Nephrotoxic effect radiopaque agents- abstract review of the book by Yu.A. Pytel and I.I. Zolotareva "Errors and complications in X-ray diagnostics of urological diseases."
Nephrotoxic effect of radiocontrast agents.
Toxic nephropathy should be understood as pathological changes structure and function of the kidneys due to the action of chemical and biological products that produce toxic metabolites that have a harmful effect on the kidneys. Renal damage may include proteinuria, acute tubular necrosis, medullary necrosis, and acute renal failure. The underlying pathogenesis of contrast media nephrotoxicity is vasoconstriction, which can be caused by direct endothelial injury or protein binding, as well as red blood cell agglutination and destruction.
A severe complication of X-ray contrast examination is the development of acute renal failure. R. O. Berkseth and S. M. Kjellstrand indicate that in approximately 10% of cases, acute renal failure is caused by the use of radiocontrast agents.
These complications may clinically manifest as interstitial tubular nephritis, tubular nephrosis, or shock kidney. Morphologically, vascular disorders are detected: thrombosis, infarction, fibrinoid necrosis of the wall of glomerular capillaries, inter- and intralobular arteries.
V. Uthmann et al. indicate that x-ray contrast agents have potential nephrotoxic effects. At the same time important has their osmolarity. After angiography, the authors found characteristic signs of osmotic nephrosis in the proximal renal tubules. Signs of acute renal failure may appear for the first time hours after the introduction of contrast agents into the blood. Despite renal failure, hypokalemia occurs, then dyspeptic disorders develop, abdominal pain and skin rashes appear, which are usually regarded as a manifestation of intolerance to the drug. Acute renal failure occurs due to ischemia of the renal cortical substance in response to a blood flow disorder. Pathological data indicate the development of acute interstitial or tubular-interstitial nephritis. Necrosis of the renal cortical substance is occasionally observed.
D. Kleinkheght et al. explain the development of acute renal failure by the fact that circulating immune complexes can cause a decrease in cortical perfusion, leading to renal ischemia and anuria. This opinion is based on the results of determining the hemagglutination reaction and hemolytic reaction of antibodies to a number of contrast agents using an antiglobulin test. At the same time, the authors do not exclude the possibility of developing acute renal failure due to hemolysis as a result of the formation of the antigen-antibody complex and the fixation of complement on the patient’s red blood cells.
Nephrotoxicity of some contrast agents may also be caused by high concentration in the tubular cells of those substances that are normally excreted by the liver, but do not enter the bile due to obstruction of the gallbladder or damage to the liver parenchyma.
In case of liver diseases, especially when its antitoxic function is impaired, when the kidneys compensatoryly provide its neutralizing function, the nephrotoxic effect of contrast agents increases sharply and the occurrence of kidney complications is more likely. In this regard, X-ray contrast studies of the kidneys in hepatopathy are unsafe.
There are reports of the occurrence of acute renal failure after excretory urography in patients with multiple myeloma.
In the pathogenesis of renal failure in patients with multiple myeloma, mechanical blockage of the renal tubules by protein casts occurs, followed by atrophy of the nephrons involved in the process and cessation of urine formation. During excretory and especially infusion urography, dehydration of the body occurs, therefore, in such patients it is necessary to maximize diuresis and administer sufficient quantity liquids. This recommendation also applies to patients with proteinuria of unknown origin for whom X-ray contrast examination of the kidneys is indicated.
Treatment of complications is symptomatic rather than pathogenetic; their prevention is difficult. Discussed following reasons: allergic reactions, direct toxicity, pharmacological iodine syncrasia, dehydration, etc.
Because reactions to contrast agents resemble anaphylactic shock due to the frequently observed dyspnea and collapse, which disappears after the use of adrenergic drugs, it is widely believed that these reactions are allergic.
There is an opinion that the reaction depends on the amount and concentration of the contrast agent. R. May and R. Nissi believe that adverse reactions of an allergic nature would be equally pronounced with any dose of contrast agent. However, J. V. Gillenwater, while not a supporter of the allergic theory, still believes that at high concentrations and in large doses, contrast agents become toxic to tissues. According to S. Hansson and G. Lindholm, M. J. Chamberlain and T. Sherwood, N. Milton and P. Gottlieb, infusion urography, in which a large amount of contrast agent is used, only in rare cases worsens the course of the underlying disease in severe renal disease insufficiency. This is explained by the fact that in case of renal failure, the contrast agent is released by the liver and intestines.
For patients with latent renal failure, in order to quickly remove the contrast agent and obtain its greater dilution, it is advisable to prescribe Lasix after the study.
So, High-contrast drugs used in urological studies are relatively low-toxic, however, if there is hidden or obvious functional failure of the kidneys or liver, then their introduction into the vascular bed can cause nephro- or hepatopathy.
Angiographic examination not only provides valuable information for establishing a diagnosis and determining rational treatment tactics, but also serves as a “provocative” test that reveals hidden functional failure of some parenchymal organs. This allows for the prevention of complications and activation of the pathological process in the corresponding organ when preparing the patient for surgery, administering anesthesia and in the postoperative period.
This is damage to the glomerular apparatus and renal tubules caused by the action of exo- and endotoxins, hemodynamic and metabolic disorders during poisoning. It manifests itself as lower back pain, asthenic syndrome, swelling, oligoanuria, which is subsequently replaced by polyuria, and multiple organ disorders. Diagnosed using general biochemical analyzes blood and urine, Reberg, Zimnitsky samples, ultrasound and tomography of the kidneys, ultrasound examination of the renal vessels, chemical and toxicological studies. Treatment includes detoxification therapy, infusion correction of metabolic disorders, and RRT.
ICD-10
N14.4 Toxic nephropathy, not elsewhere classified
General information
Toxic nephropathy is a collective concept that unites a number of nephrological diseases with similar etiopathogenesis and clinical picture. The prevalence of the pathology reaches 0.04%, which is up to 20% of all registered cases of acute renal failure. The increase in incidence is associated with the increasingly widespread use chemicals in various industries and in everyday life: according to observations, every year up to 10 million people are constantly in contact with nephrotoxic chemicals. Besides, reverse side The pharmaceutical industry's success has been the emergence of new drugs that affect the kidneys. Relevance timely detection toxic form of nephropathies is caused by high level mortality and severe outcomes due to irreversible destruction of kidney tissue.
Reasons
Damage to the renal parenchyma is caused by exposure to chemicals that have a direct or indirect nephrotoxic effect. In most cases, renal dysfunction, and in severe cases and tissue destruction, cause exogenous production and household poisons, although in some patients the disease is caused by endogenous intoxication. Specialists in the field of urology and nephrology identify the following groups of reasons that lead to the development of nephropathy:
- Taking substances with nephrotoxic effects. When poisons of this group enter the kidneys, acute glomerulopathy or tubular necrosis caused by reabsorption occurs large quantities toxic substances. Salts have a direct damaging effect on kidney tissue heavy metals(cadmium, lead, mercury, gold, arsenic, iodine, bismuth, chromium, etc.), ethylene glycol, oxalic and boric acids, gasoline, phenol, toluene, orellanic mushroom toxins, poisons of some animals.
- Indirect toxic kidney damage. Poisoning with substances with a hemolytic effect ( acetic acid, arsenous hydrogen, copper sulfate, snake venom etc.) are complicated by blockage of nephrons with hemoglobin. Similar damage is caused by massive crushing of tissues and prolonged compartment syndrome, in which myoglobinuria is observed. With toxic liver damage, the renal parenchyma is secondarily damaged by xenobiotics and endogenous toxins.
- General clinical manifestations poisoning. A number of chemicals do not have a direct nephrotoxic effect, but systemic manifestations that occur when they are taken lead to severe renal dysfunction. Most often, toxic forms of nephropathy develop against the background of poisoning with symptoms of shock, uncompensated acidosis, and severe metabolic disorders. The same situation occurs under the influence of endo- and exotoxins of pathogenic and opportunistic microflora.
Constant expansion of the range medications, primarily antibacterial and antitumor drugs, has led to an increase in the number of cases of toxic drug-induced nephropathy. According to research results, in more than 30% of patients, non-oliguric renal failure is associated with taking pharmaceuticals.
Pathogenesis
The mechanism of development of toxic nephropathy is determined by the reasons that provoked renal dysfunction. The pathogenesis of disorders caused by direct-acting nephrotoxins is based on a violation biochemical processes in nephrons, epithelial cells of proximal and distal tubules. After filtration by the glomeruli, the toxic substance enters the tubular system, where, due to the reabsorption of water, its level increases almost 100 times. The resulting concentration gradient promotes the entry and accumulation of xenobiotics in the tubular epithelium to a certain critical level.
Depending on the type of exotoxin, processes of destruction of cellular and mitochondrial membranes, lysosomes, cytoplasmic components, smooth endoplasmic reticulum, ribosomes, etc. occur in epithelial cells with the development of acute tubular necrosis in the most severe cases. Some nephrotoxins, due to the initiation of hyperimmune processes, destroy the glomerular apparatus of the cortex. Precipitation of immune complexes in glomerular structures or the formation of complex antigens in membranes followed by an attack by antibodies provokes the onset of acute glomerulonephritis or interstitial nephritis without damage to tubular epithelial cells. An important factor in direct nephrotoxicity is the ability of certain substances to stimulate the formation of free radicals.
The pathogenesis of indirect kidney damage due to tubular blockage is based on the development of necrotic processes in their cells and impaired reabsorption capacity. Intrarenal stasis of urine is accompanied by retrograde flow of glomerular filtrate and subsequent damage to nephrons. For nephropathies that arise against the background general poisoning, the basis of pathomorphological changes is usually cell ischemia and disruption of biochemical processes due to acid-base and water-electrolyte imbalance. At the initial stage, epithelial cell dysfunction occurs, which can subsequently be complicated by toxic degeneration and necrosis of the tubular epithelium, destruction of glomerular basement membranes, and interstitial edema.
Classification
Systematization of forms of toxic nephropathy is carried out taking into account the characteristics of the etiopathogenesis of the disease and the severity of symptoms. This approach allows us to develop optimal patient management tactics, and in some cases prevent the development of irreversible tissue destruction. Taking into account etiological factor and the mechanism of kidney damage, the following forms of the disease are distinguished:
- Toxic specific nephropathy. Develops under the influence of exogenous and endogenous substances with direct and indirect nephrotoxic effects. It is characterized by the rapid development of tissue destruction, which in some patients is irreversible. Requires more often early start renal replacement therapy.
- Toxic nonspecific nephropathy. It complicates the course of poisoning and diseases with severe intoxication syndrome, in which hemodynamic and metabolic disorders become the leading ones. On initial stages the disorders are functional in nature and tissue destruction begins only later.
At mild flow nephropathy is detected laboratory: in clinical analysis urine is determined increased content protein, leukocytes, erythrocytes, cylinders appear. Average degree characterized by a decrease in the amount of urine and impaired filtration function with an increase in the level of urea, creatinine, and potassium in the blood serum. For severe course The clinical picture of acute renal failure is characteristic, up to the onset of uremic coma.
Symptoms of toxic nephropathy
Within 1-3 days after poisoning clinical symptoms manifested by a feeling of heaviness, dullness aching pain in the lumbar region, general weakness, rapid fatigue. With significant dysfunction and destruction of the kidneys, urine may be stained with blood (gross hematuria). From the 2-4th day, the volume of diuresis decreases, characteristic “renal” swelling appears on the face, which decreases or completely disappears by the end of the day. The patient is constantly thirsty and complains of headache and muscle soreness.
Nausea, vomiting, and diarrhea occur. Skin and visible mucous membranes become dry and icteric. The increase in renal failure is accompanied by an almost complete cessation of urination, increased swelling, its downward spread to other parts of the body, and the appearance of a petechial rash. With severe lesions, brain symptoms develop - lethargy, lethargy, stunnedness, auditory, visual, tactile hallucinations, convulsive syndrome. Signs of severe renal dysfunction usually persist for 7-14 days.
On next stage development of the disease, lasting from 10-15 to 30 days, oligoanuria is replaced by a gradual increase in diuresis. The patient produces from 1.8 to 5-8 liters or more of urine per day. Weakness, fatigue, excruciating thirst persist, and body weight decreases. The duration of the convalescence period for intoxication nephropathy depends on the volume and nature of the lesion. Typically, it takes from 6 months to 2 years to restore the functional capacity of an organ.
Complications
In 20-70% of cases, toxic nephropathy ends fatal due to massive irreversible destruction of the renal parenchyma. A decrease in filtration function in patients with acute renal failure leads to hyperkalemia with a slowdown heart rate, fibrillation and ventricular asystole. Impaired cardiac function in combination with hypoproteinemia increases the risk of developing pulmonary edema.
Long-term uremia is accompanied by increased release of nitrogenous metabolites through the skin, serous and mucous membranes with the development of uremic pericarditis, pleurisy, gastritis, enterocolitis, laryngotracheitis, toxic liver damage, bone marrow. If the secretion of components of the renin-angiotensin system is impaired, arterial hypertension may develop. Long-term consequences toxic kidney damage are chronic tubulointerstitial nephritis, chronic renal failure, neoplasms of the urinary tract.
Diagnostics
Making a diagnosis of toxic nephropathy is usually not difficult in cases where the disease arose after poisoning with a chemical substance. The diagnostic search is aimed at assessing the nature and extent of possible tissue damage and determining the severity of renal dysfunction. The following laboratory and instrumental research methods are recommended for patients with nephropathy:
- General urine test. Proteinuria, leukocyturia, microhematuria, and cylindruria are determined. The relative density of urine in the oligoanuric phase exceeds 1030 g/l, in the polyuric phase it is below 1003 g/l. Additional conduct Zimnitsky's test for polyuria reveals a decrease in concentration function.
- Biochemical blood test. Serum creatinine levels rise until urine output is restored, uric acid, urea nitrogen, potassium, calcium, inorganic phosphorus. Impaired filtration capacity of glomeruli is also confirmed by the results of the nephrological complex and the Rehberg test.
- Kidney ultrasound. When echography, toxic type nephropathy is manifested by an increase in the size of the renal parenchyma due to interstitial and lymphostatic edema. Areas of necrosis have the appearance of hypoechoic cavities or hyperechoic inclusions. Doppler ultrasound of the renal vessels reveals hemodynamic disturbances.
- Renal tomography. Computed tomography of the kidneys allows you to obtain a layer-by-layer image of the renal tissues and detect even small areas of destruction. For safety reasons in case of toxic lesions, it is recommended to conduct the study without contrast or replace it with MRI, although in this case the information content is somewhat reduced.
To confirm the toxic nature of nephrological pathology, whenever possible, chemical and toxicological studies are carried out to determine the chemical substance that caused the disorder. Contrast research methods ( excretory urography, angiography of the kidneys) are used with caution due to the risk of aggravating the clinical situation by contrast-induced destructive processes. To monitor the condition of other organs and systems, biochemical liver tests, coagulogram, and ECG are performed. Changes general analysis blood are nonspecific: anemia, moderate leukocytosis, increase in ESR, thrombocytopenia.
Nephropathy of toxic origin is differentiated from secondary nephropathies of other origins (contrast-induced, diabetic, dysmetabolic, etc.), acute glomerulonephritis, ischemic necrosis of the kidneys, traumatic injuries of the renal parenchyma, atheroembolic disease. As prescribed by the urologist-nephrologist, the patient is consulted by a toxicologist, anesthesiologist-resuscitator, neurologist, therapist, cardiologist, pulmonologist, and hepatologist.
Treatment of toxic nephropathy
Patients whose kidneys are damaged as a result of exo- or endotoxin poisoning are hospitalized in the ward intensive care. The main therapeutic goals are the rapid elimination of the chemical substance, correction of metabolic disorders, prevention possible complications. Taking into account the stage of the disease, patients are shown:
- Detoxification therapy. It is carried out in the first hours and days after poisoning. For accelerated elimination Toxin is treated with gastric lavage, forced diuresis with the administration of osmotic diuretics and saluretics, and the use of adsorbents, laxatives, and specific antidotes. In difficult cases, hemosorption, hemofiltration, ultrafiltration, hemodialysis, and peritoneal dialysis are effective. Some patients are prescribed transfusions of blood and its components.
- Infusion correction of metabolic disorders. It begins immediately after hospitalization and continues in the oligoanuric period of acute renal failure. To restore electrolyte balance and acid-base balance Potassium antagonists (usually calcium preparations), glucose infusion with insulin, and alkalizing polyionic solutions are used. Further intake of enterosorbents that bind toxic metabolites is possible. In case of significant renal dysfunction, RRT is justified.
When the patient’s condition worsens, a comprehensive antishock therapy, docked emergency conditions(uremic coma, pulmonary edema, convulsive syndrome, hypertensive crisis). In the polyuric phase, massive continues (up to 5-6 l/day) infusion therapy to maintain blood volume and physiological concentration of metabolites. At the recovery stage, restorative treatment is carried out and tactics for further management of the patient are determined, taking into account the degree of safety renal functions.
Prognosis and prevention
Toxic nephropathy is a severe, prognostically unfavorable disorder with high performance lethality. Timely identification of the toxin, correct assessment of the morphological integrity and functional viability of the renal parenchyma, and adequate intensive therapy increase the chances favorable outcome nephropathy. Prevention of the disease is aimed at preventing toxic substances from entering the body: limiting the time of contact with nephrotoxic poisons, using drugs personal protection(respirators, protective clothing), refusal to eat unfamiliar mushrooms.
Employees of enterprises with hazardous production conditions are recommended to undergo preventive medical examinations For early detection renal dysfunction. To reduce the number of cases of hemodynamic and metabolic damage to renal cells in systemic disorders, patients with poisoning are recommended to regularly monitor the functional capacity of the kidneys and adequate relief acute condition. Taking into account the increasing prevalence of drug-induced nephropathy, when prescribing nephrotoxic drugs, a thorough examination of the patient is necessary to identify the prerequisites for toxic damage to the renal parenchyma.
CHAPTER 7.7. NEPHROTOXICITY
Nephrotoxicity is the property of chemical substances that act on the body in a non-mechanical way to cause structural and functional disorders of the kidneys. Nephrotoxicity can manifest itself both as a result of direct interaction of chemicals (or their metabolites) with the kidney parenchyma, and indirect action, mainly through changes in hemodynamics, acid-base balance of the internal environment, massive formation in the body of products of toxic destruction of cellular elements that are subject to excretion through kidneys (hemolysis, rhabdomyolysis).
In the strict sense nephrotoxicants Only those substances that directly act on the kidneys can be named, to which the organ’s sensitivity threshold is significantly lower than that of other organs and systems. However, in practice, nephrotoxicants are often called any substance that has nephrotoxicity.
Table 1 presents a list of toxicants with relatively high direct nephrotoxic activity. The list of known substances that have an indirect toxic effect on the kidneys is much wider and includes more than 300 items.
Table 1. Substances that cause acute and chronic forms of kidney damage
MetalsTechnical fluidsMiscellaneous Arsenic
Bismuth Cadmium Copper
Chromium Carbon tetrachloride
Dichloroethane
Trichlorethylene
Chloroform
Ethylene glycol
Diethylene glycol
Epichlorohydrin
Ethylene glycol ethers
Hexachlor-1,3-butadiene
Dichloroacetylene
Carbon disulfide
DioxaneParaquat
Mycotoxins (including toadstool toxins)
Cantharidin
Penicillin
Acetylsalicylic acid derivatives
Cephaloridine
Puromycin
Aminonucleoside
Due to drug therapy, accidental or intentional intoxication, or working or living in a contaminated environment, a significant portion of the population is constantly exposed to potential nephrotoxicants. It is currently not possible to quantify the contribution of each of these causes to the total number of registered chronic and acute nephropathies.
According to some data, more than 10 million people in the world have constant contact with substances that have severe nephrotoxicity. The frequency of recorded cases of acute renal failure is about 2 per 1000. According to some researchers, approximately 20% are a consequence of chemical influences, mainly drugs. Medicines are also the main cause of chronic nephropathies, among other chemical factors. According to some data, only the abuse of non-narcotic analgesics underlies a third of cases of chronic renal failure. It should be noted that in half of the detected cases of organ diseases, the causes of the pathology remain unclear. It is possible that kidney pathology occurs as a result of chronic exposure to environmental pollutants and industrial hazards (heavy metals, organic solvents, etc.) much more often than is commonly believed. Some observations confirm this assumption. Thus, among people constantly exposed to heavy metals (lead, cadmium), the frequency of deaths from renal failure is significantly higher than the statistical average.
1. Anatomical and physiological features of the organ
The kidneys are an extremely complex organ, both in terms of morphology and physiology, the main functions of which are the excretion of metabolic products from the body (see section “Isolation of xenobiotics from the body (excretion)”), regulation of water and electrolyte balance. Other functions include: synthesis of vitamin D metabolism enzymes, renin, which takes part in the formation of angiotensin, aldosterone, synthesis of some prostaglandins, etc.
The paired organ, weighing only about 300 grams (less than 1% of the human body weight), receives about 25% of the minute volume of cardiac blood output. Blood is delivered to the nephrons - the functional and morphological units of the kidneys (about 10 6 nephrons per kidney). Each nephron consists of a vascular part - an afferent arteriole, a capillary glomerulus, an efferent arteriole; Bowman's capsule surrounding the glomerulus, into which primary urine is filtered; systems of convoluted and straight tubules (the U-shaped structure of the straight segment of the renal tubule is called the loop of Henle), connecting Bowman's capsule with the connecting and collecting duct, through which urine is excreted from the organ.
The capillary glomerulus, surrounded by Bowman's capsule, is a complex molecular filter that retains substances with a molecular weight of more than 40,000 daltons (most blood proteins), but is permeable to most xenobiotics and metabolic products of endogenous substances (“waste”). Approximately 20% of the volume of blood plasma flowing through the kidneys passes (filters) from the capillaries into the glomerular capsule (180 liters per day). From the resulting filtrate, in the tubules, most of the water, sodium chloride, and other salts are resorbed back into the blood. Due to the ongoing processes, toxicants released in the urine are significantly concentrated in certain parts of the nephron (mainly the proximal parts of the renal tubules) and interstitial tissue of the kidneys.
In the region of the vascular pole of the renal glomerulus, at the point where the afferent arteriole enters it, the periglomerular (juxtaglomerular) complex is located. It is formed from the juxtaglomerular epithelioid cells themselves, forming a cuff around the afferent arteriole, specialized cells of the “dense spot” of the distal part renal tubule(lies in the area of its anatomical contact with the pole of the glomerulus) and mesangial cells filling the space between the capillaries. The function of the complex is control blood pressure and water-salt metabolism in the body, by regulating the secretion of renin (regulation of blood pressure) and the speed of blood flow through the afferent renal arteriole (regulation of the volume of blood entering the kidney). The participation of the complex in the pathogenesis of toxic kidney damage has been shown (see below).
Since the main transport and concentration processes occur in the proximal tubule, it is this section of the nephron that is most often damaged by toxicants. In addition, the processes taking place in the proximal parts of the renal tubules (water reabsorption, secretory processes) are extremely energy-intensive, which makes them very sensitive to ischemia.
In the loop of Henle, further concentration of urine occurs due to the counterflow mechanism. Some substances, such as analgesics and urea, are not reabsorbed in the proximal tubules, but are intensively concentrated in the loop of Henle. The highest concentration of such substances is observed in the medulla of the kidneys.
Further concentration of urine, due to the reabsorption of water and salts, occurs in the distal tubules and collecting duct. This process is controlled by antidiuretic hormone. In the same section of the nephron, due to the secretion of excess either hydrogen or ammonium ions from the blood, urine pH is formed.
Another important function of the kidneys that affects the nephrotoxicity of a number of substances is their ability to metabolize xenobiotics. Although the intensity of metabolism is much lower than in the liver, the same enzymatic systems are determined here, and the intensity of biotransformation is quite high. The level of activity of cytochrome P450-dependent oxidases is highest in straight line(pars recta) of the proximal renal tubules, an area particularly sensitive to toxicants. Although many xenobiotics are simultaneously metabolized to form reactive radicals in both the liver and kidneys, organ damage appears to be due to the portion of the total amount metabolized in the kidneys.
The proximity of the metabolic processes occurring in the liver and kidneys determines the almost identical sensitivity of these organs to many xenobiotics (chlorinated hydrocarbons, toadstool toxins, paraquat, etc.). The predominant damage to one or another organ during intoxication is largely due to the route of entry of the substance into the body (inhalation, parenteral, through the gastrointestinal tract), that is, which of the organs will be first on the path of the compound distributed through the bloodstream (for example, in case of inhalation damage carbon tetrachloride affects the kidneys to a greater extent; when taking the substance orally, the liver).
Thus, the high sensitivity of the kidneys to the effects of toxicants is determined by:
High intensity of renal blood flow and sensitivity of the organ to hypoxia;
The ability to concentrate xenobiotics in the process of urine formation;
Reverse resorption of part of the excreted xenobiotics into the epithelial cells of the renal tubules;
Biotransformation of xenobiotics, accompanied in some cases by the formation of highly toxic intermediate products.
2. Characteristics of nephrotoxic action
2.1. Mechanisms of action
The mechanisms of nephrotoxicity are biochemical, immunological and hemodynamic in nature. The damage to the organ by many toxicants is mixed.
Prerenal;
Renal;
Postrenal.
Prerenal causes include pathological conditions leading to hemodynamic disturbances, accompanied by a decrease in renal hemoperfusion (hypovolemia, shock, etc.).
The renal causes of the pathology are caused by damage to the kidney tissue.
Postrenal causes are associated with blockage of the distal nephron tubules and/or collecting ducts with pathological secretions or agglomerates of toxic substances and their metabolites.
2.1.1. Biochemical mechanisms
The mechanisms of nephrotoxic action of xenobiotics are diverse and at the same time develop according to a fairly general scenario. Having passed through the filtration barrier in the glomeruli, the toxicant is concentrated (about 100 times) inside the tubules due to the reabsorption of most of the water contained in the primary urine (see section “Excretion”). Under the influence of the resulting concentration gradient or due to active reabsorption processes, xenobiotics enter the tubular epithelial cells and accumulate there. The nephrotoxic effect develops when a critical concentration of the toxicant in the cells is reached.
Depending on the physicochemical properties of substances, they interact with receptor molecules (membrane structures, enzymes, structural proteins, nucleic acids) that are part of the structure of one of the cellular compartments: lysosomes (aminoglycosides, etc.), cytoplasm (heavy metals - cadmium ), ribosomes, smooth endoplasmic reticulum, etc., which initiates the development of the toxic process.
For many organic compounds, the stage of their nephrotoxic action is preceded by the stage of their bioactivation, which takes place with the participation of enzymatic, metabolizing systems. In the mechanism of nephrotoxic action of many xenobiotics (cephaloridine, puromycin, aminonucleoside, paraquat, carbon tetrachloride), their ability to initiate the formation of free radicals in cells plays an important role.
2.1.2. Immunological mechanisms
Nephrotoxic processes of the immune type are usually the result of two main processes: (1) deposition of the antigen-antibody complex in the glomerular structures of the kidneys; (2) the formation of complex antigens in situ, during the interaction of kidney proteins with a toxicant, followed by an attack on them by antibodies circulating in the blood. Since antibodies and immune complexes are high-molecular formations, they, as a rule, are not detected outside the glomerular apparatus. In this regard, immune mechanisms can lead to the formation of glomerulonephritis (for example, membranous glomerulonephritis induced by gold salts, mercury, d-penicillamine) or acute interstitial nephritis (penicillin derivatives), but not damage to the epithelium of the renal tubules.
The exact mechanism by which the toxicant initiates the hyperimmune reaction leading to kidney damage is unknown in most cases. Sometimes xenobiotics exhibit the properties of haptens (methicillin), forming some kind of their own antigen, or promote the release of normally hidden antigens into the blood. In some cases, a hyperimmune reaction may be a consequence of polyclonal activation of immunocompetent cells, as is the case with nephropathies caused by gold, mercury, and penicillamine.
Damage to kidney tissue occurs through the implementation of a certain chain of events characteristic of the development of allergic or autoimmune processes (see section “Immunotoxicity”).
2.1.3. Hemodynamic mechanisms
Hemodynamic disturbances are a common cause of the development of toxic nephropathies.
At acute defeat a toxicant of the renal tubules, the functions of the organ can be disrupted due to blockage of the lumen of the tubules by the decay products of epithelial cells, retrograde flow of the glomerular filtrate, increased pressure in Bowman's capsule, and as a consequence of this, blood in the capillary network of the renal glomerulus. An increase in blood pressure in the glomeruli activates the juxtaglomerular apparatus of the kidneys, causing hypersecretion of renin. The local effect of the renin-angiotensin system determines arteriolar preglomerular spasm, which entails, on the one hand, cessation (or sharp weakening) of blood flow into the glomerulus, suspension of glomerular filtration, and on the other hand, ischemia of the renal tubules and their secondary necrosis. Tissue damage is aggravated by the release of biologically active substances such as thromboxanes and endothelin into the vascular bed.
In cases where the volume of glomerular filtration decreases by more than 70%, the evolution of the process towards renal failure becomes irreversible, probably due to the fact that initially intact nephrons are progressively involved in the pathological process.
2.2. Manifestations of toxic effects
The main manifestations of kidney damage from toxicants are:
The appearance of blood in the urine (hematuria) due to damage to the wall of the glomerular capillaries;
The appearance of protein in the urine of more than 0.5 g in a daily sample (proteinuria). Proteinuria can be of glomerular origin, with predominantly high-molecular-weight proteins (more than 40,000) found in the urine, and tubular – predominantly low-molecular-weight proteins (less than 40,000) are found in the urine. Glomerular proteinuria indicates destruction of the glomerular blood-urine barrier; tubular - for damage to the proximal renal tubules;
Decreased amount of urine output - less than 600 ml per day (oliguria);
An increase in the blood plasma content of nitrogen-containing low-molecular substances, such as urea, creatinine, b 2 -microglobulins, etc. (azotemia);
General edema, which in the absence of heart failure or cirrhosis indicates sharp decline blood protein levels (hypoalbuminemia);
Hypertension developing as a result of glomerulosclerosis.
These manifestations are combined into certain syndromes. The main syndromes developing as a result of acute or chronic intoxication are:
Acute renal failure, characterized by acute depression of renal function with azotemia and, often, oliguria;
Chronic renal failure is a permanent impairment of kidney function with azotemia, acidosis, anemia, hypertension and a number of other disorders;
Tubulointerstitial nephritis (acute or chronic) with various signs of tubular dysfunction (tubular-type proteinuria, urine acidosis, loss of salts, decreased specific gravity of urine, etc.);
Nephrotic syndrome, characterized by severe proteinuria (more than 3.5 g of protein in daily urine), hypoproteinemia, edema, hyperlipidemia, hyperlipiduria. Nephrotic syndrome can be a consequence of various types of glomerulonephritis;
Rapidly progressive glomerulonephritis, manifested by hematuria and oliguria, leading to renal failure within a few weeks.
Substances that cause the formation of certain types of nephropathy are presented in Table 2.
Table 2. Poisonings accompanied by toxic nephropathy
Variants of toxic nephropathyToxicants ACUTE RENAL FAILURE:
1. Prerenal causes
2. Postrenal causes
3. Renal reasons
A. Acute tubular necrosis
B. Acute interstitial nephritis
Antihypertensive drugs, diuretics, laxatives, ergotamine
Butadione, fluoroquinolones, bromocriptine, etc.
Amanitin, phaloidin; heavy metals (mercury, chromium, arsenic); halogenated hydrocarbons; glycols (ethylene glycol); hemolytics (stibine, arsine, etc.); antibiotics (cephalosporin, aminoglycosides, etc.); antitumor agents (cisplatin, etc.).
Allopurinol, cephalosporins, indomethacin. rifampicin, etc. CHRONIC RENAL FAILURE:
A. Interstitial nephritis; glomerclosclerosis
B. Nephrotic syndrome
Metals (cadmium, lead, beryllium, lithium); cyclosporine
Metals (mercury, gold); captopril, heroin, D-penicillamine
3. Brief description individual nephrotoxicants
Nephrotoxicants are extremely widely used in everyday life and at work. Thus, organic solvents are components of numerous varnishes, paints, adhesives, cleaning products, pesticides, etc. Various heavy metals and their compounds are widely used in everyday activities. The routes by which substances enter the body are also varied: inhalation, transdermal, nutritional. In production conditions, inhalation intoxications are the most common. Solvents often act through the skin. For the rest of the population, the most typical route of entry of nephrotoxicants into the body is through nutrition, through contaminated food and drinks.
3.1. Metals
Many heavy metals are pronounced nephrotoxicants, the defeat of which even in small doses leads to the appearance of glucosuria, aminoaciduria, and polyuria. In severe metal poisoning, necrotic changes form in the kidneys, anuria and proteinuria develop, and death is possible. In experiments, when small doses of metals that do not cause clinical damage are introduced into the body of animals, their high concentration is determined in the lysosomes of kidney cells. This binding of metals by lysosomes may be a consequence of lysosomal endocytosis of metal-protein complexes, autophagy of organelles damaged by metals (for example, mitochondria), and binding of metals by lipoproteins of lysosome membranes. When high doses of toxicants are administered, metals are also detected in other cell organelles.
3.1.1. Lead
In the recent past, lead was a common cause of acute and chronic nephropathies. The literature describes numerous cases of necrosis of the tubular epithelium due to accidental or intentional intake of large doses of lead salts. Cases of chronic renal failure were recorded in persons who drank alcohol stored in vessels containing lead, in workers constantly in contact with lead-containing substances, in adults who suffered acute intoxication with lead dyes in childhood, etc. Currently, cases of lead injury are recorded much less frequently.
Chronic lead nephropathy is manifested by progressive tubulointerstitial nephritis, which is characterized by the absence of proteinuria and albuminuria at the initial stage of pathology formation and reveals itself when studying the glomerular filtration rate. The accumulation of lead in kidney tissue, especially in the epithelial cells of the proximal tubules, is accompanied in the early stages of the disease by damage to cell mitochondria and disruption of the absorption functions of cells. Later, inclusions formed by complexes of lead with acidic proteins appear in the nuclei of these cells. These intranuclear bodies usually disappear as the pathology progresses. Kidney pathologies in lead intoxication are often accompanied by hypochromic anemia, hypertension, and neuropathy.
With the help of chelating agents (EDTA or dimercaptosuccinate), it is possible to mobilize lead accumulated in tissues and thereby accelerate its elimination from the body. The lead content in the patient’s urine is more than 800 mcg in a daily sample after intravenous administration EDTA at a dose of 0.5 grams indicates a high metal content in the body tissues.
3.1.2. Cadmium
Chronic cadmium intoxication is often accompanied by the development of progressive tubulointerstitial nephritis.
Infections in humans are usually a consequence of consumption of contaminated food or, in industrial conditions, inhalation of dust containing cadmium. Epidemiological studies among persons professionally exposed to cadmium have revealed a high incidence of renal pathology. Cases of chronic intoxication of people living in regions with high levels of the element in water and soil have been described. Thus, in Japan, among women who eat rice grown on soils with a high content of cadmium, a disease (Itai-itai) is observed, which is manifested by anemia, destruction of bone tissue, and impaired renal function (damage to the epithelium of the proximal tubules). The disease begins with the excretion in the urine of specific low-molecular proteins, such as b 2 -microglobulins or retinol-binding protein, as well as cadmium, mainly in the form of a complex with the protein metallothionein. The binding of cadmium by metallothionein appears to protect some organs from damage. At the same time, it is in the form of such a complex that the substance is captured by the kidneys and deposited in the organ (the half-life of cadmium from the human body is 10 - 20 years).
In persons with initial forms of kidney damage, the concentration of cadmium in the urine is usually more than 10 mcg per 1 g of creatinine excreted in the urine.
In case of acute cadmium intoxication, EDTA-Ca,Na is a fairly effective means of removing the substance from the body. In case of chronic intoxication, it is not yet possible to mobilize the element with the help of complexing agents available to the doctor.
The mechanism of the toxic effect of the metal has not been fully established. Apparently, it consists in the interaction of the metal with carboxyl, amine, SH groups of protein molecules, disruption of the functions of structural proteins and enzymes. It has also been shown that Cd largely follows the metabolic pathways of Zn +2 and Ca +2. For example, it is taken up by cells using mechanisms designed to take up Zn. It is believed that at the molecular level the mechanism of the toxic effect of Cd may also be due to its ability to replace Zn and other divalent ions in biological systems. Zinc deficiency modifies the distribution pattern of Cd and significantly potentiates its toxicity.
3.1.3. Mercury
Acute intoxication with certain inorganic and organic mercury compounds is accompanied by the development of necrosis of the epithelium of the proximal renal tubules and renal failure. It is well known that taking mercury diuretics in small doses is accompanied by the binding of Hg 2+ to cell membrane enzymes containing sulfhydryl groups in the molecule and involved in sodium reabsorption, inhibiting their activity. Administration of drugs in unreasonably high doses can lead to acute glomerulonephritis with characteristic proteinuria and nephrotic syndrome.
Acting in moderate doses, mercury vapors and salts can cause various subclinical forms of renal dysfunction, accompanied by proteinuria and urinary excretion of certain low-molecular-weight enzymes. In persons with severe occupational mercury intoxication, chronic glomerulonephritis is usually recorded.
To speed up the elimination of a substance from the body, various chelating agents are used. The most commonly used are dimercaprol, D-penicillamine, and dimercaptosuccinate.
3.1.4. Arsenic
Necrosis of the renal tubular epithelium is a common complication of acute poisoning with trivalent and pentavalent arsenic compounds. To accelerate the removal of arsenic from the body, chelating agents from the dithiol group (2,3-dimercaptopropanol, unithiol, etc.) are successfully used.
Poisoning with arsine (AsH 3) leads to secondary kidney damage from hemoglobin released into the blood plasma due to massive hemolysis. Acute renal failure, which develops in this case, is the main cause of death in poisoned people. The use of complexing agents during intoxication with this substance is inappropriate.
3.2. Technical fluids
A number of technical liquids, and among them primarily organic solvents, widely used in everyday life and in production, are potential nephrotoxicants. Depending on the dose of the substance, mild forms of proteinuria develop, accompanied by moderate proteinuria, moderate and severe forms of kidney damage, occurring in the form of acute tubular necrosis.
Often, kidney damage develops in drug addicts who inhale, for the purpose of obtaining pleasure, glues and dyes containing toluene as a solvent. The symptom complex that forms in this case resembles Fanconi syndrome (glucosuria, proteinuria, acidosis, etc.).
Subchronic and chronic intoxication with hydrocarbons (gasoline) can cause glomerulonephritis with the characteristic Goodpasture syndrome (rapidly progressing glomerulonephritis, accompanied by periodic pulmonary hemorrhages and the presence of antibodies to the glomerular membrane in the blood).
Depending on the type of solvent, in addition to the kidneys, other organs are often involved in the pathological process, mainly the liver, blood, and nervous system.
3.2.1. Ethylene glycol
Ethylene glycol - diatomic alcohol (CH 2 OH-CH 2 OH) - is part of various formulations of antifreeze and brake fluids. Poisoning with the substance is possible only when taken orally (as a substitute for alcohol) and leads to acute kidney damage. An absolutely lethal dose for humans is 90 - 100 ml.
The substance is quickly absorbed from the gastrointestinal tract. The largest amount accumulates in the liver and kidneys, where the xenobiotic undergoes biological oxidation with the formation of glycolates, glyoxalates, oxalates, which mainly initiate the development of the toxic process. The half-life of the substance is about 3 hours. Within 6 hours after taking 100 ml of alcohol, about 70 ml of toxic substances are formed in the body. Ethylene glycol itself and the products of its metabolism are released from the body slowly and are detected in the blood for about a day.
Talking about nephrotoxic drugs, what do you think?
Aristolochic acid? Antibiotics? Cyclosporine? Anti-inflammatory drugs?
If you think of two or three of these, congratulations, you are the patient who is responsible for your net worth, but you still need to know: because most drugs need to pass through the kidneys, more than these types of nephrotoxic drugs may be greater.
Many medicines and health products often said that it can be preserved, this is not correct! Medicines, everything is there side effect, and therefore, when choosing medications, be sure to choose medications that have little side effects.
The following are some nephrotoxic drugs, the doctor and the patient can all pay attention!
In nephrotic syndrome, Non-steroidal anti-inflammatory drugs: aspirin, ibuprofen, acetaminophen, naproxen, naphthoquinone, diclofenac, etc. These western medicines are nephrotoxic. And so if you are currently taking these medications, contact your doctor to determine if you can eat.
If you have any questions, please fill out the form below. You will undoubtedly receive free medical advice from specialists within 24 hours.
Many of the clinical important substances, which can cause toxic kidney damage. Most of them have a direct toxic effect on cells in a known or unknown way. Others may damage the kidneys indirectly, often not obvious from what we know about this substance. The nephrotoxic effect of many substances is associated with the formation of methemoglobin.
If the patient has kidney disease You should be especially careful with medications that cannot be eliminated from the body. main role the kidneys are playing. In renal failure, the binding of acidic drugs to proteins is significantly reduced due to loss of plasma proteins. Protein binding is important not only for pharmacokinetics, but also for cellular toxicity in many organs. Renal failure also affects the processes of oxidation and reduction of drugs, their conjugation with glucuronide, sulfates and glycerol, acetylation and hydrolysis.
Only a few nephrotoxins can be examined in more detail here. In hospitals, of course, main reason nephrotoxic renal failure (about 25% of all cases acute failure) - This use of antibiotics, primarily aminoglycosides. Streptomycin, kanamycin, neomycin, gentamicin, tobramycin, amikacin and sisomicin are nephrotoxic. They accumulate in the cells of the proximal tubules, cause the formation of cytosegrosomas (cytoplasmic organelles that can fuse with the lysosome to remove non-viable material) with amyloid bodies, increase the content of enzymes and protein in the urine, and reduce creatinine clearance; if the toxic effect is not very pronounced, it usually leads to non-oliguric renal failure. Aminoglycosides appear to have synergistic toxicity with cephaloridine, cephalothin, and methicillin. Due to accumulation, toxicity may appear delayed or early repeat course treatment. Polypeptides, such as polymyxin, have a direct and predictable nephrotoxic effect, as do bacitracin and the fungicide amphotericin B. Expired tetracycline can cause Fanconi-like syndrome.
In the development of acute tubulointerstitial nephritis (TIN), caused by penicillins (especially methicillin), rifampin, sulfonamides or a combination of trimethoprim and sulfamethoxazole are involved allergic processes.
The diagnosis of acute TIN can be assumed when elevated temperature, eosinophilia, eosinophiluria, increased IgE levels and positive results radioisotope imaging of kidneys with gallium; A renal biopsy is used to confirm the diagnosis.
All radiocontrast agents Somewhat nephrotoxic, especially when administered intra-arterially. Predisposing risk factors (in addition to frequent use of these substances) include tissue hypoperfusion, depletion of extracellular fluid volume, renal failure, age over 60 years, solitary kidney, diabetes, myeloma, hyperuricemia, and heart failure.
Nephropathy associated with analgesics is responsible for approximately 2% of end-stage renal disease in the United States and 20% or more in Australia and South Africa. In general, virtually all anti-inflammatory painkillers peripheral action are potentially nephrotoxic, but most central analgesics are not. Salicylates have a direct nephrotoxic effect and act as synergists for mixed analgesic nephropathies. It is difficult to estimate how widely they are used in routine practice.
Almost everything non-steroidal anti-inflammatory analgesics(they are prostaglandin synthetase inhibitors of varying potency) can cause tubular epithelial damage, hypoperfusion, papillary necrosis and chronic TIN. Many of them are now readily available.
Most heavy metals accumulates in proximal nephrons due to their transport or the presence of binding sites, such as sulfhydryl (SH) groups. The toxic effect of lead is observed in food perversions, industrial influences, drinking contaminated water, wine or other alcoholic beverages, at mining enterprises, inhaling smoke or combustion products of gasoline with lead additives. Tetraethyl lead penetrates intact skin and lungs.
Manifestations chronic lead poisoning include wrinkled buds, uremia, hypertension, anemia with basophilic granulation, encephalopathy, peripheral neuropathy and Fanconi syndrome. With more acute poisoning Possible spasmodic pain in the abdomen (lead colic). The incidence of toxic kidney injury caused by mercury, bismuth, and thallium now appears to be declining, but nephrotoxicity associated with exposure to cadmium, copper, gold, uranium, arsenic, and iron is still common; the latter of these elements can cause proximal myopathy in hemochromatosis and other forms of iron overload, such as in dialysis patients with multiple transfusions.
Nephrotoxicity of solvents manifests itself mainly when inhaling hydrocarbons (Goodpasture syndrome), exposure to methanol, glycols and halogen-containing compounds, for example carbon tetrachloride and trichlorethylene. The involvement of halogenated anesthetics (eg, methoxyflurane) is also suspected.
TO medicinal substances, causing immune complex kidney damage, proteinuria and many signs of nephrotic syndrome include penicillamine, captopril, levamisole and gold salts administered parenterally in the treatment of rheumatoid arthritis.
Ed. N. Alipov
"Causes of toxic nephropathy" - article from the section