Nephrotoxic effect of radio-opaque substances - an 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 radiopaque substances.

Toxic nephropathy should be understood as pathological changes in the structure and functions of the kidneys, caused by the action of chemical and biological products that produce toxic metabolites that have a harmful effect on the kidneys. Kidney damage can manifest as proteinuria, acute tubular necrosis, medullary necrosis, and acute renal failure. The basis of the pathogenesis of contrast medium nephrotoxicity is vasoconstriction, which can be caused by direct damage to the endothelium or protein binding, as well as agglutination and destruction of erythrocytes.

A serious complication of X-ray contrast studies is the development of acute renal failure. R. O. Berkseth and S. M. Kjellstrand indicate that in about 10% of cases, acute renal failure is due to the use of X-ray contrast agents.

These complications can be clinically manifested as interstitial tubular nephritis, tubular nephrosis, or shock kidney. Morphologically, vascular disorders are detected: thrombosis, heart attacks, fibrinoid necrosis of the wall of the capillaries of the glomeruli, inter- and intralobular arteries.

V. Uthmann et al. indicate that X-ray contrast agents have a potential nephrotoxic effect. In this case, their osmolarity is of great importance. After angiography, the authors found characteristic signs of osmotic nephrosis in the proximal renal tubules. Signs of acute renal failure may occur for the first time hours after the introduction of contrast agents into the blood. Despite renal failure, hypokalemia occurs, then dyspeptic disorders develop, abdominal pains, 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 cortex in response to blood flow disturbances. Pathological data indicate the development of acute interstitial or tubular-interstitial nephritis. Occasionally, necrosis of the renal cortex is 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 the determination of the hemagglutination reaction and the 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 the development of acute renal failure due to hemolysis as a result of the formation of an antigen-antibody complex and fixation of complement on the patient's erythrocytes.

The reason for the nephrotoxicity of some contrast agents may be a high concentration in the tubular cells of those substances that are normally excreted by the liver, but do not enter the bile when the gallbladder is obstructed or the liver parenchyma is damaged.

In liver diseases, especially in violation of its antitoxic function, when the kidneys compensatory provide for its detoxifying function, the nephrotoxic effect of contrast agents increases sharply and the occurrence of complications from the kidneys is more likely. In this regard, carrying out radiopaque studies of the kidneys with hepatopathy is unsafe.

There are reports of the emergence of acute renal failure after excretory urography in patients with multiple myeloma.
In the pathogenesis of renal failure in patients with multiple myeloma, there is a mechanical blockage of the renal tubules with protein cylinders, followed by atrophy of the nephrons involved in the process and cessation of urination. During excretory and especially infusion urography, dehydration of the body occurs, therefore, in such patients, it is necessary to maximize diuresis and inject them with a sufficient amount of fluid. This recommendation also applies to patients with proteinuria of unknown origin for whom radiopaque renal examination is indicated.

Therapy for complications is symptomatic rather than pathogenetic; their prevention is difficult. The following reasons are discussed: allergic reactions, direct toxicity, pharmacological iodidiosyncrasy, dehydration, etc.

Since the reactions to the administration of contrast medium resemble anaphylactic shock due to the often 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 about the dependence of the reaction on the amount and concentration of the contrast medium. R. May and R. Nissi believe that adverse reactions of an allergic nature would be equally pronounced at any dose of contrast agent. However, J. V. Gillenwater, not being a supporter of the allergic theory, nevertheless believes that at high concentrations and in high doses, contrast agents become toxic to tissues. According to S. Hansson and G. Lindholm, M. J. Chamberlain and T. Sherwood, N. Milton and R. 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 failure. This is explained by the fact that with renal failure, a 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 a greater dilution, it is advisable to prescribe lasix after the study.

So, the high-contrast drugs used in uroradiological studies are relatively low-toxic, but if there is a latent or obvious functional failure of the kidneys or liver, then their introduction into the vascular bed can be the cause of nephro- or hepatopathy.

Angiographic examination not only provides valuable information for the diagnosis and determination of rational treatment tactics, but also serves as a "provocative" test that reveals the latent functional insufficiency of some parenchymal organs. This allows for the prevention of complications and activation of the pathological process in the corresponding organ during the preparation of the patient for surgery, anesthesia and in the postoperative period.

Nephrotoxicity is a property of chemicals, acting 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 the direct interaction of chemicals (or their metabolites) with the renal 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 to be excreted through kidneys (hemolysis, rhabdomyolysis).

In the strict sense nephrotoxicantsonly those substances directly acting on the kidneys can be named, to which the threshold of sensitivity of the organ is significantly lower than that of other organs and systems. However, in practice, any substance that has nephrotoxicity is often called nephrotoxicants.

Table 1 shows 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 names.

Table 1. Substances causing acute and chronic renal damage

Metals Technical fluids VariousArsenic

Bismuth Cadmium Copper

Chromium Carbon tetrachloride

Dichloroethane

Trichlorethylene

Chloroform

Ethylene glycol

Diethylene glycol

Epichlorohydrin

Ethylene glycol ethers

Hexachloro-1,3-butadiene

Dichloroacetylene

Carbon disulfide

DioxanParaquat

Mycotoxins (including the toxins of the pale toadstool)

Cantharidin

Penicillin

Acetylsalicylic acid derivatives

Cephaloridin

Puromycin

Aminonucleoside

Due to drug therapy, accidental or deliberate intoxication, work or living in an infected environment, a significant part 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 recorded chronic and acute nephropathies.

According to some data, more than 10 million people in the world have constant contact with substances with pronounced nephrotoxicity. The frequency of reported cases of acute renal failure is about 2 per 1000. According to some researchers, about 20% is a consequence of chemical effects, mainly drugs. Medicines are also the main cause of chronic nephropathy, among other chemical factors. According to some reports, only the abuse of non-narcotic analgesics accounts for 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 ecopolutants, industrial hazards (heavy metals, organic solvents, etc.) much more often than is commonly believed. Some observations confirm this assumption. Thus, among persons constantly exposed to heavy metals (lead, cadmium), the frequency of deaths from renal failure is significantly higher than the average.

(AKI) reaches 2000-3500 patients / million, i.e. within a year, about 0.2-0.3% of the total population suffers acute renal damage of various etiologies. Acute kidney injury can be experienced by doctors of all specialties, both therapeutic and surgical. AKI itself is a rather serious syndrome that can be associated with both a short-term threat to the patient's life and a long-term risk of developing chronic renal failure. Acute renal injury also worsens the course of the underlying disease, can lead to the development of type 3 cardiorenal syndrome, and is associated with the high cost of treating patients. Moreover, in some patients, the development of acute renal damage can be avoided, primarily by minimizing the intake of nephrotoxic drugs.

There are several main classes of drugs that have a potentially nephrotoxic effect. Of course, this list is not limited to the medicines shown on the slide and discussed further, it is much broader. The listed groups of drugs contain commonly used classes of drugs, some of which, moreover, can be bought without a prescription at any pharmacy.

It should be specifically said about the use of potentially nephrotoxic drugs in patients with pre-existing (CPD). The results of long-term follow-up in the AASK study demonstrate that almost 8.5% of patients with CKD have episodes of a sharp decrease in the glomerular filtration rate, i.e. there is a layering of acute renal damage to chronic renal failure. Therefore, in relation to patients with chronic kidney disease, special attention is required to the potential nephrotoxic effect of drugs, drug interactions, and, if necessary, to eliminate hypovolemia before the appointment of diagnostic tests or the prescription of drugs that have an effect on intrarenal hemodynamics. Moreover, since many potentially nephrotoxic drugs are available over-the-counter, the patient should be aware of the list of these drugs and consult with a nephrologist before taking any new medications (including herbal remedies and supplements).

ξ General principles for prescribing potentially nephrotoxic drugs:

• Carefully weigh the risks and benefits of taking the drug in this patient. A number of potentially nephrotoxic drugs have analogs comparable in effectiveness without side effects on the kidneys.
• A patient with chronic kidney disease should consult a doctor before taking any medications, including over-the-counter medications and dietary supplements.
• When prescribing drugs, it is necessary to take into account the glomerular filtration rate, and depending on it, reduce the dose and / or frequency of administration for a number of drugs (therefore, before taking potentially nephrotoxic drugs, it is imperative to determine the level of blood creatinine in all patients).
• After a short course of potentially nephrotoxic drugs, it is necessary to re-determine the level of creatinine in the blood and to make sure that there is no acute renal injury in the patient.
• In patients taking potentially nephrotoxic drugs for a long time, it is necessary to regularly and determine plasma potassium. It is necessary to carefully monitor the level of the drug in the blood (calcineurin inhibitors, lithium).
• If it is necessary to take one or another potentially nephrotoxic drug, it is necessary to consider the possibility of temporary cancellation of drugs already prescribed to the patient that can affect intrarenal hemodynamics (angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, aldosterone inhibitors, nonsteroidal anti-inflammatory drugs) or drive to hypovolemia (diuretics)

ξ Risk factors for the development of acute kidney injury:

• Elderly age
• Chronic kidney disease
• Heart failure
• Atherosclerosis
• Liver disease
• Diabetes
• Hypovolemia
• Taking nephrotoxic drugs

ξ Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are one of the most commonly used drug classes in general practice. Since NSAIDs are on non-prescription leave, the patient should always be informed about their possible nephrotoxic effects and the need to minimize their intake. In addition, it must be remembered that the patient does not always have a sufficient stock of knowledge to classify the prescribed drug (or simply a “good” pain reliever or “anti-influenza” drug recommended by friends) to the NSAID class. Therefore, before buying or taking medications, the patient must read the package insert in order to find out about the belonging of a particular drug to the class of non-steroidal anti-inflammatory drugs. It should be noted that absolutely all NSAIDs, including selective type 2 cyclooxygenase inhibitors, have a potentially nephrotoxic effect.

The main mechanism of nephrotoxicity for NSAIDs is a decrease in the synthesis of prostaglandins (which have a vasodilating effect) in the kidney tissue, which can lead to an increase in the tone of the afferent arteriole of the renal glomerulus and, accordingly, a decrease in blood flow in the glomerulus and a decrease in urine production. In this case, acute renal damage can develop. Even with short-term use, due to inhibition of the synthesis of vasodilating prastoglandins, NSAIDs can lead to an increase in blood pressure and a decrease in the effectiveness of antihypertensive drugs, fluid retention with the occurrence of edema and the development of heart failure. With prolonged use of NSAIDs, analgesic nephropathy can develop, which in a number of countries plays a very significant role in the structure of end-stage chronic renal failure.

Since the main indication for taking NSAIDs is pain, it should be said that pain can have different mechanisms of occurrence, and does not always require NSAIDs. In addition, dosage reduction of NSAIDs is possible due to their combination with drugs of other classes for pain therapy. There is a lot of literature on the pathogenesis and treatment of pain, including a special issue of the Russian Medical Journal on Pain Syndrome in the public domain.

If the clinical situation does not allow avoiding the use of analgesics and NSAIDs, then one should remember about the stepwise scheme of their appointment (and for patients with chronic kidney disease - about the features compared to the general population), which is aimed primarily at minimizing the development of adverse reactions.

The stepwise scheme of prescribing analgesics involves several levels:

1. At the first stage, if possible, it is necessary to start with the use of topical gels or creams with NSAIDs, which avoids systemic exposure, including the development of nephrotoxicity.
2. If the pain syndrome is severe, or the use of gels / creams with NSAIDs is not effective enough, then the next step is the appointment of acetaminophen (paracetamol). Paracetamol has a predominant effect on the metabolism of prostaglandins in the central nervous system, while the effect on other systems is minimal compared to other analgesics. For patients with chronic kidney disease, remember that the acetaminophen dose should not exceed 650 mg * 4 times a day. In addition, as with any medication, acetaminophen intake requires adequate fluid intake to ensure adequate hydration and maintain normal intrarenal hemodynamics.
3. With insufficient effectiveness of local drugs and paracetamol, NSAIDs can be prescribed with minimal side effects (both in terms of nephrotoxicity and). For the general population without chronic kidney disease, these drugs are ibuprofen or naproxen. For patients with chronic kidney disease, ibuprofen alone is recommended as a drug with a short half-life. It should also be noted that even taking ibuprofen is recommended at a reduced dosage, and the total daily dose should not exceed 1200 mg for 3-4 receptions. When taking ibuprofen, consideration should be given to temporarily discontinuing other prescribed drugs that affect intrarenal hemodynamics (including ACE inhibitors, ARBs, renin inhibitors, aldosterone blockers) or potentially leading to hypovolemia of diuretics to reduce the risk of nephrotoxic effects of NSAIDs.
4. If the above treatment is not effective enough, you should switch to drugs of other classes for the treatment of pain syndrome. It should be specially noted that the use of such rather widespread representatives of NSAIDs as diclofenac and indomethacin, as well as other NSAIDs with a long half-life (i.e., with a frequency of taking 1 or 2 times a day) in patients with chronic kidney disease should be avoided.

In patients with a glomerular filtration rate of less than 30 ml / min / m 2, any NSAIDs should be avoided, using drugs of other classes for pain therapy.

It should also be remembered that the simultaneous administration of lithium and NSAIDs is contraindicated, since in this case the risk of nephrotoxicity increases significantly.

ξ Radiocontrast drugs

Radiocontrast drugs used in a number of X-ray research methods can lead to the development of acute renal damage, primarily among patients with risk factors for AKI (see above). It must be remembered that even in patients without chronic kidney disease (i.e. all patients), adequate hydration is required - oral or intravenous, depending on the assessment of the risk of developing contrast-induced nephropathy. Recommendations for the use of radiocontrast drugs and measures to prevent the development of contrast-induced nephropathy were included in both the official and (translated into Russian).

In particular, for patients with GFR less than 60 ml / min / m 2 when using X-ray contrast agents, it is necessary:

• Carefully weigh the risks and benefits of research
• Avoid the use of high-osmolarity X-ray contrast agents
• Use the lowest possible dose of a radiocontrast drug
• If possible, discontinue potentially nephrotoxic drugs before and after the study
• Provide adequate hydration before, during and after the examination
• 48-96 hours after administration of a radiocontrast drug

For the use of preparations containing gadolinium:

• It is highly discouraged to use gadolinium-containing drugs for GFR<15 мл/мин/1,73м 2
• If it is necessary to use gadolinium-containing drugs for GFR< 30 мл/мин/1,73м 2 рекомендуется использовать макроциклические хелированые формы

ξ Antibiotics

A variety of antibiotics have potentially nephrotoxic effects and can lead to acute kidney injury. First of all, this applies to aminoglycosides, amphotericin B and sulfonamides... If possible, you should choose analogs of these drugs with comparable antibacterial efficacy without nephrotoxic effect. In this case, as with the appointment of any other drugs, it should be taken into account in the patient to correct the frequency and / or dose of drug administration.

Recommendations sharply limit the use of amphotericin B in patients with GFR< 60 мл/мин/1,73м 2 , и предлагают назначать его больным с хронической почечной недостаточность только если нет другого выхода. В отношении аминогликозидов такой рекомендации в KDIGO нет, однако частое развитие нефротоксического и ототоксического эффектов при применении аминогликозидов в общей популяции делают этот класс антибиотиков препаратами запаса, которые должны использоваться только в исключительных клинических ситуациях.

Regarding sulfonamides and the combination trimethoprim / sulfametaxazole, which is quite popular in Russia (co-trimoxazole, biseptol, bactrim, and other brand names), it should be said that it has practically lost its significance in the treatment of infections - both due to frequent nephrotoxic reactions and side effects from other organs, as well as a fairly high percentage of E. coli resistance to co-trimoxazole.

ξ Inhibitors of the renin-angiotensin-aldosterone system

Angiotensin converting enzyme (ACE inhibitors) inhibitors and angiotensin II receptor blockers (ARBs) are the main classes nephroprotective drugs, i.e. aimed at slowing the progression of renal dysfunction, reducing the decrease in the glomerular filtration rate and the severity of proteinuria. Their nephroprotective effect has been proven in numerous studies in a wide range of nephropathies..

At the same time, it should be said that these classes of drugs, due to their effect on intrarenal hemodianamics, can lead to the development of acute renal damage. Therefore, it is imperative to remember the absolute contraindications to the appointment of RAAS inhibitors - bilateral renal artery stenosis (or stenosis of the artery of a single kidney), pregnancy, uncorrected hyperkalemia, individual intolerance. With caution, RAAS inhibitors should be prescribed for advanced atherosclerosis, with type 2 diabetes, in the elderly, with dehydration, while taking NSAIDs (if they cannot be canceled), and other conditions in which a significant decrease in intra-glomerular GFR is possible. A few days before starting an ACE inhibitor or ARB, drugs with a possible nephrotoxic effect should be noted, and, if possible, diuretics should be temporarily canceled to minimize the risk of hypovolemia.

It is imperative to measure the content of blood creatinine c, to determine the content of plasma potassium before starting taking an ACE inhibitor or ARB, as well as 7-10 days after starting their intake. If the increase in creatinine level or decrease in GFR is 30% or more from the baseline, then these classes of drugs are canceled.

Treatment should be started with low doses, and after each increase in the dose of an ACE inhibitor or ARB (as well as periodically while taking stable doses of these drugs), creatinine should be measured and GFR calculated, and plasma potassium should be determined to exclude the development of kidney damage. As with the first appointment, and with long-term use of an ACE inhibitor or ARB, hypovolemia should be avoided (or corrected if it is suspected). To minimize the risk of developing nephrotoxicity, the patient should be informed that while taking an ACE inhibitor or ARB, the potentially nephrotoxic drugs described above (primarily non-steroidal anti-inflammatory analgesics) should be avoided.

It should be specially emphasized that despite the possible nephrotoxicity of ACE inhibitors and ARBs, for the overwhelming majority of patients, they are a mandatory basic drug for nephroprotection, for which the benefits of taking them significantly outweigh the possible risks.

ξ Drugs of other classes

A number of drugs listed on the first slide (immunosuppressants, anticancer drugs) and other drugs can potentially lead to acute renal damage, but their use in a significant proportion of patients has no alternatives. Therefore, to minimize the likelihood of developing nephrotoxicity, it is necessary to observe the general principles of prescribing listed above, as well as to ensure adequate hydration of the patient, and to monitor renal function (both before starting to take them to adjust the dose and / or frequency depending on GFR, and for the timely diagnosis of AKI ).

ξ Drugs without nephrotoxic effect

There are a number of drugs that do not have a nephrotoxic effect, but have a narrow therapeutic window and are completely or largely eliminated by the kidneys. In particular, this applies to digoxin and metformin. For such drugs, the risk of overdose and associated adverse reactions increases significantly with the development of acute renal damage and, accordingly, a decrease in their excretion in the urine. Therefore, the recommendations are advised in the development of serious intercurrent diseases that increase the risk of developing acute renal damage, or if it is necessary to prescribe potentially nephrotoxic drugs, temporarily cancel digoxin, metformin and other drugs with predominantly renal elimination.

Nephrotoxicity is a property of chemicals, acting on the body non-mechanical

by causing structural and functional disorders of the kidneys. Nephrotoxicity may

manifest itself as a result of direct interaction of chemicals (or their metabolites) with

renal parenchyma, and indirect action, mainly through changes in hemodynamics,

acid-base balance of the internal environment, massive formation of products in the body

toxic destruction of cellular elements to be excreted through the kidneys (hemolysis,

rhabdomyolysis).

In the strict sense, nephrotoxicants can be called only those directly acting

on the kidneys, substances to which the threshold of sensitivity of the organ 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 a relatively high direct nephrotoxic

activity. List of known substances that have an indirect toxic effect on the kidneys

much broader and includes more than 300 items.

Table 1. Substances causing acute and chronic kidney damage

Metals Technical fluids Miscellaneous

Carbon tetrachloride

Dichloroethane

Trichlorethylene

Chloroform

Ethylene glycol

Diethylene glycol

Epichlorohydrin

Ethylene glycol ethers

Hexachloro-1,3-butadiene

Dichloroacetylene

Carbon disulfide

Paraquat

Mycotoxins (including pallidum toxins

Cantharidin

Penicillin

Acetylsalicylic acid derivatives

Cephaloridin

Puromycin

Aminonucleoside

Due to drug therapy, accidental or deliberate intoxication, work or

living in a contaminated environment, a significant part of the population is constantly exposed to

exposure to potential nephrotoxicants. Quantify the contribution of each of these

reasons in the total number of recorded chronic and acute nephropathies are currently not

seems possible.

According to some data, more than 10 million people in the world have constant contact with substances,

with pronounced nephrotoxicity. The frequency of reported cases of acute renal

deficiency of about 2 per 1000. According to some researchers, about 20% is a consequence

chemical influences, mainly drugs. Medicines are also the main one, among

other chemical factors that cause chronic nephropathy. According to some reports, only

abuse of non-narcotic analgesics accounts for 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 due to

chronic effects of eco-pollutants, industrial hazards (heavy metals, organic

solvents, etc.) much more often than is commonly believed. Some observations confirm this.

assumption. So, among people who are constantly exposed to heavy metals (lead,

cadmium), the frequency of deaths from renal failure is significantly higher than the average.

1. Anatomical and physiological features of the organ

The kidney is an extremely complex organ, both in terms of morphology and physiology, the main functions

which is the excretion of metabolic products from the body (see the section "Isolation of xenobiotics from

organism (excretion) "), regulation of water and electrolyte balance. Among other functions: synthesis

enzymes of metabolism of vitamin D, renin, which is involved in the formation of angiotensin,

aldosterone, synthesis of some prostaglandins, etc.

A paired organ weighing only about 300 grams (less than 1% of a person's body weight) receives about

25% of cardiac output minute volume. Blood is delivered to the nephrons - functionally

morphological units of the kidneys (about 106 nephrons per kidney). Each nephron consists of a vascular

parts - bringing arteriole, capillary glomerulus, efferent arteriole; bowman capsule,

surrounding the vascular glomerulus, into which the primary urine is filtered; systems

convoluted and straight tubules (the U-shaped structure of a straight segment of the renal tubule is called

loop of Henle), connecting the Bowman capsule with a connecting and collecting tube, through which

urine is excreted from the organ.

The capillary glomerulus, surrounded by Bowman's capsule, is a complexly organized molecular

filter that traps substances with a molecular weight of more than 40,000 daltons (most proteins

blood), but permeable to most xenobiotics and metabolic products of endogenous substances

("slags"). Approximately 20% of the volume of blood plasma flowing through the kidneys is transferred (filtered)

from the capillaries into the glomerulus capsule (180 liters per day). From the resulting filtrate, in the tubules, back

most of the water, sodium chloride, and other salts are resorbed into the blood. Thanks to the ongoing

processes excreted in the urine toxicants are significantly concentrated in certain departments

nephron (mainly the proximal renal tubules) and interstitial tissue of the kidneys.

In the region of the vascular pole of the renal glomerulus at the confluence of the bringing arteriole into it

there is a peri-glomerular (juxtaglomerular) complex. It is formed from itself

juxtaglomerular epithelioid cells that form a cuff around the afferent arteriole,

specialized cells of the "dense spot" of the distal renal tubule (lies in the area

its anatomical contact with the pole of the glomerulus) and mesangial cells filling the space

between the capillaries. The function of the complex is to control blood pressure and water-salt

metabolism in the body, by regulating the secretion of renin (regulation of blood pressure) and blood flow velocity along the

renal arteriole (regulation of the volume of blood flowing into the kidney). The participation of the complex in

pathogenesis of toxic kidney damage (see below).

Since the main transport and concentration processes occur in the proximal

tubules, it is this section of the nephron that is most often damaged by toxicants. In addition, the processes

passing in the proximal renal tubules (water reabsorption, secretory processes),

extremely energy intensive, which makes them very sensitive to ischemia.

In the loop of Henle, further concentration of urine is carried out due to the counterflow mechanism.

Some substances, such as analgesics, urea, are not reabsorbed in the proximal tubules, but

intensely concentrate in the loop of Henle. The highest concentration of such substances is noted in

tubules and collecting tube. This process is controlled by antidiuretic hormone. IN

the same section of the nephron, due to the secretion from the blood of an excess of either hydrogen or ammonium ions,

urine pH is formed.

Another important function of the kidneys, which affects the nephrotoxicity of a number of substances, is their

the ability to metabolize xenobiotics. Although the metabolic rate is significantly lower than in

liver, the same enzymatic systems are determined here, and the tension of biotransformation

high enough. The activity level of cytochrome P450-dependent oxidases is highest in the straight segment

(pars recta) of the proximal renal tubules, an area especially sensitive to toxicants.

Although many xenobiotics are simultaneously metabolized to form active radicals in the liver and

in the kidneys, organ damage is most likely due to the action of that part of the total

a substance that is metabolized in the kidneys.

The proximity of metabolic processes in the liver and kidneys determines practically

the same sensitivity of these organs to many xenobiotics (chlorinated hydrocarbons,

toxins of a pale toadstool, paraquat, etc.). The predominant defeat of one or another organ with

intoxication is largely due to the way in which the substance entered the body (inhalation,

parenterally, through the gastrointestinal tract), that is, which organ will be the first on the way

a compound distributed with the blood stream. For example, with inhalation injury

the kidneys are more affected by carbon tetrachloride, and when the substance is taken per os - the liver.

Thus, the high sensitivity of the kidneys to the action of toxicants is determined by:

High intensity of renal blood flow and organ sensitivity to hypoxia;

The ability to concentrate xenobiotics during the formation of urine;

Reverse resorption of a part of the excreted xenobiotics into the epithelial cells of the renal tubules;

Biotransformation of xenobiotics, accompanied in some cases by the formation

highly toxic intermediates.

2. Characteristics of nephrotoxic action

2.1. Mechanisms of action

The mechanisms of nephrotoxicity are biochemical, immunological, and hemodynamic in nature.

The defeat of the organ by many toxicants is of a mixed nature.

deficiencies can be attributed to one of the following groups:

Prerenal;

Renal;

Post-renal.

Prerenal causes include pathological conditions leading to a violation

hemodynamics, accompanied by a decrease in renal hemoperfusion (hypovolemia, shock, etc.).

Renal causes of pathology are caused by damage to the kidney tissue.

Postrenal causes are associated with blockage of the distal tubules of the nephron and / or collecting

tubes with pathological secretions or agglomerates of toxic substances and their metabolites.

2.1.1. Biochemical mechanisms

The mechanisms of the nephrotoxic action of xenobiotics are diverse and, at the same time, develop according to

the general scenario is enough. Toxicant passed through the filtration barrier in the glomeruli

concentrates (approximately 100 times) inside the tubules due to the reabsorption of most of the water,

concentration gradient or due to processes of active reabsorption, xenobiotics enters the cells

tubular epithelium and accumulates there. The nephrotoxic effect develops upon reaching

the critical concentration of the toxicant in the cells.

Depending on the physicochemical properties of substances, they interact with molecules

receptors (membrane structures, enzymes, structural proteins, nucleic acids) included in

the structure of one of the cellular compartments: lysosomes (aminoglycosides, etc.), cytoplasm (heavy

metals - cadmium), ribosomes, smooth endoplasmic reticulum, etc., which initiates the development

toxic process.

For many organic compounds, the stage of their nephrotoxic action is preceded by the stage of their

bioactivation taking place with the participation of enzymatic, metabolizing systems. In the mechanism

nephrotoxic effect of many xenobiotics (cephaloridin, puromycin, aminonucleoside, paraquat,

carbon tetrachloride), an important role is played by their ability to initiate the formation process in

cells of free radicals.

2.1.2. Immunological mechanisms

Nephrotoxic processes of the immune type, as a rule, are the result of two main

processes: (1) deposition in glomerular structures of the kidneys of the antigen-antibody complex; (2) education

complex antigens in situ, during the interaction of renal proteins with a toxicant, followed by an attack

on them antibodies circulating in the blood. Since antibodies and immune complexes are high molecular weight

education, 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 salts of gold, mercury, d-penicylamine) 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 response is

leading to kidney damage in most cases is unknown. Sometimes xenobiotics show

properties of haptens (methicillin), forming a certain own antigen, or contribute to the release into the blood

normal latent antigens. In some cases, a hyperimmune reaction may result from

polyclonal activation of immunocompetent cells, as is the case with nephropathies,

caused by gold, mercury, penicylamine.

Damage to the renal tissue occurs through the implementation of a certain chain of events, characteristic

for the development of allergic or autoimmune processes (see section "Immunotoxicity").

2.1.3. Hemodynamic mechanisms

Hemodynamic disorders are a common cause of the development of toxic nephropathies.

In case of acute damage to the renal tubules by a toxicant, the functions of the organ may be impaired due to

obstruction of the lumen of the tubules with the products of decay of epithelial cells, retrograde flow of the glomerular

filtrate, increase in pressure in Bowman's capsule, and as a result, blood in the capillary network

renal glomerulus. Increased blood pressure in the renal glomeruli activates juxtaglomerular

renal apparatus, causing renin hypersecretion. Local effect of the renin-angiotensin system

determines arteriolar preglomerular spasm, which entails, on the one hand,

cessation (or sharp weakening) of blood supply to the glomerulus, suspension of glomerular

filtration, and on the other - ischemia of the renal tubules and their secondary necrosis. Tissue damage

aggravated by the release of biologically active substances such as thromboxanes into the vascular bed,

endothelin.

In cases where the volume of glomerular filtration is reduced by more than 70%, evolution

process towards renal failure becomes irreversible, probably due to the fact that

the initially intact nephrons are progressively involved in the pathological process.

2.2. Manifestations of toxic effects

The main manifestations of kidney damage by toxicants are:

The appearance of blood in the urine (hematuria) due to damage to the wall of the capillaries of the glomeruli;

The appearance of protein in the urine of more than 0.5 g in a daily sample (proteinuria). Proteinuria may be

glomerular origin, while in the urine mainly high molecular weight

proteins (more than 40,000), and tubular - predominantly low molecular weight proteins are found in the urine

(less than 40,000). Glomerular proteinuria indicates destruction of the glomerular blood-urine barrier;

tubular - for damage to the proximal renal tubules;

Decrease in the amount of urine discharge - less than 600 ml per day (oliguria);

An increase in the blood plasma content of nitrogen-containing low molecular weight substances, such as

urea, creatinine, 2-microglobulins, etc. (azotemia);

General edema, which in the absence of heart failure or cirrhosis of the liver indicates a sharp

Hypertension due to 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 suppression of renal function with azotemia

and, often, oliguria;

Chronic renal failure - permanent impairment of renal function with azotemia,

acidosis, anemia, hypertension and a number of other disorders;

Tubulointerstitial nephritis (acute or chronic) with various signs of tubular

dysfunctions (tubular proteinuria, urinary acidosis, salt loss, decreased urine specific gravity and

Nephrotic syndrome characterized by severe proteinuria (more than 3.5 g of protein per day

urine), hypoproteinemia, edema, hyperlipidemia, hyperlipiduria. Nephrotic syndrome can

be the result of various types of glomerulonephritis;

Rapidly progressive glomerulonephritis, manifested by hematuria and oliguria, leading to

kidney failure for several weeks.

Substances that cause the formation of certain types of nephropathy are presented in table 2.

Table 2. Poisoning accompanied by toxic nephropathy

Toxic options

nephropathy

Toxicants

ACUTE RENAL

FAILURE:

1. Prerenal

2. Post-renal

3. Renal causes

A. Acute tubular

B. Sharp

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 and

etc.); antineoplastic agents (cisplatin, etc.).

Allopurinol, cephalosporins, indomethacin. rifampicin, etc.

CHRONIC

Renal

FAILURE:

A. Interstitial

nephritis; glomerclosclerosis

B. Nephrotic

Metals (cadmium, lead, beryllium, lithium); cyclosporine

Metals (mercury, gold); captopril, heroin, D-penicylamine

3. Brief description of individual nephrotoxicants

Nephrotoxicants are extremely widely used in everyday life and at work. So, organic

solvents are components of numerous varnishes, paints, adhesives, cleaning agents, pesticides

etc. Heavy metals and their compounds are widely used in everyday activities. Paths

the intake of substances into the body is also different: inhalation, transdermal, alimentary. In conditions

the most frequent production is inhalation intoxication. Solvents often act

and through the skin. For the rest of the population, the most characteristic route of intake of nephrotoxicants

into the body is alimentary, with contaminated food, 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, polyuria. For severe poisoning

metals form necrotic changes in the kidneys, develop anuria, proteinuria, it is possible

fatal outcome. In the experiment, when small doses of metals are introduced into the body of animals, no

causing a clinical lesion, their high concentration is determined in the lysosomes of renal cells. it

binding of metals by lysosomes can be a consequence of lysosomal endocytosis of metal-proteid

complexes, autophagy of metal-damaged organelles (for example, mitochondria), binding

metals lipoproteins of lysosomal membranes. With the introduction of high doses of toxicants, metals

are determined in other cell organelles.

3.1.1. Lead

In the recent past, lead was a common cause of acute and chronic nephropathies. IN

the literature describes numerous cases of tubular epithelium necrosis due to accidental or

deliberate intake of large doses of lead salts. Cases of chronic renal failure

were registered in persons who took alcohol stored in vessels containing lead, in workers,

constantly in contact with lead-containing substances, in adults who have experienced acute

intoxication with lead dyes, etc. Currently, lead cases

are registered 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 formation

pathology and revealing itself in the study of the rate of glomerular filtration. Accumulation

lead in kidney tissue, especially in epithelial cells of the proximal tubule, is accompanied by

early stages of the disease by damage to cell mitochondria and impaired absorption functions

cells. Later, inclusions formed by complexes of lead with acidic cells appear in the nuclei of these cells.

proteins. These intranuclear bodies, as a rule, disappear as the pathology progresses.

Kidney pathologies in lead intoxication are often accompanied by hypochromic anemia, hypertension,

neuropathy.

With the help of chelating agents (EDTA or dimercaptosuccinate), it is possible to mobilize

lead accumulated in tissues and thereby accelerate its excretion from the body. Lead content in

a patient's urine more than 800 μg in a daily sample after intravenous administration of EDTA at a dose of 0.5 gram

indicates a high content of metal in body tissues.

3.1.2. Cadmium

Chronic cadmium intoxication is often accompanied by the development of progressive

tubulointerstitial nephritis.

Human involvement is usually due to the consumption of contaminated food or, in

industrial conditions, inhalation of dust containing cadmium. Epidemiological research

among those professionally in contact with cadmium, revealed a high incidence of renal

pathology. Cases of chronic intoxication of people living in regions with high

growing on soils with a high cadmium content, there is a disease (Itai-itai), which

manifested by anemia, destruction of bone tissue, impaired renal function (epithelial damage

proximal tubules). The disease begins with urinary excretion of specific

low molecular weight proteins such as 2-microglobulins or retinol-binding protein, and

cadmium, mainly in the form of a complex with the protein metallothionenin. Cadmium binding

metallothionein apparently helps protect some organs from damage. In 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 (period

the half-life of cadmium from the human body is 10 - 20 years).

In individuals with initial forms of kidney damage, the concentration of cadmium in urine is usually more than

10 μg per 1 g of creatinine excreted in the urine.

In acute intoxication with cadmium, a fairly effective means of removing the substance from

organism is EDTA-Ca, Na. In case of chronic intoxication, mobilize the element with

complexing agents available to the doctor have not yet been successful.

The mechanism of the toxic effect of the metal has not been finally established. Apparently, it consists

in the interaction of a metal with carboxy-, amino-, SH-groups of protein molecules, dysfunction

structural proteins and enzymes. It was also shown that Cd largely follows the metabolic pathways of Zn + 2 and

It is believed that at the molecular level, the mechanism of the toxic effect of Cd can also be due to

its ability to replace Zn and other divalent ions in biological systems. Zinc deficiency

modifies the character of Cd distribution and significantly potentiates its toxicity.

3.1.3. Mercury

Acute intoxication with certain inorganic and organic mercury compounds

accompanied by the development of necrosis of the epithelium of the proximal renal tubules and renal

failure. It is well known that the use of mercury diuretics in small doses is accompanied by

binding of Hg2 + to cell membrane enzymes containing sulfhydryl groups in the molecule and

participating in sodium reabsorption, inhibiting their activity. The introduction of drugs into unreasonably high

doses can lead to acute glomerulonephritis with characteristic proteinuria and nephrotic

syndrome.

Acting in moderate doses, mercury vapor and salts can cause various subclinical forms

impaired renal function, accompanied by proteinuria, urinary excretion of some

low molecular weight enzymes. In persons with severe occupational mercury intoxication, as a rule,

chronic glomerulonephritis is recorded.

Various chelating agents are used to accelerate the elimination of a substance from the body.

The most commonly used are dimercaprol, D-penicylamine, dimercaptosuccinate.

3.1.4. Arsenic

Necrosis of the tubular epithelium of the kidneys is a frequent complication of acute compound poisoning

trivalent and pentavalent arsenic. To accelerate the elimination of arsenic from the body with success

used chelating agents from the group of dithiols (2,3-dimercaptopropanol, unitiol, etc.).

Arsine (AsH3) poisoning leads to secondary damage to the kidneys by hemoglobin released in

blood plasma due to massive hemolysis. Acute renal failure that develops with

this, is the main cause of death of the poisoned. The use of complexing agents for

intoxication with this substance is inappropriate.

3.2. Technical fluids

A number of technical fluids, and among them primarily organic solvents, are widely

used in everyday life and at work are potential nephrotoxicants. Depending on the

doses of the substance develop lungs, accompanied by moderate proteinuria, moderate

severity and severe, proceeding in the form of acute tubular necrosis, forms of kidney damage.

Often, kidney damage develops in drug addicts who inhale in order to obtain

pleasure, adhesives, dyes containing toluene as a solvent. Forming in this

the case of the symptom complex resembles Fanconi's syndrome (glucosuria, proteinuria, acidosis, etc.).

Subchronic and chronic intoxication with hydrocarbons (gasoline) can cause

glomerulonephritis with characteristic Goodpasture syndrome (rapidly progressive glomerulonephritis,

accompanied by periodic pulmonary hemorrhages and the presence of antibodies in the blood to

glomerular membrane).

Depending on the type of solvent, in addition to the kidneys, the pathological process often involves

other organs, mainly liver, blood, nervous system.

3.2.1. Ethylene glycol

Ethylene glycol - dihydric alcohol (CH2OH-CH2OH) - is part of various formulations of antifreeze

and brake fluids. Poisoning with a substance is possible only when taken orally (as

alcohol surrogate) and leads to acute kidney damage. An absolutely lethal dose for humans -

The substance is rapidly absorbed in the gastrointestinal tract. The largest amount accumulates in

liver and kidneys, where the xenobiotic undergoes biological oxidation with the formation of glycolate,

glyoxalates, oxalates, which, in general, initiate the development of a toxic process. Period

the half-elimination of the substance is about 3 hours. Within 6 hours after taking 100 ml of alcohol in

the body produces about 70 ml of toxic substances. Ethylene glycol itself and its metabolic products

excreted from the body slowly and determined in the blood for about a day.

Acting as a whole molecule, ethylene glycol exhibits the properties of a typical non-electrolyte, providing

sedative-hypnotic action (see "Neurotoxicity"). Formed during metabolism

aldehydes and organic acids (in particular oxalic acid) cause metabolic acidosis (in

severe cases - blood pH less than 6.9), suppression of tissue respiration, the formation of crystals in the tissues

water-insoluble calcium oxalate; and hypocalcemia. These phenomena underlie the defeat

internal organs especially sensitive to changes in the properties of the internal environment and energy deficiency -

CNS and kidney.

Signs of kidney damage, as a rule, develop on days 2 - 3 of intoxication (after a period

cerebral phenomena). In extremely severe cases, oliguria is noted; erythrocytes are determined in the urine,

protein, crystals of calcium oxalate. On the 8-14th day, with symptoms of uremia, the victims may

perish. At autopsy, those who died show significant changes in the kidneys: degeneration of the epithelium

convoluted tubules, small hemorrhages in the parenchyma of the organ. In the renal tissue, microscopy shows

oxalate crystals, mechanically injuring the organ.

Complex therapy of poisoning, among other measures, provides for early introduction

victims of ethyl alcohol at a rate of up to 1 g / kg (by mouth or intravenously) followed by repeated

the introduction of the substance within 3 - 4 days. This provides competitive suppression of the process

biotransformation of ethylene glycol. In an experiment, in order to treat a lesion, an inhibitor was tested

alcohol dehydrogenase 4-methylpyrosol.

4. Assessment of nephrotoxicity of xenobiotics

The nephrotoxicity of substances is assessed in the course of acute subacute, chronic toxicological

experiments. It is desirable to carry out experiments on several types of laboratory animals. During

studies, to assess the functional state of the kidneys, use methods that are widely used in

clinical practice.

During screening for xenobiotics, tests such as urine density,

It is important to keep in mind that none of these tests provide an unambiguous assessment of the developing

renal pathology. In some cases, the identified disorders simply reflect physiological reactions

body to other adverse effects.

Among the simplest and most frequently performed studies that allow more definite

to judge the mechanism of damage, the creatinine test applies. With a decrease in the speed of the glomerular

filtration, the level of creatinine in the blood plasma increases. When interpreting the test, it is necessary

take into account the nonlinear nature of the relationship "creatinine content - insufficient filtration". So,

the sample becomes distinctly positive when the filtration rate is reduced by more than 30-50%.

Methods for determining the clearance of creatinine, inulin,

isotopically labeled xenobiotics. However, these tests are complex and cannot be used to

conducting routine research. Moreover, in the early stages of pathology, when compensatory

processes ensure the functioning of the organ (up to 50% of the renal parenchyma is damaged), indicators

the clearance of substances are simply not informative.

The appearance of protein in the urine is often the most sensitive sign of toxic kidney damage. FROM

high molecular weight (such as albumin) to recognize glomerular pathology, and

low molecular weight (eg, 2-microglobulin, retinol-binding protein), to detect

damage to the proximal tubules.

The study of the ratio of the content of low- and high-molecular-weight proteins in urine makes it possible to identify

the ability of toxicants to predominantly cause tubular or glomerular nephropathy.

The appearance of renal enzymes in the urine indicates damage to the organ parenchyma. One of

acetylglucosaminidase. The enzyme activity in the renal tissue is high, it is stable in the urine, has a high

molecular weight, which excludes the possibility of its extrarenal origin. These

circumstances ensure the reliability of the test.

Toxic damage to renal tissue is accompanied by the appearance of structural

components with antigenic properties. Methods of immune determination have been developed.

carbonic anhydrase, alanine aminopeptidase, etc. The appearance of renal antigens in the urine is usually

indicates an acute process in the kidneys.

5. Identification of __________ toxic kidney damage in humans

Diagnosis of acute toxic nephropathy is based on clinical and laboratory data.

During routine examinations of persons in contact with potential nephrotoxicants, for

proteinuria, enzymuria, excretion of renal antigens.

In a poisoned person it is necessary: \u200b\u200bto study the chemical composition of urine; conduct her microscopy; estimate

glomerular filtration rate in terms of the concentration of creatinine, urea in the blood,

clearance of creatinine, inulin, isotopically labeled compounds; determine the condition of tubular

functions (concentration capacity, proton-excretory capacity, phosphate clearance, etc.).

In especially difficult cases, a radiographic and radioisotope study of the kidneys is indicated,

microscopic, electron microscopic, immunofluorescent study of kidney biopsies.

Currently, due to the prevalence of elementary hygiene measures,

protecting a person from the massive effects of toxicants, much more often one has to face

with subclinical forms of renal pathology of chemical etiology, manifested by mild

proteinuria, enzymuria, etc. These renal effects are indicative of failure

measures to prevent injury by nephrotoxicants at work, in some cases

reflecting the initial phenomena of progressive pathology, it is possible to identify only with the help

technically complex techniques and expensive precision equipment.

Of great importance in the diagnosis of toxic nephropathy is the survey of the subject. During the survey

it is necessary to find out whether or not the subject had contact with toxicants, what, when and for how long.

It should be borne in mind that intoxication may be the result of taking nephrotoxic drugs.

(antibiotics, analgesics), consumption of contaminated water and food, exposure to toxicants in everyday life and on

production (solvents, metals), substance abuse, etc. It must be remembered that kidney damage

can occur with the action of toxicants in very small doses in persons with various types of pathology or

in contact with other toxic substances (for example, acute renal failure can

develop under the influence of very small doses of carbon tetrachloride in persons taking barbiturates -

the phenomenon of synergy).

The diagnosis of toxic nephropathies can be made on the basis of studies that allow

identify specific signs of intoxication. So, chronic lead poisoning is accompanied by

violation of hemoglobin synthesis; concomitant nephropathy disorders of the liver and central nervous system -

sign of inhalation damage by halogenated hydrocarbons; characteristic signs of defeat

the nervous system may allow the detection of mercury poisoning.

Diagnosis of toxic nephropathy is greatly facilitated if the biomaterial (urine, blood,

rinse waters, biopsies, etc.), it is possible to determine the increased content of the toxicant. IN

depending on the toxicokinetic properties of the substance, the time during which the toxicant or its

metabolites are determined in the body, varies in a very wide range from several hours

(carbon disulfide) up to weeks and even years (heavy metals: lead, cadmium).