nephrotoxic drugs. Antibiotics that are toxic to the kidneys

Kushnirenko S.V. ., K. honey. n., Associate Professor of the Department of Nephrology, NMAPE named after N.I. P.L. Shupyk, Kyiv, Ukraine

The correct choice of an antibacterial drug and the tactics of antibiotic therapy largely determine the success of the fight against infections in nephrological patients.

The main indications for the use of antibiotics in nephrology are

Upper and lower urinary tract infections

Fluoroquinolones

Cephalosporins 3rd generation

Prevention of risk factors in patients with chronic kidney disease, including those on dialysis

Streptococcal aggression (penicillins)

Diarrhea (fluoroquinolones)

Somatic microbial processes in all categories of patients, including both glomerulonephritis and pyelonephritis, and prevention of infectious complications in patients with renal insufficiency.

Pyelonephritis.

For the treatment of pyelonephritis today there are three possibilities:

In the hospital - antibiotic stepwise therapy
Outpatient antibiotic peros
Hospital / home - intravenously in a hospital, peros on an outpatient basis.

The drugs of choice in the treatment of pyelonephritis in adults and children are cephalosporins (Table 1). Preference is given to the 3rd generation, to a lesser extent the 2nd and 4th. Speaking of stepwise therapy, we mean parenteral administration of an antibiotic: we start with intravenous administration (it is necessary to abandon intramuscular administration !!!) and, as soon as positive dynamics are achieved in the form of temperature normalization for 24 hours, regression of symptoms of intoxication, a tendency towards normalization of blood and urine parameters , we have the right to transfer the patient to oral administration.

Non-stepped tepapia is more often used in the outpatient practice of pediatricians, internists and family doctors. In this case, one drug (cefutil or cefix, leflocin or ciprofloxacin) is administered orally for 10 days. It should be noted that with gram-positive flora, amoxicillin in combination with clavulanic acid can be considered as the drug of choice.

Generation	Oral	parenteral
	Cefuroxime axetil (cefutil)	Cefuroxime (cefumax)
	Cefixime (cefix)
	Ceftibuten (Cedex)
	Cefpodoxime (cefodox)
			x3r, 3–5 days	resistance
Co-amoxicillin/clavulanate 500 mg	x2r, 3–5 days
Cephalexin 500 mg	x3r, 3–5 days	resistance
	once
Trimethoprim–sulfamethoxazole	x2r, 3–5 days	Do not use trimethoprim in the 1st trimester and sulfamethoxazole in the 3rd trimester

Table 2. Treatment of bacteriuria and cystitis in pregnant women.

Treatment of pyelonephritis in pregnant women

Pyelonephritis in pregnant women, of course, should be considered as a complicated infectious and inflammatory process. For the treatment of pyelonephritis, cephalosporins, piperacillin, ampicillin are used (Table 3). Currently, the duration of treatment for pregnant women, upon receipt of positive dynamics, has been reduced from 14 to 10 days with a mandatory subsequent transition to preventive treatment.

Antibiotic	Dose
	1-2 g IV or IM per day
	1 g IV x2-3r
Piperacillin-tazobactam	3.375–4.5 g IV x4p

Imipenem-cilastatin	500 mg IV x4
Gentamicin (possibly ototoxic effect on the fetus!!!)	3–5 mg/kg/day i.v. x 3p

Table 3. Treatment of pyelonephritis in pregnant women.

Summarizing the above, I want to emphasize that

for the treatment of lower urinary tract infection, it is better to use cephalosporins (treatment for the first episode - 3 days, for relapse - 7 days)
for the treatment of pyelonephritis, the most rational today is a stepwise therapy scheme (detoxification in combination with intravenous administration of a 3rd generation cephalosporin, followed by a transition to oral administration of Cefix for 10 days)
in the future, it is necessary to switch to prophylactic treatment (prophylactic dose of the drug, canephron N).

Glomerulonephritis

Antibiotic therapy in patients with glomerulonephritis is carried out

in the presence of a clear connection between the infectious agent and the manifestation of the process

in the presence of foci of chronic infection

in case of prolonged stay of the subclavian catheter.

Etiotropic antibiotic therapy is carried out for 10-14 days using cephalosporins of the second and third generation (cefadox 10 mg / kg can be used, due to its tropism for the respiratory system; cefutil, due to its wide spectrum of action on gram-positive and gram-negative flora, macrolides).

In cases where there is vascular access, intravenous antibiotics are best given to prevent catheter-associated infection.

If a patient has positive titers of antistreptoloisin O or is a carrier of β-hemolytic streptococcus, after the end of a 14-day course of antibiotic therapy, it must be transferred to adjuvant forms of penicillin (for example, bicillin 5). If indicated, antibiotic therapy may be continued. When carrying out the prevention of catheter-associated infections, the dose of antibiotics should be 30-50% of the therapeutic dose.

Chronic kidney disease (CKD).

According to experts from different countries, from 13 to 17.6% of patients with CKD die from infectious complications. To date, infectious complications in dialysis patients are the third leading cause of death after cardiovascular and oncological diseases.

The risk group consists of patients with polycystic kidney disease, diabetes mellitus, urolithiasis, vesicoureteral reflux, neurogenic urinary disorders, preparing for or undergoing kidney transplantation.

I want to note that most antibiotics do not require dose adjustment at a glomerular filtration rate of at least 20-30 ml / min (which is equivalent to the third stage of renal failure), with the exception of potentially nephrotoxic drugs (aminoglycosides, glycopeptides). This applies not only to CKD, but also to acute renal failure.

Remember that the combination of loop diuretics with cephalosporins, aminoglycosides is nephrotoxic!

Hemodialysis

Antibiotics in patients on hemodialysis are administered intravenously to avoid the occurrence of caterer-associated infections (CAI) after the dialysis procedure. The risk of CAI increases significantly with prolonged catheter stay (more than 10 days).

CAI prevention is the creation of a permanent vascular access and antibiotic prophylaxis (cefoperazone, cefotaxime, ceftriaxone 1.0 g intravenously after hemodialysis).

If the patient has signs of a catheter-associated infection but it is not possible to remove the catheter, fluoroquinolones are used (leflocin at a saturation dose of 500 mg, then 250 mg every 48 hours; vancomycin 1 g for 710 days; imipenem 250500 mg every 12 hours).

kidney transplant

Bacteriuria after kidney transplantation is observed in 3580% of patients, and the risk is highest in the early postoperative period. Recurrent urinary tract infections are observed in 42% of patients.

In this regard, the following tactics are used in the treatment of patients with kidney transplantation:

mandatory treatment of infections in the recipient prior to transplantation
preoperative antibiotic prophylaxis
prophylaxis with trimethoprim/sulfamethoxazole 480 mg daily for the next 6 months after transplantation
nitrofurantoin and tetracyclines are contraindicated!!!
empiric treatment of overt infections with cephalosporins, fluoroquinolones, trimethoprim/sulfamethoxazole for 1014 days.

Negative effects of antibiotics

1. Toxic effect

Nephrotoxic effect of aminoglycosides (impaired concentration function of the kidneys, proteinuria, azotemia). 72 hours after the appointment of aminoglycosides, it is necessary to monitor blood creatinine - an increase in creatinine by 25% indicates the onset of a nephrotoxic effect, 50% or more is an indication for discontinuation of the drug.

Ototoxicity, vestibulotoxicity (aminoglycosides, vancomycin). Therefore, these drugs are not prescribed for pregnant women.

Paresthesia, dizziness (sodium colistimethate).

2. Change in the qualitative composition of urine:

Glucosuria (transient) as a result of the action of cephalosporins, which temporarily disable the membrane carrier proteins responsible for the reabsorption of glucose in the proximal tubules.

Cylindruria, interstitial nephritis can provoke trimethoprim with sulfamethoxazole, glycopeptides, carbapenems.

Crystalluria can be provoked by taking fluoroquinolones, due to an increase in the excretion of uric acid.

3. Disorders of the function of the gastrointestinal tract

Almost any drug can cause diarrhea and dyspeptic symptoms (nausea, vomiting). But it has already been proven that the frequency of diarrhea associated with taking antibiotics does not depend on the route of administration of the drug (parenteral or oral). The more frequent occurrence of loose stools when oral antibiotics in the form of a syrup are taken by children can often be explained by the laxative effect of sorbitol, which is part of the drug. The same thing happens with macrolides, which, due to the effect on such receptors, increase the frequency of defecation.

4. Development of acute renal failure. Almost any antibiotic can potentially cause acute renal failure:

When using aminoglycosides, the nephrotoxic effect develops in 10-15% of patients after 710 days of treatment, due to damage to the S1, S2 segments of the proximal tubules.

Amphotericin B

Cephalosporins (localization of toxic damage - interstitium)

Fluoroquinolones, penicillins, polymyxins, rifampicin, sulfonamides, tetracycline, vancomycin

conclusions

1. To date, cephalosporins are the most popular group of antibiotics used for all nephrological nosologies (urinary tract infections, glomerulonephritis, acute renal failure, chronic kidney disease).

2. Fluoroquinolones are most commonly used for urinary tract infections.

3. Aminopenicillin/clavulanate is used in gram-positive microbial inflammatory kidney disease and as prophylaxis in invasive studies in patients with chronic renal failure.

4. Carbapenems, glycopeptides, sodium colistimethate are reserve drugs and are used in the treatment of catheter-associated infections.

Protocol for the treatment of children with infections of the sich system and tubulointerstitial nephritis No. 627 dated 3.11.2008

Protocol for the treatment of children with chronic nirk deficiency No. 365 dated 20.07.2005

· Protocol of medical assistance for ill for pyelonephritis No. 593 dated 2.12.2004.

The report was presented at the scientific-practical seminar "Protecting the kidneys - save the heart" (11.02.2011), dedicated to the World Kidney Day, held at the NMAPE named after N.I. P.L. Shupyk in Kyiv. National Medical Internet Portal LIKAR. INFO acted as an information sponsor of the event.

(API) reaches 2000-3500 patients / million, i.e. during the year, about 0.2-0.3% of the total population suffers acute kidney injury of various etiologies. Acute kidney injury can be encountered by physicians of all specialties, both medical and surgical. AKI in itself is a rather serious syndrome that can be associated with both a short-term threat to the life of the patient and a long-term risk of developing chronic renal failure. Acute kidney injury also causes worsening of the underlying disease, may lead to the development of type 3 cardiorenal syndrome, and is associated with a high cost of patient care. At the same time, in some patients, the development of acute renal injury can be avoided, primarily by minimizing the use 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 below, it is much wider. 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 existing (CKD). The results of long-term follow-up in the AASK study show that almost 8.5% of patients with CKD experience episodes of a sharp decrease in the glomerular filtration rate, i.e. there is a layering of acute renal injury on chronic renal failure. Therefore, in patients with chronic kidney disease, special attention is required to the potential nephrotoxic effects of drugs, drug interactions, and, if necessary, to eliminate hypovolemia before prescribing diagnostic studies or prescribing drugs that affect intrarenal hemodynamics. Moreover, since many potentially nephrotoxic drugs are available over-the-counter, the patient should know the list of these drugs himself, and consult a nephrologist before starting any new medications (including herbal preparations and nutritional 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 analogues comparable in effectiveness without side effects on the kidneys.
A patient with chronic kidney disease should consult a physician before taking any medication, including over-the-counter drugs 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 necessary to determine the level of blood creatinine in all patients).
After a short course of taking potentially nephrotoxic drugs, it is necessary to re-determine the level of creatinine in the blood and to make sure that the patient does not have acute kidney injury.
In patients taking potentially nephrotoxic drugs for a long time, it is necessary to regularly 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 temporarily canceling drugs already prescribed to the patient, which can affect intrarenal hemodynamics (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, aldosterone inhibitors, non-steroidal anti-inflammatory drugs) or cause 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 available over the counter, the patient should always be informed of their possible nephrotoxic effects and the need to minimize their use. In addition, it must be remembered that the patient does not always have sufficient knowledge to classify the prescribed drug (or simply a “good” painkiller or “anti-influenza” drug recommended by friends) to the NSAID class. Therefore, before buying or taking medications, the patient must read the package leaflet to find out if a particular drug belongs to the class of non-steroidal anti-inflammatory drugs. It should be noted that absolutely all NSAIDs, including selective cyclooxygenase type 2 inhibitors, have a potentially nephrotoxic effect.

The main mechanism of nephrotoxicity for NSAIDs is a decrease in the synthesis of prostaglandins (which have a vasodilatory 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 with. Even with short-term use due to inhibition of the synthesis of vasodilating prastostaglandins, NSAIDs can lead to an increase in blood pressure and a decrease in the effectiveness of antihypertensive drugs, fluid retention with edema and the development of heart failure. With long-term use of NSAIDs, analgesic nephropathy can develop, which in some countries plays a very significant role in the structure of terminal chronic renal failure.

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

If the clinical situation does not allow avoiding the use of analgesics and NSAIDs, then one should remember about the stepwise scheme of their prescription (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 for prescribing analgesics involves several levels:

At the first stage, if possible, it is necessary to start with the use of topical gels or creams with NSAIDs, which avoids systemic effects, including the development of nephrotoxicity.
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, it should be remembered that the dose of acetaminophen should not exceed 650 mg * 4 times a day. In addition, as with any medication, taking paracetamol requires adequate fluid intake to ensure sufficient hydration and maintain normal intrarenal hemodynamics.
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, only ibuprofen 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 doses. 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 diuretics potentially leading to hypovolemia, in order to reduce the risk of developing a nephrotoxic effect of NSAIDs.
With insufficient effectiveness of the above treatment, you should switch to drugs of other classes for the treatment of pain. It should be specifically noted that the use of such fairly common representatives of NSAIDs as diclofenac and indomethacin, as well as other NSAIDs with a long half-life (i.e. with a frequency of dosing 1 or 2 times a day) in patients with chronic kidney disease should be avoided.

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

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

ξ Radiocontrast agents

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

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

Carefully weigh the risks and benefits of the study
Avoid the use of high osmolar radiopaque agents
Use the lowest possible dose of radiocontrast agent
If possible, stop potentially nephrotoxic drugs before and after the study
Ensure adequate hydration before, during and after the study
48-96 hours after the administration of the radiocontrast agent

Regarding the use of products containing gadolinium:

The use of gadolinium-containing drugs in GFR is strongly discouraged<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 number of antibiotics have a potential nephrotoxic effect and can lead to the development of acute kidney injury. First of all, this applies to aminoglycosides, amphotericin B and sulfonamides.. If possible, analogues of these drugs with comparable antibacterial efficacy without nephrotoxic effect should be chosen. 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 severely 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.

With regard to sulfonamides and the combination trimethoprim / sulfamethaxazole, 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 inhibitors (ACE 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 glomerular filtration rate and the severity of proteinuria. Their nephroprotective effect has been proven in numerous studies with a wide range of nephropathies..

At the same time, it should be noted that these classes of drugs can lead to the development of acute renal injury due to the effect on intrarenal hemodynamics. Therefore, you should definitely remember about 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 widespread 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 intraglomerular 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 also be temporarily discontinued to minimize the risk of hypovolemia.

Be sure to measure blood creatinine c before starting taking ACE inhibitors or ARBs, and also 7-10 days after the start of taking them, to determine the content of plasma potassium. If the increase in creatinine or decrease in GFR is 30% or more from baseline, then these drug classes are discontinued.

Treatment should be started at low doses, and after each increase in the dose of ACE inhibitors or ARBs (and 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. Hypovolemia should be avoided (or corrected if it is suspected) for both initial use and long-term use of ACE inhibitors or ARBs. 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 specifically emphasized that despite the possible nephrotoxicity of ACE inhibitors and ARBs, for the vast majority of patients, they are a mandatory basic drug for nephroprotection, in respect of which the benefits of taking them significantly exceed the possible risks.

ξ Drugs of other classes

A number of drugs listed on the first slide (immunosuppressants, antineoplastic) and other drugs can potentially lead to acute kidney injury, but their use in a significant proportion of patients has no alternatives. Therefore, to minimize the likelihood of developing nephrotoxicity, it is necessary to follow the general principles of prescribing listed above, as well as ensure adequate hydration of the patient, and monitor renal function (both before starting their administration to adjust the dose and / or multiplicity 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 injury and, accordingly, a decrease in their excretion in the urine. Therefore, the recommendations advise in the development of serious intercurrent diseases that increase the risk of developing acute kidney injury, or if it is necessary to prescribe potentially nephrotoxic drugs, to temporarily stop digoxin, metformin and other drugs with predominantly renal elimination.

»» 2 / 2002

EAT. Lukyanova
Russian State Medical University, Moscow

The use of antibacterial drugs is the main cause of disease for all age groups. Kidney damage occurs through two main mechanisms, in particular directly and with the help of immunological mediators. For some antibiotics (aminoglycosides and vancomycin), nephrotoxicity, which is reversible after discontinuation of the drug, is a very common side effect, up to the onset of acute renal failure, the incidence of which is currently increasing. Antibacterial drugs are very commonly used in the neonatal period, especially in very low birth weight neonates.

Determination of early non-invasive markers of kidney damage (urinary microglobulins, proteins and growth factors) is very important as long as the values of traditional laboratory parameters of nephrotoxicity deviate from the norm only in the presence of significant kidney damage.

Currently, aminoglycosides and glycopeptides are often used as monotherapy or in combination, despite their low therapeutic index. Nephrotoxicity can be caused by (beta-lactams and related compounds. The potential for nephrotoxicity is distributed in relation to drugs as follows: carbapenems > cephalosporins > penicillins > monobactams. Third-generation cephalosporins are often used in newborns.

The nephrotoxicity of other classes of antibacterial drugs is not discussed, either because they are given to newborns under exceptional circumstances, such as chloramphenicol or co-trimoxazole (trimethoprim-sulfamethoxazole), or because they are not associated with significant nephrotoxicity, such as macrolides, clindamycin, quinolones, rifampicin and metronidazole.

When choosing antibiotic therapy in newborns, the following parameters should be taken into account:

Antibiotic nephrotoxicity, antibacterial spectrum of activity, pharmacokinetics, post-application effect, clinical efficacy, major side effect profile, and cost of treatment.

The main causes of kidney damage are the significant nephrotoxicity of some antibacterial drugs, the predominant renal excretion of most antibiotics, high renal blood flow, and a high degree of specialization of tubular cells. Antibiotics can damage the kidneys through two mechanisms. The direct type of damage (the most common) is dose-dependent, often with an insidious onset (symptoms are often not detected in the early stages), and is characterized by necrosis of a part of the cells of the proximal tubules of the kidney. Pathological changes in severe cases correspond to the picture of acute tubular necrosis, which is typical for damage resulting from exposure to aminoglycosides and glycopeptides. In newborns, this type of damage is noted.

The immunologically mediated type of damage does not depend on the dose of the drug and usually occurs acutely, accompanied by allergic manifestations. Histologically, it is characterized by the presence of infiltrates consisting of mononuclear cells, plasma cells, and immunoglobulin IgE [3]. The hypersensitivity reaction can occur through cellular mechanisms (most often), resulting in acute tubulointerstitial nephritis, or through humoral mechanisms (less often), resulting in focal glomerulonephritis. Such damage is typical of penicillins and is very rare in neonates. Cephalosporins can potentiate both direct and immunologically mediated damage.

It should be noted that the development of drug-induced nephropathy is completely different from that of idiopathic nephropathy. Indeed, kidney damage usually subsides when the drug is discontinued [I]. However, damage to kidney function can interfere with the pharmacokinetics of antibiotics, reducing renal excretion and creating a dangerous vicious circle. A possible consequence may be the involvement of other organs, such as the organ of hearing, the development of acute renal failure.

In a third of cases in adults, acute renal failure is caused by taking antibacterial drugs. In the absence of systematic epidemiological data on the occurrence of AKI in newborns, the incidence has increased by 8 times over the past 10 years in both newborns and children of all ages. The role of antibiotics in causing nephrotoxicity remains unclear, as antibiotics are given to neonates who are often seriously ill, who have hemodynamic and/or electrolyte disturbances, which are concomitant factors in the occurrence of renal disorders.

Antibacterial drugs are quite often used in the neonatal period. In very low birth weight newborns, the use of antibiotics is very common, up to 98.8% of newborns, and this group of patients may be exceptionally prone to developing kidney damage. Thus, neonatal age may be a risk factor for the development of antibiotic-induced nephrotoxicity, and it becomes more important the greater the degree of prematurity. Many researchers argue that kidney damage caused by taking antibacterial drugs (especially aminoglycosides or glycopeptides) is less common and less severe in newborns than in adults.

Currently, there are three generally accepted hypotheses: (1) the ratio of "renal volume to body volume" is higher in newborns; (2) neonates achieve less antibiotic uptake by the proximal tubules due to incomplete tubular maturation; (3) immature kidneys are less sensitive to the toxic agent. It is important to emphasize that dose adjustment should always be performed in patients with impaired renal function before antibiotic accumulation can lead to an increase in renal and extrarenal side effects.

Definition and evaluation of nephrotoxicity

The definition of nephrotoxicity is well established for aminoglycosides and can be used for other antibiotics. Aminoglycoside-induced nephrotoxicity was initially defined clinically as an increase in serum creatinine greater than 20% from baseline. Later, nephrotoxicity was defined in more detail: an increase in serum creatinine by >44.2 micromol/L (0.5 mg/dL) in patients with baseline creatinine<265 {микромоль/л (3 мг/дл), и увеличение уровня сывороточного креатинина на >88 micromol/l in patients with baseline creatinine levels >265 micromol/l (3 mg/dl) was regarded as an indicator of the nephrotoxic effect of the prescribed drug.

However, traditional laboratory parameters of nephrotoxicity, such as serum creatinine, urea nitrogen, and urinalysis, were abnormal only in the presence of significant kidney injury. Recently, a new indicator of cystatin C has been isolated in newborns, which is a marker of glomerular function during the period of the absence of an increase in creatinine. Biomarkers of nephrotoxicity in urine (microglobulins, proteins and growth factors) are used in neonatology for early non-invasive identification of renal tubular damage that occurs when antibiotic therapy is used. Moreover, they help in determining the degree of damage and monitoring transit time.

Functional damage to the tubules. Urinary microglobulins, (beta 2-microglobulin, alpha 1-microglobulin and retinol-binding protein are low molecular weight proteins (<33000 D), фильтруются клубочками и практически полностью, реабсорбируются и катаболизируются на уровне клеток проксимальных канальцев . Поэтому в норме только небольшое количество микроглобулинов определяется в моче. В случае нарушения функции канальцев снижается количество реабсорбируемых микроглобулинов и повышается уровень микроглобулинов в моче. Данные параметры были измерены также в амниотической жидкости и моче плода для определения функции почечных канальцев у плода . Измерение альфа 1 микроглобулина предпочтительнее измерения бета 2 -микроглобулина ввиду того, что измерение вышеуказанного не учитывает наличия внепочечных факторов и/или кислого рН мочи .

Structural damage to the tubules. Structural lesions are diagnosed by measuring urinary enzyme levels, proximal (such as adenosine deaminase binding protein) and distal tubular antigens, and phospholipids (total and phosphatidylinositol).

The most important enzymes are N-acetyl-beta-D-glucosaminidase (EC: 3.2.1.30), present in lysosomes, and alanine aminopeptidase (EC: 3.4.11.2), found in the brush border of tubular cells. Due to their large molecular weight (136,000 and 240,000 D, respectively), they are not filtered by the glomeruli. In the presence of intact glomerular function, high levels of alanine aminopeptidase and activity of H-acetyl-beta-D-glucosaminidase in the urine appear only with damage to the renal parenchyma.

Elimination of renal failure. The elimination of renal failure is carried out by growth factors, which are polypeptides or proteins that regulate the main points of cell proliferation through autocrine and / or paracrine mechanisms. Of particular importance is the epidermal growth factor (molecular weight - 6045 D), produced by the cells of the loop of Henle and the distal tubules. Urinary epidermal growth factor levels decrease in acute or chronic renal failure, and their increase after kidney injury is predictive of the level and degree of recovery of kidney function. Other important factors are insulin-like growth factor (IGF)-1 and IGF-2, transforming growth factor (TGF)-alpha and TGF-beta, and Tam-Horsfall protein.

Aminoglycosides

Aminoglycosides still continue to be used despite their low therapeutic index. In neonatology, the combination of ampicillin plus an aminoglycoside is currently proposed as the first choice therapy for empiric treatment at the onset of a bacterial infection, and a large number of neonates are receiving aminoglycoside therapy. For example, approximately 85% of all newborns received the antibiotic netilmicin.

Approximately 50% of cases of acute renal failure that occurred in the hospital while taking medications in patients of all ages account for the use of aminoglycosides. 6-26% of patients developed acute renal failure while taking gentamicin. In the structure of acute renal failure that occurred when taking antibiotics, 80% accounted for insufficiency that occurred when taking aminoglycosides (60% when treated with one drug and 20% when combined with cephalosporins).

Glomerular injury during aminoglycoside therapy has occurred in 3–10% of adult patients (and up to 70% in high-risk patients) and in 0–10% of neonates [1]. Tubular injury has been observed in 50-100% of both adults and neonates treated with aminoglycosides despite individual therapeutic drug monitoring. And urinary levels of M-acetyl-beta-D-glucosaminidase increased up to 20 times their baseline levels in adults and up to 10 times in newborns.

Aminoglycosides are almost completely excreted by glomerular filtration. In the cells of the proximal tubules, aminoglycosides interact with the brush border, which causes a violation of the normal reabsorption of proteins in the tubules. Specifically, aminoglycosides bind to glycoprotein 330, a receptor on proximal tubular cells that mediates aminoglycoside cellular uptake and toxicity. Clinically, aminoglycoside-induced nephrotoxicity is characterized by an asymptomatic rise in serum creatinine that occurs after 5-10 days of treatment and returns to normal within a few days of discontinuation of therapy. Patients usually do not show oliguria, although more severe disorders may be less common, especially when there is concomitant kidney injury. The appearance of low molecular weight proteins and enzymes in the urine is a finding that may anticipate an increase in serum creatinine. In particular, an increase in the level of proteins in the urine is the first detectable indicator in the development of renal failure caused by the action of aminoglycosides.

In proximal tubular cells, aminoglycosides accumulate in lysosomes, where they bind to phospholipids. Lysosomal phospholipids are released when the lysosome breaks, mitochondrial respiration is disturbed, protein synthesis by the endoplasmic reticulum is disrupted, and the sodium-potassium pump is inhibited. Subsequent structural damage can lead to cell necrosis, which can be seen with light (accumulation of multilayer membrane structures: myeloid bodies) or electron microscopy.

Aminoglycosides also inhibit cell repair processes in case of damage. A decrease in epidermal growth factor levels has been found in newborns receiving tobramycin in the absence of therapeutic drug monitoring of the drug.

It has been hypothesized that the neonatal kidney has a low susceptibility to the development of aminoglycoside-induced nephrotoxicity. However, the transplacental effects of gentamicin on cells of the proximal tubules of the kidney in rats to which gentamicin was administered intrauterine (20% decrease in the final number of nephrons, delayed maturation of the filtration barrier in the glomeruli and proteinuria) indicate that caution is required in prescribing aminoglycosides to which immature children are exposed. kidneys, especially in the first days of life.

Risk factors associated with aminoglycosides.

degree of toxicity. Aminoglycosides can be classified in the following order according to their tendency to have a toxic effect on the glomeruli: gentamicin > tobramycin > amikacin > netilmicin. High tolerability of netilmicin by the adult renal tubules has also been observed in neonates when the degree of structural damage to the kidney was measured by urinary protein levels, but not when urinary phospholipids were used as an indicator. However, none of the aminoglycosides has been found to be less nephrotoxic than the others.

Dosing regimens. Although aminoglycosides are usually given daily in two or three doses, a series of data suggest that once-daily use at a higher dosage provides benefits in terms of efficacy, safety for the body as a whole, and separately for the kidneys. Experimentally, aminoglycoside administration regimens (continuous or intermittent infusion) affect the kinetics of aminoglycoside accumulation despite their nephrotoxicity. Gentamicin and netilmicin can accumulate in the kidneys. The accumulation of gentamicin and netilmicin in the renal medulla is significantly lower if the dose of the drug is given at long intervals, preferably once a day. Prins et al. in a population study of 1250 patients showed that there was a 5-fold difference in gentamicin nephrotoxicity between once and three times a day regimens (5% of patients received the entire dose in one dose per day and 24% patients several times a day). In another 12 studies in 1250 patients treated with various aminoglycosides, no statistically significant difference was observed, although a trend towards a decrease in nephrotoxicity appeared with the administration of the drug once a day.

Tobramycin, in contrast, does not accumulate in the kidneys. The kinetics of accumulation of amikacin in the kidneys is mixed, accumulating at low serum concentrations, and not accumulating at high, which is confirmed by clinical studies. In contrast, in 105 term and preterm infants in the first 3 months of life who received gentamicin by continuous or intermittent infusion, when taking the same daily dose, no significant differences were found in terms of fermenturia (alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase) . Moreover, no significant differences were found for urinary excretion of alanine aminopeptidase in 20 full-term infants (in the first 3 months of life) receiving the same dose of aminoglycoside twice or once a day.

In adults, the results of a recent series of meta-analyses comparing the once-daily regimen with the multiple-daily regimen showed that the former regimen was also effective and potentially less toxic than the latter. In contrast, the results of a recent review of once-daily aminoglycoside regimens in adults found that this regimen was not found to be more effective or less toxic. According to the authors of this review, the importance of once-daily administration of aminoglycosides in reducing the toxic effects of these drugs in the neonatal period requires further study.

High residual and peak concentrations. Currently, the issue of the possibility of reducing nephrotoxicity with the help of therapeutic drug monitoring is being discussed. The occurrence of elevated serum residual concentrations over an extended period (achieved with a multiple-daily regimen) is more likely to cause nephrotoxicity (and ototoxicity) than the occurrence of transient, high peak levels achieved following a once-daily regimen. Although high peak and trough concentrations seem to correlate with toxicity, they may still be weak predictors of nephrotoxicity in many patients. Many researchers attribute nephrotoxicity to high residual concentrations (measured immediately after taking the previous dose of aminoglycoside).

prolonged therapy. In adult studies, the incidence of aminoglycoside-induced nephrotoxicity can range from as low as 2-4% to as high as approximately 55% of patients, according to the duration of treatment. An increase in the risk of nephrotoxicity was noted with an increase in the duration of treatment (more than 10 days).

Risk factors associated with comorbidities

Clinical conditions most commonly seen in neonates may exacerbate aminoglycoside-induced nephrotoxicity. Neonatal hypoxia causes renal distress in 50% of newborns. In newborns with asphyxia, the level of retinol-binding protein in the urine is an indicator that anticipates the development of acute renal failure. Studies with beta 2 -microglobulin demonstrate that neonatal anoxia and the use of aminoglycosides have a mutually potentiating effect.

Respiratory distress syndrome and mechanical ventilation have a well-known negative effect on the kidneys. These effects are enhanced by the use of aminoglycosides. In newborns with hyperbilirubinemia, bilirubin and its photoderivatives, as well as the use of aminoglycosides, lead to an increase in the damaging effect on the kidneys (focusing on fermenturia). These damaging effects are expected as a result of the influence of each factor separately, probably by affecting the target cells themselves (oxidative phosphorylation).

Gram-negative sepsis is associated with aminoglycoside-induced renal injury, especially in the setting of renal hypoperfusion, fever, and endotoxemia.

Electrolyte abnormalities (hypercalcemia or potassium and magnesium depletion) in neonates may pose an additional risk for aminoglycoside-induced nephrotoxicity. On the other hand, aminoglycoside therapy in preterm infants can start a vicious cycle, provoking an increase in the excretion of sodium and magnesium.

It remains unclear whether underlying renal failure actually predisposes to aminoglycoside-induced nephrotoxicity or simply makes it easier to identify. The above hypothesis has not been confirmed.

Pharmacological risk factors

The nephrotoxicity resulting from the combined use of aminoglycosides and cephalosporins has been widely reported in the literature, but no definite conclusion has been reached.

The use of indomethacin could increase aminoglycoside-induced nephrotoxicity in two ways: (1) by increasing both peak and trough aminoglycoside concentrations, (2) by blocking urinary prostaglandin E2 synthesis, and (3) by blocking a vasodilator that is normally produced by development of aminoglycoside-induced nephrotoxicity. In rats treated with aminoglycosides, the level of M-acetyl-beta-D-glucose deaminase in the urine was inversely proportional to the level of PGE 2 in the urine.

Furosemide, the most commonly used diuretic in the neonatal period, exacerbates aminoglycoside-induced nephrotoxicity, especially in cases of BCC depletion. Other nephrotoxins are amphotericin and radiocontrast agents. Both groups should be avoided during treatment with aminoglycosides.

In discussing this issue, the rationale for the use of aminoglycosides must first be considered. For example, the low nephrotoxic potential of third-generation cephalosporins and aztreonam is a significant argument for a wider use of these drugs than, for example, aminoglycosides in most children with serious infections. In particular, the use of aminoglycosides should be avoided in patients with a potential risk of developing factors such as hypovolemia, decreased renal perfusion, impaired renal function. From a practical point of view, in the presence of high urinary excretion of N-acetyl-beta-D-glucose deaminase before treatment (greater than 99°: >2 U/day in the first 2 weeks of life), alternative antibiotic therapy for empiric treatment of the infection may be required. Likewise, the marked increase in N-acetyl-beta-D-glucose deaminase during treatment suggests that aminoglycoside therapy should be continued with caution.

If it was decided to carry out therapy with aminoglycosides, then less nephrotoxic substances (netilmicin, amikacin) should be used.

In each case, the empiric starting dosage should be: 2.5 mg/kg every 12 hours for gentamicin, tobramycin, and netilmicin at 1 week of age, then every 8 hours or every 18 hours for very low birth weight infants for the entire first month life and 7.5 mg/kg every 12 hours when using amikadin at 1 week of life (or at very low birth weight), then 7.5 to 10 mg/kg every 8 to 12 hours thereafter.

It is necessary to conduct therapeutic drug monitoring: peak and residual concentrations should be measured after the administration of the 5th dose of the aminoglycoside if the drug is used twice a day.

Every second day of treatment, determination of plasma creatinine and electrolytes is mandatory, and electrolyte disturbances must be corrected. If plasma creatinine rises to >44.2 mmol/l (0.5 mg/dl), aminoglycoside therapy should be discontinued, even if the concentration is subtoxic and no other source of renal damage is found. If the toxic residual concentration has been reached, it is necessary to adjust the dose and / or dose interval of administration.

Glycopeptides

Currently, the use of glycopeptides, especially vancomycin, in newborns is very widespread. In fact, vancomycin is currently the antibiotic of choice for the treatment of severe staph infection. Moreover, the combination of vancomycin and ceftazidime may be recommended for the empiric treatment of neonatal late sepsis, especially in neonatal intensive care units where there is significant methicillin resistance in coagulase-negative staphylococci. In some neonatal intensive care units, resistance to methicillin can be as high as 70%. However, the use of vancomycin is very often accompanied by the appearance of anaphylactoid reactions and toxic effects on the organ of hearing and kidneys. The use of teicoplanin implies advantages in the regimen of the drug and is associated with fewer side effects.

Vancomycin. Currently, there is no complete understanding of the mechanism of vancomycin nephrotoxicity. However, a large number of experimental and clinical studies have highlighted some aspects of this problem:

The accumulation of vancomycin in the lysosomes of proximal tubular cells is not similar to that of aminoglycosides;

Aminoglycosides are associated with more nephrotoxicity than glycopeptides. Tobramycin was found to be significantly more toxic than vancomycin, and the combination of the two drugs was much more toxic than the single drug. The same results were obtained for vancomycin and gentamicin;

Toxicity, which occurs some time after vancomycin administration, is assessed by the state of the brush border and lysosomal enzymes. Moreover, morning doses of the drug are associated with fewer side effects than evening ones;

From a pharmacodynamic point of view, the nephrotoxicity of vancomycin is associated with the combined effect of a large area under the concentration-time curve and duration of therapy;

In most cases, vancomycin-associated nephrotoxicity is reversible even after high doses of the drug;

The main mechanism of vancomycin nephrotoxicity involves two distinct processes: (1) energy-dependent tubular transport of glycopeptides from the blood to tubular cells across the basolateral (basal) membrane, as happens with the saturation of some aminoglycosides by this transport, which occurs at a certain concentration; (2) tubular reabsorption, although this mechanism is likely involved. However, it does not appear to be so strongly associated with the occurrence of nephrotoxicity.

The results of clinical studies published on the nephrotoxicity of vancomycin are conflicting. In fact, the results of these studies vary considerably depending on the following factors: observation period, treated population, dosage regimen used, duration of therapy, determination of nephrotoxicity, sensitivity of methods used to determine kidney injury, type of infection treated, and the presence of concomitant diseases and / or drugs.

Nephrotoxicity with vancomycin treatment is rated as moderate and occurs in less than 5% of patients in all age groups; however, some studies suggest a greater frequency when co-administered with aminoglycosides. The more highly purified the drug, the less common side effects. The incidence of glomerular toxicity in 460 adult patients treated with vancomycin as single drug therapy was 8.2%. On the contrary, the values of the main biomarkers in urine remained stable in healthy volunteers who received vancomycin for 3 days.

Although the topic is controversial, neonatal kidneys are generally less sensitive to vancomycin toxicity than adult kidneys, as evidenced by a large number of experimental observations. The immaturity of proximal tubular cells may account for lower vancomycin uptake compared to other pediatric ages. The incidence of nephrotoxicity was 11% in children treated with vancomycin alone. In another study, neonates and young children treated with vancomycin were found to be well tolerated with no abnormalities in renal function tests. However, BUN and serum creatinine levels should be measured 2 or 3 times per week or weekly in newborns receiving vancomycin therapy.

Risk factors associated with vancomycin. There is still controversy about the need for therapeutic monitoring of vancomycin. While the pharmacokinetics of vancomycin are highly variable in neonates, therapeutic monitoring of the drug is strongly recommended to maintain adequate concentrations and to avoid side effects. The situation remains unclear because in different studies, the time of sampling after infusion varies from 15 minutes to 3 hours or more. Plasma concentrations should be measured 30 minutes before and 30 minutes after the infusion, especially after the third dose of vancomycin. There is also no consensus on how often such determinations should be repeated: it depends on the presence of various risk factors.

High residual values. Residual vancomycin concentrations greater than 10 mg/l are associated with a 7.9-fold increase in the risk of nephrotoxicity. Moreover, high residual concentrations of the drug may indicate an abnormal pharmacodynamic profile with an increased risk of both nephrotoxicity and ototoxicity. If therapeutic drug monitoring is not practicable, the suggested dosage should be calculated at 1 week of age based on gestational age and renal function after 1 week of age. The table provides guidelines for dosing vancomycin.

78% of patients treated according to these guidelines had optimal and peak and residual concentrations of vancomycin. Taking the drug by continuous infusion is also rated as well tolerated by the kidneys.

High residual concentrations. There is no confirmed evidence that transient high residual concentrations (>40 mg/l) are associated with the occurrence of toxicity. Therefore, some authors believe that continuous monitoring of the medicinal product can ensure that all the necessary information is available.

prolonged therapy. Patients who received treatment for more than 3 weeks and, accordingly, received a large total dose, were more at risk of developing nephrotoxicity. In the neonatal period, therapy is extremely rarely prolonged for more than 2 weeks.

Table

Dosing of vancomycin in neonates

Risk factors associated with comorbidity, High baseline serum creatinine and the presence of liver disease, neutropenia, and peritonitis are considered significant risk factors for the development of nephrotoxicity.

Pharmacological risk factors. When vancomycin is combined with other nephrotoxic drugs such as aminoglycosides, amphotericin or furosemide, the risk of nephrotoxicity can be very high, with an incidence of up to 43%. The combination of an aminoglycoside with vancomycin is thought to increase the risk of nephrotoxicity by a factor of 7; in pediatric patients, the incidence of nephrotoxicity was 22%. In contrast, careful therapeutic monitoring of both glycopeptide and aminoglycoside minimized nephrotoxicity in 60 children and 30 neonates. Moreover, vancomycin has not been found to potentiate amikacin-induced tubular nephrotoxicity in children with leukemia, fever, and neutropenia. However, the aminoglycoside plus vancomycin combination should be used with caution in alternative combinations where therapeutic monitoring of both drugs is not feasible and in very low birth weight neonates.

The use of indomethacin in combination with vancomycin was associated with a twofold increase in the half-life of the glycopeptide. Similar results have been described in patients treated with vancomycin and extracorporeal membrane oxygenation.

Teicoplanin. In a meta-analysis of 11 comparative studies in adults, the overall incidence of side effects was significantly lower in those patients who received teicoplanin rather than vancomycin (14 vs. 22%). Moreover, teicoplanin nephrotoxicity was less common (4.8%) when given in combination with any aminoglycoside than when vancomycin was combined with an aminoglycoside (10.7%).

In a large population-based study of 3377 hospitalized adults treated with teicoplanin, the incidence of nephrotoxicity (in this case, defined as a transient increase in serum creatinine) was 0.6%. In pediatric patients, the incidence of nephrotoxicity was found to be similar or lower.

Results and reviews of 7 studies have been published on this issue in newborns, and none of the 187 study participants who received teicoplanin experienced a transient increase in serum creatinine. Study participants received a dose of 8-10 mg/kg following a loading regimen of 15-20 mg/kg/day. In the same group of patients, two studies compared the incidence of nephrotoxicity between vancomycin and teicoplanin. In the first study, which included 63 neutropenic children, no increase in serum creatinine was observed in 11.4% of patients treated with vancomycin and 3.6% of patients treated with teicoplanin, respectively. In the second study, which included 36 very low birth weight infants (21 received teicoplanin, 15 vancomycin), a significant difference was described between the mean serum creatinine levels in the teicoplanin and vancomycin groups (60.5 and 84.4 cmol/l, respectively) ; however, both values were within the normal range.

Good general and renal safety has been demonstrated for teicoplanin in preterm infants with late staphylococcal sepsis and when the drug has been used prophylactically in very low birth weight neonates. Teicoplanin has been shown to be well tolerated by the kidneys even when the dose is exceeded in neonates; the values of serum creatinine, cystatin C, urea nitrogen and biomarkers in urine remained constantly within the normal range.

Cephalosporins

Cephalosporins and other third-generation antibiotics are very commonly used in neonatal emergency care. Low nephrotoxicity is the main argument for their more frequent use, instead of aminoglycosides, in children with severe infectious diseases. The combination ampicillin + cefotaxime is used as a substitute for ampicillin + gentamicin as the therapy of choice in neonatal sepsis and meningitis, especially when therapeutic drug monitoring is not possible.

The nephrotoxicity of cephalosporins, which has been extensively studied, depends mainly on two factors:

1) intracortical concentration of the drug and

2) internal reactivation of the drug.

intracortical concentration. The importance of the transport of organic acids is absolutely confirmed. In fact, the nephrotoxicity caused by cephalosporins (mainly (3-lactams) is limited to components transported outside this system. Moreover, the prevention of nephrotoxicity is possible by inhibiting or suppressing this transport. Ultimately, increasing the intracellular uptake of cephalosporins increases toxicity.

internal reactivity. The intrinsic reactivity of cephalosporins is divided into three levels according to its potential negative interaction with cellular targets: lipid peroxidation, acetylation and inactivation of cellular proteins, and competitive inhibition of mitochondrial respiration. Lipid peroxidation plays a major role in the pathogenesis of cephaloridine-induced damage. Competitive inhibition of mitochondrial respiration may be a common pathological pathway in the expansion of damage in the case of combined therapy with aminoglycosides with cephalosporins. Cephaloridine and cephaloglycine at therapeutic doses are the only cephalosporins that can cause damage in a child's body at the level of mitochondrial destruction.

According to the decreasing degree of nephrotoxicity for cephalosporins, the distribution is as follows: cephaloglycine > cephaloridine > cefaclor > cefazolin > cephalothin > cephalexin > ceftazidime. Cephalexin and ceftazidime are associated with very little nephrotoxicity compared to other agents. Ceftazidime is considered to be minimally toxic in the development of renal damage when administered at an adequate time.

Third generation cephalosporins. The presence of directed nephrological toxicity (depending on a pronounced increase in blood creatinine levels) associated with the use of third-generation cephalosporins was observed in less than 2% in the observed patients, with the exception of cefaperazone, in which this figure was 5%.

When measuring blood creatinine levels, cephalosporins are able to alter the course of the Jaffe reaction, which is commonly used in laboratory studies of blood and urine creatinine levels.

Cephalotaxime. It is uncommon for cephalotaxime to cause significant renal damage. It does not show an increase in urinary levels of the enzymes alanine-aminopeptidase and N-acetyl-beta-D-glucosaminidase, usually caused by aminoglycosides and furosemide.

Similar results are found with urinary enzyme levels in patients with severe infections or in patients undergoing complex surgery. Cephalotaxime is actively used in pediatrics, well tolerated by newborn patients, even if it is prescribed with netilmicin.

Another interesting characteristic of cephalotaxime is its low sodium content (about 20 and 25% sodium in cefazidime and ceftriaxone, respectively), which is optimal for patients with hypernatremia and/or high fluid content.

Ceftriaxone. Renal tolerance to ceftriaxone was found both in all children (a change in blood creatinine levels was noted in only 3 of 4743 patients treated with ceftriaxone) and in newborns, even in combination with gentamicin. Ceftriaxone is attractive because it is administered once a day. In addition, it may be given to newborns, especially during the 1st week of life and/or low birth weight newborns, for two reasons:

with the release of bilirubin and albumin with diarrhea observed in 24-40% of treated children. It must also be remembered that the sodium content in the preparation is 3.2 mmol. The neonatal dose of imipenem is 20 mg/kg every 12 hours.

Meropenem has been shown to have a lower potential for epileptogenic activity and nephrotoxicity at all ages. However, these data require further confirmation.

Monobactams

Aztreonam is the first of the monobactam class. No evidence of nephrotoxicity has been demonstrated for this drug in adults (2388 patients) or children (665 patients). Based on the results of 5 international studies in 283 treated newborns, only in two cases there was an increase in serum creatinine levels (0.7%), and fermenturia values remained within normal limits even in children with low birth weight. Thus, aztreonam is a reasonable alternative to aminoglycoside therapy in neonates with gram-negative infection to avoid nephro- and ototoxicity, or when therapeutic drug monitoring of aminoglycosides is not possible. At 1 week of life, the following regimen is most appropriate: 30 mg/kg every 12 hours, then the same dose is given every 8 hours.

conclusions

Antibacterial drugs are the leading cause of drug-induced kidney disease in all age groups. The occurrence of damage occurs through two mechanisms, namely toxic and immunological damage. When discussing neonatal nephrotoxicity, toxic damage is primarily taken into account. In general, nephrotoxicity is reversible upon discontinuation of therapy. However, acute renal failure can occur, and the role of drugs in causing kidney damage is increasing, especially in neonates who are in the intensive care unit. Preventing injury will reduce mortality and reduce the length and cost of hospital stays.
In newborns, especially very low birth weight newborns, antibiotic susceptibility can be widespread. Aminoglycosides (in combination with ampicillin) and vancomycin (in combination with ceftazidime) are widely suggested as empiric treatment for early and late onset neonatal infections.
Aminoglycosides are the most nephrotoxic antibiotics and vancomycin may be associated with significant renal toxicity. The above is partly true in high-risk patients. Other antibiotics, such as penicillins, cephalosporins, and monobactams, are less nephrotoxic.

Ways to prevent the occurrence of nephrotoxicity are as follows.

Minimizing the use of proven nephrotoxins. Third-generation cephalosporins (such as cefotaxime) or monobactams (such as aztreonam) may be used instead of aminoglycosides for empiric treatment of early-onset infections in patients at high risk or when therapeutic drug monitoring of aminoglycosides is not possible. In these circumstances, teicoplanin may be an alternative to vancomycin in the treatment of late-onset infections.
Minimization of the nephrotoxic potential of antibiotics can be obtained by correct administration of the drug: namely, by conducting therapeutic drug monitoring and maintaining residual concentrations within the normal range, avoiding unnecessary duration of treatment and, if possible, the administration of concomitant nephrotoxins.
Early detection of nephrotoxicity, especially acute renal failure, followed by rapid withdrawal of the damaging agent. Increased urinary excretion of low molecular weight proteins and enzymes may precede an increase in serum creatinine levels. In particular, a rapid and marked increase (>99° percentile) in urinary N-acetyl-beta-D-glucosaminidase may indicate the need for re-evaluation or even discontinuation of therapy.

Thus, in view of the extremely widespread use of antibiotics in neonatology and the many potentially nephrotoxic factors in neonates, knowledge of the points covered in this article is especially important to prevent iatrogenic effects.

Abstract

Antibacterial drugs are a common reason of drug induced nephrotoxity. The mostly nephrotoxic antibiotics are aminoglycosides and vancomycin. The rest of antibacterial drugs, such as b-lactams, are less toxic to the kidney. There are several ways to overcome drug induced nephrotoxity:

1. Minimization of usage medicines with certanately proven naphrotoxic properties.

2. Rational usage of antibacterial drugs could minimize potential kidney damage.

3. Nephrotoxity disclosure in the early treatment stages, particular acute renal insufficienc allowes terminate actual treatment scheme.

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Many of the clinically important substances that can cause kidney toxicity. Most of them have a direct toxic effect on cells in a known or unknown way. Others may damage the kidneys in an indirect way, often not obvious from what we know about the substance. The nephrotoxic effect of many substances is associated with the formation of methemoglobin.

If a patient has a kidney disease, one should be especially careful about drugs in the excretion of which the kidneys play a major role from the body. In renal insufficiency, the binding of acidic drugs to proteins is significantly reduced due to the loss of plasma proteins. Association with proteins 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 medicinal substances, their conjugation with glucuronide, sulfates and glycerol, acetylation and hydrolysis.

Only a few nephrotoxins can be considered here in more detail. In hospitals, undoubtedly the main cause of nephrotoxic renal failure (about 25% of all cases of acute insufficiency) is the use of antibiotics primarily aminoglycosides. Streptomycin, kanamycin, neomycin, gentamicin, tobramycin, amikacin and sisomycin are nephrotoxic. They accumulate in the cells of the proximal tubules, cause the formation of cytosegrosomes (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 neoliguric renal failure. Aminoglycosides appear to be synergistic in toxicity with cephaloridine, cephalothin, and methicillin. Due to cumulation, toxicity may occur with a delay or at the beginning of a repeat course of treatment. Polypeptides such as polymyxin have direct and predictable nephrotoxic effects, as do bacitracin and the fungicide amphotericin B. Expired tetracyclines 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 may be suggested by fever, eosinophilia, eosinophiluria, elevated IgE, and positive gallium radioisotope imaging of the kidneys; a renal biopsy is used to confirm the diagnosis.

All radiopaque agents to some extent nephrotoxic, especially when administered intra-arterially. Predisposing risk factors (in addition to frequent use of these substances) include tissue hypoperfusion, decreased extracellular fluid volume, renal insufficiency, age over 60 years, solitary kidney, diabetes, myeloma, hyperuricemia, and heart failure.

Nephropathy associated with taking analgesics, is responsible for approximately 2% of end-stage renal disease in the US and 20% or more in Australia and South Africa. In general, virtually all peripherally acting anti-inflammatory analgesics are potentially nephrotoxic, while most central analgesics are not. Salicylates have a direct nephrotoxic effect and act as synergists in mixed analgesic nephropathies. It is difficult to assess how widely they are used in normal practice.

Almost all non-steroidal anti-inflammatory analgesics(they are inhibitors of prostaglandin synthetase of varying efficacy) can cause damage to the tubular epithelium, hypoperfusion, papillary necrosis and chronic TIN. Many of them are now readily available.

Most heavy metals accumulates in the proximal nephrons due to their transport or the presence of binding sites, such as sulfhydryl (SH) groups. The toxic effect of lead is observed during food perversions, industrial exposure, the use of contaminated water, wine or other alcoholic beverages, in mining enterprises, by inhalation of smoke or combustion products of gasoline with lead additives. Tetraethyl lead penetrates through intact skin and lungs.

Manifestations chronic lead poisoning include shriveled kidneys, uremia, hypertension, basophilic granular anemia, encephalopathy, peripheral neuropathy, and Fanconi syndrome. With more acute poisoning, spastic pains in the abdomen (lead colic) are possible. The incidence of toxic kidney injury due to mercury, bismuth, and thallium appears to be declining now, 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.

Solvent nephrotoxicity manifests itself mainly with the inhalation of hydrocarbons (Goodpasture's syndrome), the action of methanol, glycols and halogenated compounds, such as carbon tetrachloride and trichlorethylene. The participation of halogen-containing anesthetics (eg, methoxyflurane) is also expected.

Drugs that cause immunocomplex kidney damage, proteinuria, and many of the features of nephrotic syndrome include penicillamine, captopril, levamisole, and parenterally administered gold salts in the treatment of rheumatoid arthritis.

Ed. N. Alipov

"Causes of toxic nephropathy" - an article from the section

These medicines are essential and can even save lives. But it has also been proven that such medicines directly affect the activity of the kidneys.
Our kidneys perform the function of filtering the blood. This means that any toxins in the body must enter the kidneys, where they are transformed and excreted in the urine. All the blood in the body is cleansed several times a day by these two small organs.

Kidney disease is so difficult to detect that even if you lose up to 90% of your kidney function, you may not experience any symptoms!
Medicines that can seriously damage the kidneys are known as nephrotoxic drugs. These drugs are poisonous and cause kidney dysfunction in 25% of cases. For people with even mild renal insufficiency, this is a reason to seriously think and consult a doctor before taking these medicines.
This list includes the usual antibiotics and analgesics that everyone takes.
Antibiotics such as "Ciprofloxacin", "Methicillin", "Vancomycin", sulfonamides. Kidney dysfunction due to antibiotics is characterized by intense thirst, an increase or decrease in the amount of urine excreted, pain in the lumbar region, an increase in the level of creatinine and urea in the blood.

Analgesics, including "Acetaminophen" and non-steroidal anti-inflammatory drugs (NSAIDs): "Ibuprofen", "Naproxen", "Paracetamol", "Aspirin". They reduce blood flow to the kidneys, increasing the risk of kidney damage, up to kidney failure. Analgesics should be taken only when absolutely necessary and in as small doses as possible.
Selective COX-2 inhibitors, including Celecoxib, Meloxicam, Nimesulide, Nabumeton and Etodolac. When taking these drugs, kidney damage is possible: reversible renal failure with increased creatinine levels, tubular necrosis, acute interstitial nephritis, nephrotic syndrome.

Heartburn medications a class of proton pump inhibitors (PPIs) such as omeprazole, lansoprazole, pantoprazole. According to a study at Johns Hopkins University in Baltimore, taking PPI twice a day increased the risk of chronic kidney disease by 46%.

Antivirals, including Acyclovir, Indinavir and Tenofovir. Used to treat viral infections, herpes and HIV infection. These dangerous pills cause chronic kidney failure and increase the risk of kidney disease. In addition, these drugs have been proven to provoke acute tubular necrosis (ATN).
high blood pressure pills, including Captopril, Lisinopril, Ramipril. Angiotensin receptor blockers such as Candesartan and Valsartan. In some cases, they can lead to a decrease in kidney function when first taken, they should be avoided in patients with dehydration.

Medicines for rheumatoid arthritis including Infliximab. The danger is represented by the drugs used to treat malaria and lupus erythematosus - "Chloroquine" and "Hydroxychloroquine". In the case of extensive tissue damage, kidney function is reduced, which leads to the development of chronic renal failure, which is often the cause of death.
Antidepressants, in particular lithium preparations used to treat bipolar disorder. According to a study by the Salerno Medical School, patients taking Amitriptyline, Doxepin, Fluoxetine are at an eightfold risk of developing acute renal failure.

Chemotherapeutic drugs such as Interferon, Pamidronat, Carboplatin, Cisplatin, Quinine. As well as some thyroid medications, such as Propylthiouracil, which are prescribed to treat an overactive thyroid.

Diuretics, or diuretics such as Triamterene cause acute interstitial nephritis and crystalline nephropathy.

Now you know which pills you can not drink so as not to spoil the kidneys. If you see drugs containing the above substances in the list of recommendations, ask your doctor if it is possible to replace them with other, less toxic ones. A real specialist will always treat your request with understanding.
Alcohol drinkers have a high risk of developing both kidney and liver failure. Therefore, enjoy strong drinks in moderation or completely abandon them.