropathy. [3] In addition, the use of yttrium–90–tagged (90Y-tagged) somatostatin and other radionuclides for radionuclide therapy can cause radiation nephropathy when these agents are filtered by the kidneys and reabsorbed by the renal tubule epithelium or when blood-borne exposure to the kidney cells occurs. [4] (See Etiology.)
An excess occurrence of chronic kidney disease was reported in long-term survivors of the atomic bomb explosions at Hiroshima and Nagasaki. [5] Total or partial body radiation exposures, as might occur in an accident or a belligerent exposure, may also cause kidney injury.
The term radiation nephritis was commonly used in the past; however, because radiation nephropathy is not an inflammatory condition, the term nephropathy is probably more appropriate.
Etiology
Radiation nephropathy is due to cellular injury caused by ionizing radiation. All components of the kidney are affected, including the glomeruli, blood vessels, tubular epithelium, and interstitium. [6]
In the case of local kidney irradiation or total-body irradiation, the injury is direct. In the case of injury by radionuclide therapy, a radioisotope can injure the kidneys if its pharmacokinetics cause it to lodge in the kidney while it is still a radioemitter. This is the case for 90Y-tagged somatostatin, which has been used for the treatment of neuroendocrine malignancies, and for holmium-166–tagged (166Ho-tagged) phosphonate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP). [7, 8]
More than 70% of kidney stones in the United States are diagnosed by means of computed tomography, and many of these patients are relatively young, averaging 45 years of age at first diagnosis; 20% of patients with an acute stone episode receive a 1-year cumulative medical imaging radiation dose of greater than 50 mSv. The risk of radiation to this relatively young population is, therefore, a substantial concern. [9]
Not all patients exposed to sufficient renal irradiation develop renal injury. The reason for this clinical variability is unknown. Indeed, the heterogeneity of response of healthy tissue to ionizing radiation is poorly understood. No reliable clinical predictors are available for the development of radiation nephropathy. Some individuals may develop radiation nephropathy at a dose of radiation that has no clinical effect on others.
Pathophysiology
Oxidative injury to DNA initiates injury to healthy tissue by ionizing radiation. This is a genotoxic injury. A cell with sufficient DNA injury eventually dies after several divisions. The delay in cell death may partially explain why radiation injury to healthy tissue is a delayed reaction.
The precise mechanism whereby the kidney cells and tissues malfunction after this injury remains poorly understood. In experimental models, ultrastructural damage to the glomerular endothelium is observed 3 weeks after a 10-Gy (1000 rad) dose of local kidney irradiation, and neutrophil adherence to the endothelium occurs. [6] By 6 to 10 weeks after the same dose, a wave of tubular epithelial cell deaths occurs. This is followed by interstitial scarring. The scarring tends to be most severe in the outer cortex, and it proceeds inward. The progression of these events is accelerated with higher doses of radiation.
The earliest functional evidence of experimental radiation nephropathy is proteinuria, which is evident by 6 weeks in a radiation nephropathy model with 17-Gy multifraction total-body irradiation. Azotemia and hypertension are present by 12-15 weeks in the same model. The origin of the hypertension probably is similar to that of most experimental hypertension, although pressure-natriuresis curves have not been studied. Renin levels in systemic blood are normal or low, and blood and intrarenal angiotensin II levels are within the reference range (ie, not elevated).
In clinical experience, radiation nephropathy does not occur until months after the kidneys are exposed to sufficient ionizing radiation. Early data suggested that a dose of 20 Gy (2000 rads) given in multiple fractions over several weeks can cause radiation nephropathy. [1] With total body irradiation (TBI), chronic renal failure develops within 6-12 months after 10-Gy single-fraction TBI. The long-term Hiroshima-Nagasaki data suggest that a single fraction dose as low as 1 Gy is associated with an elevated risk of chronic kidney disease over many years of follow-up.
Radiation nephropathy after BMT (BMT nephropathy) occurs following a lower dose of radiation than had been traditionally accepted as nephrotoxic. This dose is given over days, not weeks, to the whole body and is accompanied by chemotherapy, which may account for the unexpectedly dramatic effect on the kidneys. Proteinuria is usual, although generally not in the nephrotic range. Azotemia and hypertension also develop. Anemia out of proportion to the degree of azotemia is a characteristic finding.
Severe cases of radiation nephropathy after BMT may resemble hemolytic uremic syndrome (HUS), with thrombocytopenia, microangiopathic hemolytic anemia, and a high blood level of lactate dehydrogenase (LDH). This last syndrome may be the result of severe endothelial injury.
In the case of unilateral renal irradiation, progressive scarring of the irradiated kidney may occur, with severe hypertension related to renin release by the single irradiated kidney.
Epidemiology
Clinical radiation nephropathy, and its congener, the BMT nephropathy syndrome, have been reported worldwide.
Radiation nephropathy does not occur in all irradiated patients. In a study of Korean patients with normal baseline kidney function who received adjuvant radiotherapy for gastric cancer and were followed up for 5 or more years, 13 of 663 (2%) developed kidney function impairment. [10] In the large British series of classic radiation nephropathy described by Luxton, only 20% of subjects developed radiation nephropathy, although each received more than 2500 rads to the kidneys. [1] Radiation nephropathy in 10-20% of patients who receive BMT. [11]
In a United States report, 30 of 83 subjects treated with 66Ho-tagged DOTMP developed some kidney injury; 7 subjects had thrombotic microangiopathy (ie, hemolytic-uremic syndrome [HUS]). [8]
No confirmed sex-based differences in radiation nephropathy have been reported. At the BMT unit of the Medical College of Wisconsin, BMT nephropathy has affected more women than men, but other centers have not had this experience. No age-based differences in susceptibility to classic radiation nephropathy have been confirmed. However, in the case of BMT nephropathy, children appear to be more likely to develop this syndrome than adults.
No racial or ethnic predisposition to radiation nephropathy has been identified.
Prognosis
Radiation nephropathy may progress to end-stage renal disease (ESRD). The same is true of BMT nephropathy; the occurrence of ESRD in subjects who have undergone BMT is almost 20 times higher than it is in the age-matched general population. [12] The progression to ESRD has also occurred after internal radioisotope radiotherapy. Complete renal failure may evolve in weeks in severe cases, and after years in less severe cases.
One can predict when a patient will need dialysis by making a graph of 100/plasma creatinine versus time. At the point where the 100/plasma creatinine value is equal to 10, the estimated renal function is approximately 10% of normal, revealing that dialysis may be needed soon after that. (See Workup/Rate of Kidney Function Loss.)
Patients with BMT nephropathy whose kidney function declines to the point of their needing chronic dialysis have a poor prognosis compared with that of age-matched control subjects receiving dialysis. This probably is related to the burden of immunosuppression and past illness associated with BMT. Individuals with BMT nephropathy may also have accelerated atherosclerosis, which may be related to total-body irradiation and chemotherapy. [13]
A meta-analysis of 458 patients with acute kidney injury (AKI) following a hematopoietic stem cell transplant (HSCT) found that the rates of recovery varied, with 58% recovery among those with less severe AKI and 10% among patients with severe AKI requiring kidney replacement therapy. Overall, 68% of patients had a complete recovery and 29% had a partial recovery. [14]
Mortality/morbidity
As with other causes of chronic kidney disease, radiation nephropathy may be asymptomatic. When it sufficiently reduces kidney function, symptoms and signs of renal failure occur. ESRD and the need for dialysis or transplantation may develop. In patients with BMT nephropathy who are receiving dialysis, the survival rate is less than that of age-matched control subjects. [15]
Proteinuria occurs, but it is usually not a striking feature in patients with radiation nephropathy. Reports of classic radiation nephropathy generally describe non–nephrotic-range proteinuria (< 3 g/d). In BMT nephropathy, the average urinary protein level has been reported at 2.5 g/d. Fluid overload, edema, pulmonary edema, and hyperkalemia are additional complications that can occur in these patients.
In classic radiation nephropathy, malignant hypertension may affect as many as 30% of patients and can occur as late as 11 years after irradiation. In BMT nephropathy, hypertension is a cardinal feature and observed along with azotemia. Were it not for antihypertensive agents, malignant hypertension would probably be a major feature of BMT nephropathy.
On hematologic analysis, accompanying anemia is present in radiation nephropathy and BMT nephropathy and is more severe than that expected for the degree of azotemia. In severe cases of BMT nephropathy, hemolytic anemia, a high blood LDH level, and a decreased platelet count may be present. This syndrome may be mistaken for HUS or thrombotic thrombocytopenic purpura (TTP).
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Evolution of the glomerular filtration rate (GFR) versus time in a case of nephropathy related to bone marrow transplantation (BMT). GFR may be approximated as 100/plasma creatinine on the Y axis and graphed versus time on the X axis. As is true in many cases of BMT nephropathy, the evolution appears to be biphasic, with an initial rapid decline in GFR, then a slower plateau phase. The patient whose data are shown here ultimately underwent kidney transplantation.
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Photomicrograph of a kidney-biopsy sample in a case of nephropathy associated with bone marrow transplantation (periodic acid-Schiff stain). A glomerulus is in the center and is relatively hypocellular. Increased mesangial matrix is present. The glomerular basement membranes are not thickened; in some places, however, they are separated from the capillary lumens by a low-density, matrixlike material. Interstitial fibrosis separates the tubules from each other. Arteriolar thickening and arteriolar hyalin are present.
