What is Radiation Nephropathy?
The problem of radiation damage to the human body and its individual systems and organs has gained relevance over the past decades throughout the world. This is due to the widespread use of nuclear energy and radioactive substances both for military purposes and in many sectors of the national economy – in industry, medicine, research institutions, etc. As a result, an increasing number of people are exposed to the harmful effects of ionizing radiation, resulting in often to severe and irreversible consequences. Mass destruction of people by high doses of ionizing radiation is known not only during the atomic bombing in Hiroshima and Nagasaki, but also in subsequent years during the test explosions of new types of nuclear weapons, and then as a result of accidents at nuclear power plants.
The damaging effect of ionizing radiation can be caused both by external irradiation of the whole body, and as a result of the ingress of radioactive substances into the body: with inhaled air, i.e. through the respiratory tract (about 1% of all radioactivity contained in the body), with drinking water (about 5 %), and most importantly – with food products of plant and animal origin, i.e., through the gastrointestinal tract, less often – through the skin (if it is damaged) directly into the blood. Penetrating into the body, various radionuclides remain in it from several days to many years and have a damaging effect on the organs in which they are incorporated and through which they are excreted from the body, including the kidneys. In particular, cesium-137, quickly distributed throughout all organs and tissues (mainly in the muscles), is excreted from the body mainly through the kidneys and gastrointestinal tract (in a ratio of 4: 1).
For a long time it was believed that human kidneys are resistant to radiation. Unfortunately, many radiologists and radiologists, as well as some pathophysiologists, for many years (and even decades) adhered to such an erroneous opinion and did not recognize the possibility of radiation damage to the kidneys, although a few years after the discovery of X-rays by X-ray were published about the effect of radiation on the kidneys. True, these messages were also ambiguous and contradictory.
At present, no one doubts that the kidneys can be affected both by the general effect of ionizing radiation on the body, and as a result of their local exposure, as well as if radioactive substances directly enter them. Moreover, it is suggested that of all parenchymal organs, it is the kidneys that are most sensitive to the effects of ionizing radiation. It is believed that when radionuclides enter the body, radiation nephropathies develop more often and are more difficult. Standing out from the body mainly by the kidneys, radioactive substances accumulate and are often delayed for a long time, causing changes in the structural elements of the kidney tissue and a violation of the partial and total functions of the kidneys. The most common cause of radiation damage to the kidneys is the readily soluble compounds of uranium and polonium, which have the ability to accumulate in the kidney tissue and excreted in the urine, while having a nephrotoxic effect both as heavy metals and due to their inherent a-activity. The development of radiation damage to the kidneys is also possible due to the ingestion of such radionuclides as plutonium, strontium, thorium, cobalt, radium, cesium, etc. At the same time, radioactive 198Ai, 131I, which are often used in clinical practice for diagnostic and therapeutic purposes, do not a significant damaging effect on the kidneys, as they are rapidly excreted from the body.
Radiation nephropathies often occur as a result of repeated exposure to the kidneys of ionizing radiation during X-ray or radiotherapy of malignant neoplasms or other diseases with localization in the abdominal cavity. Kidney damage is possible with frequent and prolonged x-ray studies of them, as well as with repeated intravenous administration of radioisotopes for diagnostic purposes. A significant place is also taken by radiation nephropathies, which develop in individuals who are exposed to ionizing radiation during prolonged work with radioisotope substances (in research institutions, laboratories, in the conditions of industrial production of these substances, in mines during uranium mining, and also during nuclear test explosions devices and as a result of accidents at nuclear power plants).
Radiation damage to the kidneys can occur both as a result of a single exposure to the body of large doses of external radiation, or when a single dose of large doses of radioactive substances enters the body, with repeated repeated incorporation of these substances in relatively small doses.
Unfortunately, in the literature there are still no convincing data on the frequency of radiation damage to the kidneys and the doses of ionizing radiation that can cause these lesions. There are only a few reports on this issue. With local irradiation of the kidney area in a total dose of 2500-6000 rad (or 25-60 Gy), radiation nephritis develops in 30-35% of cases.
Renal lesions caused by ionizing radiation are termed “radiation nephropathies” or “radiation nephritis,” and the latter, in turn, is divided into acute and chronic. However, some researchers do not agree with this terminology, since, according to their data, the tubular epithelium and interstitial tissue are not primarily involved in the pathological process. Therefore, at the beginning of the disease, jade is absent. Given these, as well as other histomorphological changes in the structure of renal tissue, detected at various times after exposure to ionizing radiation on the kidneys, F.K. Mostofi considers it more reasonable to designate radiation damage to the kidneys as sclerosing nephrosis of varying severity. Nevertheless, in the domestic nephrological literature, this pathology of the kidneys is referred to as radiation nephropathy or radiation nephritis. In the further presentation of pathogenesis, pathomorphology, clinic, diagnosis and treatment of radiation damage to the kidneys, we will use the term “radiation nephritis”.
Pathogenesis during Radiation Nephropathy
The causes of radiation nephritis have not yet been fully elucidated. However, there is no doubt that the nature and severity of pathological changes in the kidneys, as well as in the body as a whole, as well as the severity of clinical and laboratory manifestations arising under the influence of ionizing radiation, largely depend on the total radiation dose obtained by external or internal exposure, the nature of radiation, individual sensitivity to it of renal tissue and age. Children and adolescents are more sensitive to ionizing radiation than adults.
In adults, kidney damage of varying severity usually develops with local external exposure in doses of more than 2000 P (516 mC / kg body weight). However, damage is possible with significantly lower doses. Thus, a decrease in the renal plasma flow in patients during radiotherapy sessions with total exposure is already at a dose of 400 rad (4 Gy), and a transient decrease in glomerular filtration rate with external exposure at doses of 550-1600 rad (5.5-16.0 Gr). In some patients without signs of a previous kidney disease, transient proteinuria appears during doses of radiation or immediately after it at doses less than 2500 rad (25 Gy).
A dose of external irradiation of the kidneys exceeding 2000 R (516 mCl / kg) has a damaging effect on nephrons. The critical dose is from 2000 to 6000 P (from 516 to 1548 mC / kg), obtained within 20-60 days. In this case, it is necessary to take into account the area of the irradiated surface of the kidney: if it exceeds 2/3 of the total surface, then the development of radiation jade is practically beyond doubt. Previous kidney diseases, especially of an infectious nature, abnormalities in their development, urostasis of various origins increase the sensitivity of renal tissue to radiation exposure.
It is believed that the pathogenesis of radiation nephritis does not have significant differences with the mechanism of development of radiation injuries of other organs observed in acute and chronic radiation sickness. Moreover, in violation of the structure and function of the kidneys, an important role is played not only by the direct damaging effect of ionizing radiation, but also by the influence of many toxic substances resulting from metabolic disturbances in the body.
In the mechanism of the damaging effect of ionizing radiation, a change in the activity of many enzymes is also important. In particular, there is an increase in the activity of enzymes that catalyze tissue breakdown – hydrolases, ribonuclease, acid phosphatase, as well as tissue hyaluronidase, which is accompanied by an increase in the permeability of blood vessels, tissues and cell membranes.
Significant changes under the influence of ionizing radiation occur in the immune system. A decrease in its activity, humoral and cellular defense of the body is noted even when exposed to minimal doses of radiation, which contributes to the activation of foci of endogenous infection and the development of severe infectious complications, including from the kidneys.
Due to the breakdown of proteins of their own tissues and changes in their properties, the development of autoimmune pathological processes is possible.
To the above, it should be added that radionic nephropathies develop not only in acute radiation sickness, but also after 3-6-9 months or even several years after radiation exposure.
The nature and severity of morphological changes in the kidneys due to radiation damage largely depend not only on the radiation dose (local or general), but also on the time elapsed after the radiation exposure. The highest damaging activity have radioactive substances with massive g-radiation. It has been established that the various structural elements of the kidneys have different radiosensitivity, although there is still no consensus on the degree of this sensitivity. Nevertheless, most researchers believe that they are more sensitive to the damaging effects of external ionizing radiation and to radioactive substances penetrating the kidneys, the epithelium of the proximal tubules and cells of the interstitial tissue; to a lesser extent, structural elements of the renal glomeruli. As a result of this, the earliest and most severe histomorphological and functional abnormalities are found in the proximal renal tubules, while changes in the glomeruli are less pronounced, occur later and are secondary.
If radiation damage to the kidneys occurs against the background of acute radiation sickness during its height (acute radiation nephritis – ORN), then macroscopically there is an increase in their size and weight, swelling and swelling of the renal tissue. In the section of the kidney, there is an expansion of cortical matter and hyperemia, mainly of the cerebral substance. Multiple hemorrhages of various sizes are visible on the surface of the incision.
Histological studies indicate that all structural elements of the kidney tissue — glomeruli, tubules, interstitial tissue, and blood vessels — are involved in the pathological process. At the same time, the glomeruli are enlarged, exudate accumulates in the cavities of their capsules, which is associated with an increase in permeability of glomerular capillaries; there is a thickening of the basement membranes and the walls of the glomerular capillaries themselves, as well as the walls of the bringing and interlobular arterioles, leaves of the Shumlyansky-Bowman capsule; often – fibrinoid necrosis of the glomerular capillary loops, as well as their intergrowth between themselves and the glomerular capsule. Changes in the tubules are manifested by swelling of the epithelium (mainly the proximal sections) with its subsequent desquamation, expansion of the lumen of the tubules. In the interstitial tissue, mainly periglomerularly, eosinophilic infiltration, plasmocyte accumulation are found. Subsequently, hyalinosis and glomerular sclerosis develop.
If ORN develops 7-8 months after irradiation, then by this time pronounced dystrophic changes in the epithelium of both the proximal and distal tubules are detected. As a result of vascular damage and narrowing of their lumen, the formation of heart attacks, fibrous cords in the cortical substance of the kidneys is possible. Nephrosclerosis can occur 8-14 years after exposure. Moreover, it can be bilateral or unilateral (in the case of irradiation of one kidney); develops more often and earlier if radiation damage to the kidneys is caused by the ingress of radioactive substances into the body, and the intensity of kidney sclerosis increases in parallel with an increase in the number of incorporated radionuclides.
In chronic radiation nephritis (CRF), the kidneys (or one kidney with unilateral exposure) are reduced in size. Their surface is fine-grained, fibrous capsule covering them is thickened. The section reveals a thinning of the cortical layer. Various degrees of severity (depending on the duration of the disease and the nature of its course) are noted for interstitial fibrosis and death of the renal parenchyma.
During histological examination, the glomeruli are for the most part hyalinized and sclerosed, and the remaining ones are hypertrophied. In the tubules, pronounced degenerative changes with obstruction of their lumen and the development of tubulohydrosis are noted. In many nephrons, the tubules completely disappear. In the interstitial tissue, diffuse fibrosis is noted. In small renal vessels (interlobular arterioles, bringing and taking glomerular arterioles), fibrinoid necrosis is detected, and in larger ones, intimal sclerosis. If chronic radiation nephritis is accompanied by the development of the syndrome of malignant arterial hypertension, signs of endarteritis, necrotizing vasculitis, severe sclerosis are detected in arterioles and interlobular arteries, fibrin thrombi are often noted in glomerular capillaries, and hemorrhages in interstitial tissue.
The described histomorphological changes in the kidneys that develop in patients with chronic radiation nephritis are based in most cases on autopsy data.
However, it should be noted that the pathomorphogenesis of radiation damage to the kidneys is not fully understood. In particular, in the literature there is practically no information about the results of histomorphological changes in the structural elements of the kidney tissue in the dynamics of the development and progression of this pathology, which could be obtained using intravital puncture biopsy of the kidneys. At the same time, these questions were studied in more detail in the experiment.
Chronic radiation-induced nephritis results in the development of a secondary shriveled kidney, which is clinically manifested by chronic renal failure.
Symptoms of Radiation Nephropathy
They say about ORN in cases where clinical symptoms and laboratory signs of this disease appear 3-12 months later (according to other sources, 6-9 months later) after radiation exposure on the body as a whole or only locally on the kidney area (Yu. I. Moskalev, 1991). The nature and severity of these symptoms, the timing of their appearance depend on the dose and type of exposure (external or internal, general or local), as well as age. In children and adolescents, they occur earlier, are more pronounced, and the disease is more severe.
When exposed to small doses of radiation, especially in cases where the kidneys remain outside the field of radiation, transient (within 20-45 days) violations of some functions of the kidneys can be observed, detected using special research methods. This is a decrease in glomerular filtration, filtration fraction, renal plasma flow, minute diuresis.
More pronounced symptoms of acute respiratory infections develop against the background of acute radiation sickness that occurs with general exposure in large doses, as well as with the incorporation of radionuclides excreted from the body by the kidneys. In such patients, along with other signs of acute radiation sickness, edema, arterial hypertension and urinary syndrome of varying severity – proteinuria, hematuria, cylindruria – appear. There is a decrease in the relative density of urine, glomerular filtration rate, renal blood flow and plasma flow, clearance of urea, chlorides, and concentration function of the kidneys. Violation of the aforementioned renal function is detected a few hours after irradiation and reaches its highest degree in two days. At the same time, during primary reactions with an average radiation dose of 350 R (90.3 mCl / kg), diuresis can even increase slightly, and with a high dose of radiation (700 R, or 180 mC / kg), it significantly decreases and a more pronounced inhibition of many other kidney functions. In the latent period, diuresis is restored, and sometimes increases. In the midst of radiation sickness, a decrease in diuresis is again observed and an even more significant (than during the initial reaction) decrease in partial and total renal functions.
In urine, protein is found from traces up to 10 g / l or more, hematuria (up to macrohematuria), leukocyturia, cylindruria (hyaline, granular, and often waxy cylinders), epithelial cells. Urine acquires an alkaline reaction, an acid-base balance shifts towards acidosis. Urinary syndrome develops against the background of changes characteristic of radiation sickness from the peripheral blood and bone marrow – severe anemia, leukopenia. A biochemical blood test reveals a positive C-reactive protein, an elevated level of sialic acids, dysproteinemia with hypoalbuminemia, hyper-a1- and hyper-A2-globulinemia, often with hypergammaglobulinemia, as well as hyperazotemia of varying severity.
With a favorable course of the disease during the recovery period, the clinical and laboratory signs of acute radiation nephritis (and acute radiation sickness) gradually disappear, and normalized renal function is normalized. This process lasts from 20-30 days to a year or more.
In a number of cases, acute respiratory disease, which occurs against the background of acute radiation sickness, does not differ clinically and according to laboratory data from ordinary acute glomerulonephritis, however, it is characterized by a severe course, with severe arterial hypertension, edema, hyperazotemia, and in about 30-40% it ends with acute renal failure with high lethality. This type of radiation jade is more often observed in children and adolescents. In some patients, the disease acquires a chronic course with rapid progression, the development of nephrosclerosis and chronic renal failure.
If acute radiation nephritis occurs 3-6-12 months after irradiation, the earliest and most frequent clinical signs are swelling, mainly on the face and lower extremities, and arterial hypertension, which often acquires, a malignant course with severe headache, shortness of breath, impaired vision, cerebral complications. In addition, patients complain of aching pain in the lumbar region, general weakness, a decrease in the amount of urine in the first days from the onset of the disease. Dysuric phenomena are usually absent. Protein is found in the urine (1.0-2.0 g / l, sometimes higher), red blood cells, usually in small quantities, sometimes single in the field of view, cylinders. Relatively early rates of glomerular filtration rate, nitrogen excretion and concentration function of the kidneys decrease, which is manifested by hyperazotemia and hypostenuria. From the very beginning of acute respiratory infections, severe normochromic anemia develops, caused by a violation of erythropoiesis under the influence of radiation exposure, which is not amenable to treatment.
The course of acute respiratory infections in most cases is progressive and adverse; mortality reaches 50%. The outcome of the disease significantly worsens the accession of malignant arterial hypertension.
Chronic radiation nephritis can be a consequence of OSR (secondary CRF) or develops without a previous ARS, usually 1.5-10 years after exposure (primary CRF). This disease for a long time (from 2 to 10 years) can occur secretly and is often detected during an accidental examination of such a patient. It can also develop against the background of chronic radiation sickness.
Clinically, CRF manifests itself in a very diverse way – from mild symptoms to a severe picture of subacute (malignant) or rapidly progressive nephritis. It is characterized by frequent and early development of hypertension, which in many cases becomes malignant. The disease is rarely accompanied by nephrotic syndrome; usually proceeds harder and faster than ordinary chronic glomerulonephritis. Already after 2-3 years, it can end in an unfavorable outcome due to chronic renal failure or from cerebral or cardiac complications. In this case, there is a decrease in glomerular filtration, concentration function of the kidneys with the development of hyperazotemia, hypo- and isostenuria, nocturia, and in the terminal stage of chronic renal failure – oliguria and anuria.
At the same time, other symptoms associated with nephrosclerosis and chronic heart failure join in. In rare cases, CRF occurs with less severe symptoms and less rapid progression, and therefore with a longer lifespan. Signs of chronic renal failure appear after several or many years from the onset of the disease. However, in the vast majority of cases, the course and outcome of CRF is unfavorable.
According to some authors, radiation damage to the kidneys can manifest as so-called asymptomatic proteinuria. Proteinuria in such cases occurs on average 10-11 years after irradiation, without any subjective and objective symptoms of kidney damage, is often intermittent in nature. The daily loss of protein in the urine in most cases does not exceed 1.0 g. For a long time there are no signs of renal failure, but in the future arterial hypertension joins, which makes it possible to regard asymptomatic proteinuria as a latent form of chronic kidney disease. Consequently, its transition to chronic radiation nephritis after a few years is not excluded.
Of particular interest is radiation hypertension, which is recorded in more than 50% of exposed individuals. It usually develops within 1O years after irradiation, including when irradiating only one kidney. Clinically, radiation hypertension can be benign or malignant. However, in both cases there is no doubt its true renal origin, as evidenced by the high level of diastolic pressure, a tendency to relatively rapid progression, and resistance to antihypertensive therapy. In some cases, already in the initial period of the disease, in others, laboratory signs of kidney damage are later discovered: hypostenuria develops, and then hypoisostenuria, proteinuria, erythrocyturia appear. The course of radiation hypertension, even with a benign version, is assessed as very unfavorable. The disease is characterized by relatively rapid progression and severe complications from the heart and brain. As a result, after 2-4 years from the onset of the disease, patients die either from the aforementioned complications, or (less commonly) from renal failure.
Diagnosis of Radiation Nephropathy
It is very difficult to establish a diagnosis of radiation nephritis, especially in cases where there is no history or insufficient evidence of radiation effects on the body and its doses. Therefore, for a timely diagnosis of this disease, first of all, information is needed on the effect of ionizing radiation on the patient, on the nature of this effect (general or local external exposure or as a result of the ingress of radioactive substances into the body, especially radionuclides such as polonium and uranium), on doses exposure, its duration and time elapsed from the moment when the patient was exposed to penetrating radiation.
At the same time, the diagnosis of acute radiation nephritis, developing against the background of the clinical picture of acute radiation sickness, is not particularly difficult, as there are extrarenal (edema, arterial hypertension) and renal (proteinuria, erythrocyturia, cylindruria, impaired renal function), signs of this diseases. It is more difficult if ORN occurs 3-10 months or more after irradiation. It is even more difficult to diagnose chronic (especially primary) radiation nephritis, developing, as already noted, 2-10 years after irradiation, especially since it is almost impossible to distinguish it from ordinary chronic glomerulonephritis by clinical signs and laboratory data. In such cases, a history and relevant documentation confirming the effects of ionizing radiation several months or years before the onset of signs of radiation jade are crucial in the diagnosis and differential diagnosis of both acute and chronic radiation jade. In addition, the latter, in comparison with conventional OGN or CGN, is characterized by a more frequent appearance of arterial hypertension with a malignant course and a more rapid progression of the disease with a violation of tubular and glomerular functions, up to the development of renal failure and an unfavorable outcome in the next 2-4 years from its beginning.
Treatment of Radiation Nephropathy
specific methods and means of treating patients with this pathology do not yet exist. Treatment is carried out with the same methods and means as with ordinary glomerulonephritis and interstitial nephritis. Prescribe a diet with a restriction of salt, and in the presence of edema – and fluid. With the development of hyperazotemia, the use of proteins of animal origin is limited (as with renal failure of a different etiology). Diuretic and antihypertensive drugs are also used.
Patients with acute radiation nephritis developing against the background of acute radiation sickness are prescribed medications that are currently used to treat acute radiation sickness. These are general strengthening, antihistamines, antihemorrhagic, desensitizing agents. Widely used are complexes of vitamins C, B, P, PP, amino acids (tryptophan, histidine, methionine). Particular attention is paid to radioprotectors – preparations containing sulfhydryl groups (unitiol, cystamine, cystafos, etc.).
To accelerate the removal of incorporated radioactive substances (heavy metals), complexing agents are used. However, in connection with the possible development of side effects, these drugs should be administered carefully. Anabolic and glucocorticoid hormones, gamma globulin, and blood transfusion are also prescribed.
In patients with chronic radiation nephritis with a malignant course of arterial hypertension with a lesion in one kidney, a kidney nephrectomy can be performed.
Prevention of Radiation Nephropathy
In order to prevent radiation nephritis, it is first of all necessary to strictly observe the rules of the sanitary-hygienic regime for persons working in contact with radioactive substances or in conditions of possible damage from penetrating radiation. They should be subject to constant monitoring, be carefully monitored, regularly undergo medical examinations with a mandatory examination of not only peripheral blood, but also urine, including the functional state of the kidneys. It is not recommended to allow people with already existing kidney diseases or with a history of such diseases to work with radioactive substances.
It is necessary to avoid exceeding permissible radiation doses when using x-rays and radioactive substances for diagnostic, therapeutic and other purposes. With radiation therapy, exposure to the kidneys should be avoided whenever possible. It is not recommended to often resort to kidney scanning using neohydrin labeled with 203Hg, since this radionuclide can linger in the kidney tissue for months, exerting a damaging effect on it. It is safer to use neohydrin labeled 197Hg for this purpose, at which the radiation dose is noticeably lower.
All persons exposed to hazardous X-ray exposure or exposure to radioactive substances must undergo a thorough medical examination every 3-6 months and avoid repeated exposure.