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The kidney is the most important organ for drug metabolism and excretion, and it is also the most vulnerable to drug damage. In recent years, the use of antibiotics has become more and more widespread, some of which are unreasonable use, which has led to the increasing prevalence of antibiotic resistance, increasing dosage, and more serious problems of kidney damage, especially in children and the elderly. .

 

I. Physiological characteristics of the kidney

The kidney is composed of glomeruli, renal tubules, and renal interstitium. The kidney has the following characteristics:

1. Large blood flow: The amount of drug that passes through the kidneys with blood flow is also relatively high, making the kidneys more susceptible to exposure to a large number of drugs, and more likely to produce toxic effects;

2. Abundant microvessels: Capillary endothelial cells have a large contact area with drugs, and the chance of antigen-antibody complex deposition in glomeruli is significantly increased, and autoimmune damage is more likely to occur;

3. The drug concentration of the proximal renal tubule is high: the proximal renal tubule has a drug transport function, and the drug prototype or its metabolite is filtered through the glomerulus to the renal tubule, and the drug concentration in the lumen is significantly increased. Renal tubular epithelial cells can directly damage renal tubular epithelial cells when they are absorbed back;

4. Changes in urine pH affect the solubility of the drug: some drugs form crystals in the renal tubules that directly damage the renal tubular epithelial cells.

 

II. Types and pathogenesis of kidney damage caused by antibacterial drugs

In general, kidney damage caused by drugs mostly damages the tubules and renal interstitium. The main mechanism of antibacterial drugs leading to kidney damage includes two aspects: one is the direct toxicity of antibiotics, and the other is drug-induced immune damage.

In addition, the relationship between antibacterial drugs and the kidneys is also manifested in the fact that after the decline in renal function, certain antibacterial drugs accumulate in the body through the excretion of the kidneys, causing other problems.

1. Direct damage to the kidney by antibacterial drugs

Antibacterial drugs have direct damage to the kidneys, including kidney ischemia, damage to renal tubular epithelial cells, and blockage of the renal tubule lumen. Common in aminoglycosides, amphotericin, sulfonamides and the like.

In patients with normal renal function, most of the antibacterial drugs usually do not cause kidney damage. However, when the patient has significant dehydration, hypotension, kidney damage, or the elderly, the chance of kidney damage is greatly increased. Common high risk factors are:

  1. Elderly patients;
  2. diabetes;
  3. Dehydration, hypotension;
  4. Sodium and calcium are missing;
  5. Acidosis
  6. Using a diuretic at the same time;
  7. Combined with other nephrotoxic drugs such as non-steroidal anti-inflammatory drugs (antipyretics).

2. Immunity or allergy damage caused by antibacterial drugs

Including acute and chronic interstitial nephritis and tubulointerstitial nephritis. Such kidney damage is not a direct toxic damage to the kidneys, but an immune damage similar to allergies, most of which are independent of drug dose. More common in penicillins, cephalosporins, rifampicin.

Some antibacterial drugs, as a kind of hapten, enter the human body and combine with a certain tissue protein to form an antigen, which induces hypersensitivity reaction of the body to cause tubulointerstitial inflammation. When the same drug or similar drug is contacted again, the disease may occur again.

In some patients with acute interstitial nephritis, elevated serum IgE levels, basophilic, eosinophils, and plasma cells containing IgE in renal interstitial infiltrating cells suggest IgE-mediated immediate hypersensitivity allergy Participated in the disease.

The clinical manifestations of such injuries are fever, joint pain, and rash usually occurring 2 weeks after administration. It is characterized by non-oliguric acute renal failure with renal tubular proteinuria, gross hematuria or microscopic hematuria, urinary and peripheral blood. Eosinophilia. Pathological changes were mainly renal interstitial edema, diffuse lymphocytes, monocytes and eosinophil infiltration. Small tube atrophy and interstitial fibrosis may occur in the later stages of the disease. Acute interstitial nephritis caused by drugs generally has a good prognosis, but chronic renal failure can occur if it is not diagnosed or treated in time.

 

III. Mechanism of common antimicrobial drug damage

An antibacterial drug is a drug that kills or inhibits the growth of bacteria. Commonly used antibacterial drugs include: β-lactams, aminoglycosides, macrolides, lincomycins, peptides, quinolones, sulfonamides, antituberculosis drugs, antifungals and other antibiotics. Antibiotics that are prone to kidney damage include:

1. Aminoglycosides:

Commonly used are amikacin, tobramycin, gentamicin, netilmicin, sisomicin and streptomycin. These drugs have strong antibacterial effects, low prices, and a wide range of clinical applications, resulting in a wide range of kidney damage.

Such drugs can cause acute tubular necrosis.

Aminoglycosides are almost 100% excreted from the urine and have toxic effects on the kidneys. Most scholars believe that the nephrotoxicity of aminoglycosides is related to the number of free amino groups contained in them. The more the number of free amino groups, the greater the nephrotoxicity. Streptomycin has only 2 free amino groups with minimal nephrotoxicity; kanamycin, amikacin and gentamicin all have 4 free amino groups, which are more toxic; while neomycin has 6 free amino groups, kidney The toxicity is also the biggest.

At present, neomycin has been banned due to too strong nephrotoxicity; kanamycin can cause kidney damage in normal pediatric dosage for 5 to 7 days; gentamicin is still in use, reportedly 6% to 18% Acute renal failure is caused by gentamicin and should be taken seriously.

In 2012, KDIGO (Promoting Global Kidney Disease Prognostic Organization) “Clinical Guidelines for Acute Kidney Injury” recommends: monitoring blood levels for patients who have been given aminoglycosides for more than 24 hours per day for multiple doses; Blood concentration monitoring was performed in patients with aminoglycosides for more than 48 hours.

2. Antifungal drugs:

Including amphotericin B, fluconazole, itraconazole and 5-fluorocytosine.

The most common nephrotoxicity is amphotericin B. It was observed that more than 80% of patients who used amphotericin B developed renal adverse reactions, such as renal dysfunction, polyuria, hypokalemia, and hypomagnesemia.

Amphotericin B mainly causes the renal damage and glomerular filtration rate to decrease due to the decrease of renal blood flow by contracting the glomerulus into the small arteries and the small arterioles. If the dose is too large or the concentration is too high or the drip rate is too fast, the drug will accumulate in the renal cortex in a short time, and the renal blood perfusion is drastically reduced, which may lead to acute renal failure.

3. Peptides:

Including polymyxin B, polymyxin E, vancomycin, norvancomycin and the like.

Polymyxin B and polymyxin E are mainly excreted from the kidneys, and when the renal function declines, the elimination half-life of the two drugs is significantly prolonged. Kidney toxicity can occur if the systemic dose is too large or too long, especially if the kidney disease is already present. Mainly manifested in proteinuria, tubular urine, hematuria and urea nitrogen rise, timely withdrawal can generally be restored.

80% to 90% of vancomycin is excreted from the kidneys in its original form. The elimination half-life of adults is 5 to 11 hours. When renal failure occurs, the half-life will be extended to more than 7 days. Therefore, patients with renal failure need to increase the interval and monitor the blood concentration. There is no consensus on whether the drug has nephrotoxicity, but renal function should be monitored regularly during the drug administration.

4. β-lactams:

Including penicillins, cephalosporins, new β-lactams and the like.

These drugs generally do not have direct nephrotoxicity, but induce autoimmune damage.

(1) Penicillin:

Including penicillin G, diclofenac, amoxicillin, piperacillin, azlocillin, mezlocillin and the like.

Penicillin stays in the body for a short period of time, and is excreted in the urine through the kidneys. It usually does not accumulate in the body and produces direct nephrotoxicity. Kidney damage caused by penicillin is similar to allergic reactions. Most patients occur 2 to 3 weeks after administration, and can also vary from 1 to 2 months, which is easy to be misdiagnosed.

(2) Cephalosporins:

The first generation: including cefotaxime, cephalexin, cefazolin, cefradine, etc.;

Second generation: including cefuroxime, cefaclor, cefotiam, cefoxitin, etc.;

Third generation: including ceftazidime, cefotaxime, cefoperazone, cefodizime, cefixime, etc.;

The fourth generation: including cefpirome, cefepime, ceftizox and the like.

Novel β-lactams include imipenem, panipenem, meropenem, aztreonam and the like.

The first-generation cephalosporins had the highest nephrotoxicity, and cefradine was reported several times by the National Center for Adverse Drug Reaction Monitoring because it often caused hematuria. The second generation and above cephalosporin nephrotoxicity was significantly reduced.

5. Sulfonamides:

Including compound sulfamethoxazole and so on.

The acetylated metabolites of sulfa drugs are prone to crystallize in the renal tubules and block the renal tubules, leading to tubular necrosis. It often occurs in the case of insufficient blood volume, original kidney disease, drug overdose or specific urine pH.

Sulfonamide antibiotics have been kicked out of the market due to their nephrotoxicity (less clinical applications).

6. Quinolones:

Including norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, fleroxacin, elofloxacin, lomefloxacin, sparfloxacin, gresable, trovafloxacin and the like.

A small amount of quinolones are excreted in the liver through the feces, and most of them are mainly excreted in the kidneys. Such drugs can be crystallized in the renal tubules, especially in alkaline urine.

7. Anti-tuberculosis drugs:

Commonly used are isoniazid, rifampicin, pyrazinamide, ethambutol.

Rifampicin has been reported to cause acute renal failure, and the mechanism of occurrence is allergic reaction (allergic reaction), regardless of dose.

A survey found that acute kidney damage occurred after the use of different antibacterial drugs in an infected ward. The highest incidence was amphotericin B, and 10 of 13 patients developed acute kidney injury. Other occurrences of more than 10% are: gentamicin, amikacin, ceftriaxone + gentamicin, cefazolin + gentamicin, vancomycin + ceftriaxone, vancomycin + A Mikacin, cloxacillin + gentamicin, ceftazidime + amikacin, amphotericin B + ceftriaxone, amphotericin B + vancomycin ± ceftriaxone.

The study concluded that in the infective ward, aminoglycosides, vancomycin, amphotericin B, or a combination of the above drugs had a higher rate of acute kidney injury; combined with diabetes, hypertension, and long-term use Other common kidney damage drugs (such as non-steroidal anti-inflammatory drugs, ACEI antihypertensive drugs or diuretics) are also a high risk factor for acute kidney injury in infected wards.

Bacterial infections should be treated aggressively, but the safety of the drug should also be considered. No antibiotic is absolutely safe for the kidneys. Therefore, for the treatment of bacterial infections, we must strictly grasp the indications and contraindications of medication, strictly follow the standard medication, and try to avoid the occurrence of harm while obtaining the curative effect.

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