Antibacterial drug-induced toxic nephropathy

　　The occurrence of toxic nephropathy due to antibacterial drugs may be related to the following factors:

　　One, antibacterial drugs with kidney toxicity:For example, amphotericin B, neomycin, cephalosporin II, etc., have direct nephrotoxic effects, while penicillin G, cephalosporins (IV, VI), etc., can cause kidney damage due to allergies.

　　Two, age and renal function status:In elderly patients and those with pre-existing kidney disease, the incidence and severity of nephrotoxicity are significantly higher.

　　Three, changes in effective blood volume and renal blood flow:When blood volume decreases and leads to a decrease in renal blood flow, the nephrotoxicity of antibiotics is more likely to occur.

　　Fourthly, the degree of infectious disease and electrolyte disturbance:When the patient's infection is severe, even if toxic shock occurs or electrolyte disorders are present, the nephrotoxicity of antibiotics increases.

　　Fifthly, the patient's liver function status:Some antibiotics can be detoxified in the liver and then excreted by the kidneys. When liver function deteriorates, the kidneys bear a heavier burden, leading to nephrotoxic effects.

　　There are many types of antibiotics that are commonly associated with acute allergic interstitial nephritis in clinical practice, among which beta-lactam antibiotics are the most prominent. Antibiotics that commonly cause ATN include the following categories:

　　Firstly, aminoglycoside antibiotics:These antibiotics have significant nephrotoxicity and are most likely to cause ATN, including kanamycin, gentamicin, amikacin, tobramycin, neomycin, and streptomycin.

　　Secondly, beta-lactam antibiotics:Penicillins have no significant nephrotoxicity and do not cause ATN. The first generation cephalosporins have varying degrees of nephrotoxicity, with ceftriaxone being the most significant, followed by cefalotin and cefazolin.

　　Thirdly, sulfonamide drugs:Sulfonamides such as sulfathiazole and sulfadiazine can cause: 1. Nephrolithiasis, which is more likely to occur in oliguria or when urine pH is less than 5.5. The crystalline deposits blocking the renal tubules can lead to ATN. 2. Hemoglobinuria: It can cause intravascular hemolysis in children with G6PD deficiency, leading to hemoglobinuria.

　　Fourthly, other antibiotics:For example, amphotericin B, polymyxin, vancomycin, and others also have significant nephrotoxicity, which can cause ATN.

　　Toxic nephropathy caused by antimicrobial drugs can complicate with hearing loss, tinnitus, ataxia, and some patients may progress to permanent renal failure. Severe acute renal failure can present with typical symptoms of acute renal failure, seen in toxic nephropathy caused by aminoglycoside antibiotics and inorganic mercury. Acute allergic interstitial nephritis can present with systemic allergic manifestations such as fever, rash, lymphadenopathy, and joint pain. It can also manifest as nephrotic syndrome. Severe cases may present with acute renal failure, seen in various drugs, especially in the penicillin group, sulfonamides, antituberculosis drugs, and other toxic drugs. Chronic renal failure has clinical manifestations similar to those caused by other toxic nephropathy, and sometimes renal function may continue to deteriorate slowly even after stopping exposure to the toxic substance, seen in chronic lead poisoning nephropathy.

　　The clinical manifestations of toxic nephropathy caused by antimicrobial drugs are diverse and non-specific; they can occur at any age, with normal urine volume and blood pressure, and the presence of negligible or small amounts of proteinuria. Without high vigilance, it is easy to miss the diagnosis. Patients often have systemic allergic reactions, which are unrelated to the dose of the drug. Specific manifestations are as follows:

　　Firstly, fever:Early stages of acute allergic interstitial nephritis usually present with fever, generally occurring 3 to 5 days after medication, with reports indicating that 87% to 100% of patients have fever. Recently, it has been reported that fever usually occurs in 50% to 64.3% of patients, and typically appears after the second peak of body temperature following the application of antibiotics and control of infection.

　　Secondly, drug eruptions:About 25% to 50% of patients develop drug eruptions after taking the medication, which are polymorphic, presenting as itchy papules or erythema multiforme or desquamating skin rash.

　　3. Joint pain:Highly allergic individuals may also have allergic arthritis, joint pain, lumbar pain, lymphadenopathy, or liver function damage (elevated ALT, AST) and so on. Patients may also feel bilateral or unilateral lumbar pain due to renal interstitial edema and kidney enlargement, which may stretch the renal capsule.

　　4. Hematuria:Hematuria is often the first clinical manifestation of the disease, accounting for about 95%, and gross hematuria accounts for 1/3, and proteinuria or even nephrotic syndrome often occurs. Acute renal failure and hematuria are commonly seen in benzylpenicillin allergy, and in recent years, there has been an increasing trend in hematuria caused by quinolone drugs.

　　5. Oliguria, edema, and serous cavity effusion:40% to 50% of patients have oliguria, edema, and serous cavity effusion, which may be related to renal failure and hypoproteinemia. Some patients may not have the above systemic allergic reactions. Patients with typical triad symptoms, such as fever, rash, and joint pain, are generally less than 1/3, indicating variability in diagnostic characteristics. Drug-induced interstitial nephritis often manifests as sudden deterioration of renal function, rapid development of oliguric acute renal failure (ARF), and in addition to glomerular function damage (rapid increase in serum creatinine and urea nitrogen), tubular function damage is also often very obvious, leading to renal glycosuria and low osmolality and other abnormalities. Therefore, acute drug-induced interstitial nephritis should be suspected for acute renal failure of unknown cause, and renal biopsy should be performed as early as possible to make an accurate diagnosis and prevent misdiagnosis.

　　Acute tubular necrosis caused by aminoglycoside antibiotics may have no obvious symptoms in the early stage, especially in non-oliguric patients, which is often ignored by doctors. Patients often show systemic symptoms such as fatigue, dizziness, general discomfort, decreased appetite, nausea and vomiting, decreased hearing, tinnitus, ataxia, etc. Animal experiments show that on the fourth day after intravenous injection of gentamicin in rats, the urine enzymes (including lysozyme, γ-glutamyl transpeptidase, N-acetyl-β-glucosaminidase, etc.) increased. The increase of urine enzymes is a reaction after medication and not a sign to stop medication. On the 5th to 6th day, abnormalities in urine routine, hematuria, leukocyte urine, proteinuria, glycosuria, a large number of necrotic renal epithelial cells, and cell casts may appear. At this time, it indicates severe tubular damage. After the 7th day, blood urea nitrogen and creatinine levels increase significantly. The nephrotoxicity of gentamicin is related to dosage and time. When clinical symptoms such as proteinuria, hematuria, purulent urine, cast urine, oliguric or non-oliguric acute renal failure, and significantly increased blood urea nitrogen and creatinine levels occur, it is a clinical indication for discontinuation of medication. Non-oliguric refers to acute tubular necrosis without oliguria or anuria. Patients have an average urine output of more than 1000ml per day. Most patients start to improve renal function within a few days after discontinuation of medication, but some patients continue to rise in blood creatinine levels for 10 days after discontinuation of medication. On average, it can recover or approach normal within 42 days after onset. Some patients may progress to permanent renal failure. Although the clinical manifestations of non-oliguric patients are less severe than those with oliguria and the incidence of complications and mortality is low, there are still 26% of cases that should be paid attention to. Early dialysis should be considered for elderly and weak patients or those with pre-existing kidney disease, which can improve survival rate and reduce mortality.

　　The preventive methods for toxic nephritis caused by antimicrobial drugs are as follows:

　　1. Strictly control the indications, drug dosage, and course of treatment. The general dose is used as the usual dose, such as the dosage of gentamicin is 80,000 to 160,000 U/d, and the course of treatment is 5 to 6 days, which generally should not exceed 10 days, and repeated medication should be avoided.

　　2. Avoid using this class of drugs in cases of insufficient blood volume. If it is necessary to use it, it is best to correct the disorder of water and electrolytes before medication to avoid increased nephrotoxicity.

　　3. For the elderly, diabetics, and those with chronic kidney disease, especially those with chronic renal insufficiency, it is best to avoid and use this class of drugs with caution. Although renal toxicity is common in elderly patients using aminoglycoside antibiotics, if the course does not exceed one week, it can effectively reduce renal toxicity.

　　4. The issue of combined medication, it should be prohibited from being used with other nephrotoxic drugs, such as first-generation or second-generation cephalosporins and other nephrotoxic drugs such as non-steroidal anti-inflammatory drugs.

　　5. Pay close attention to the monitoring of urine routine, urine enzymes, and renal function during medication to detect renal toxicity early and stop the medication in time.

　　6. Avoid using it during acidosis.

　　7. Adjust the dose and administration interval of medication according to the creatinine clearance rate of the patient, give small doses, and the course of treatment should not exceed one week. When the creatinine clearance rate
　　8. Adjust the dose and interval of medication according to renal function.

　　The specific clinical examination of antimicrobial drug-induced nephritis is as follows:

　　1. Blood routine

　　The level of eosinophils in the blood is significantly increased to 80%, but it lasts only 1 to 2 days; red blood cells and hemoglobin, and platelets are usually normal, and there may be mild anemia. The cause may be related to the damage to the interstitial tubules affecting the production of erythropoietin and the retention of toxic substances in renal failure; elevated blood IgE and positive TBM antibody.

　　2. Urinalysis

　　Two-thirds of patients have microscopic hematuria, leukocyte urine, asymptomatic pyuria, and microscopic examination of urine sediment shows that about 30% of the leukocytes are eosinophils early after Wright's staining. Some statistics show that the detection rate of urinary eosinophils in acute interstitial nephritis is more than 66%, and the proportion of urinary eosinophils in urinary leukocytes can be used as a criterion for the diagnosis of this disease. There may be leukocyte casts or erythrocyte casts, and the urinary osmolality is often higher than that of blood osmolality and the urinary sodium is reduced. Proteinuria is usually mild to moderate, and massive proteinuria can be seen in those allergic to ampicillin or norfloxacin, and it may present with nephrotic syndrome. Other antibiotics causing it are rare.

　　3. Renal tubular function indicators

　　The β2M, α1M, T-H protein (Tamm-Horsfall protein, THP), blood osmolality, and urinary retinol-binding protein (RBP) are new indicators for diagnosing the function of the proximal renal tubules in China. The damage to the renal tubular function in this disease is generally prominent, with the urinary sodium excretion fraction >2. It may present with Fanconi's syndrome, which is the dysfunction of the proximal renal tubules, accompanied by glycosuria, aminoaciduria, phosphaturia, and hyperchloremic metabolic acidosis. It may also present with the dysfunction of the distal renal tubules, reduced acidification function, accompanied by isotonic urine, sodium loss nephropathy, and potassium excretion disorders. These are often important clues for diagnosing drug-induced interstitial nephritis.

　　Fourth, glomerular function indicators

　　It is generally believed that drug-induced interstitial nephritis rarely involves the glomeruli. In recent years, it has been considered that this disease can be accompanied by glomerular lesions, such as membranous nephropathy and crescentic glomerulonephritis, and the clinical manifestation is nephrotic syndrome, so blood BUN, Scr, and blood and urine IgG, Alb, and GFR can be detected.

　　Fifth, imaging examination:

　　Ultrasound, CT, and other examinations can be found to have normal or increased size of both kidneys.

　　Sixth, renal biopsy tissue pathological examination:

　　Renal damage caused by antibiotics is often characterized by acute inflammation of the renal interstitium and renal tubules, with normal glomeruli or only mild mesangial cell proliferation. Renal biopsy is the means to diagnose this disease. Different drugs can cause similar renal pathological changes, and the lesions are distributed bilaterally and diffusely.

　　Patients with antibiotic toxic nephropathy should eat less spicy food, avoid smoking and drinking. Adolescents should pay attention to balanced and light diet while absorbing nutrition, not eating too much high-protein and high-fat food. In addition, while studying and working, attention should be paid to rest and avoid overwork. Moderate physical exercise can enhance physical fitness, but attention should also be paid to the control of exercise intensity, not to engage in too intense exercise to cause overwork.

　　The treatment methods for antibiotic toxic nephropathy:

　　The treatment of acute allergic interstitial nephritis caused by antibiotics:

　　1. Discontinue relevant antibiotics:In mild cases, AIN can spontaneously remit after discontinuing the sensitizing drug. If antibiotics are needed, it should be chosen that has no cross-reaction with these drugs.

　　2. Application of adrenal cortical hormones:Hormonal therapy often achieves the effects of diuresis, improvement of renal function, and reduction of blood creatinine to normal levels. The general dosage is prednisone 30 to 60mg/d, for about 1 month, the dose should not be too high, and the course should not be too long. There are individual reports that the acute renal failure was relieved after a high-dose methylprednisolone pulse therapy. Since most drugs-induced acute interstitial nephritis does not require hormones, simple drug discontinuation can recover quickly, therefore, the application of hormones should be weighed for the pros and cons.

　　3. Use of cytotoxic drugs:Some scholars suggest that cyclophosphamide or cyclosporine can be used to treat patients with progressive deterioration of renal function, who have no response to hormones or renal biopsy shows mild or no interstitial fibrosis. Cyclophosphamide can be added within 2 weeks of glucocorticoid treatment. If there is no improvement in renal function after 5 to 6 weeks of medication, the drug should be discontinued; if renal function improves, continue to use cyclophosphamide for 1 to 2 months, not too long, and the cumulative dose should not exceed 6g.

　　4. Strengthen symptomatic supportive treatment and dialysis treatment when necessary:The indications for dialysis are the same as for general acute renal failure: ①Anuria or oliguria for more than 2 days; ②Serum creatinine (Scr) 442 mol/L; ③BUN > 21 mmol/L; ④Carbon dioxide binding power (CO2CP) 6.5 mmol/L; ⑧Predisposition to pulmonary edema or brain edema. Dialysis can maintain life, thereby winning treatment time.

　　Second, the treatment of acute tubular necrosis caused by antibiotics

　　Mild cases usually only require discontinuation of medication and symptomatic treatment, and recovery often occurs within a few weeks. Severe cases require active treatment.

　　1. Calcium, magnesium, zinc, and other divalent cations have a protective effect against the nephrotoxicity caused by aminoglycoside antibiotics. Animal experiments show that after the use of calcium in the ATN caused by gentamicin, the pathological and biochemical changes are significantly reduced, suggesting that Ca2+ has a protective effect.

　　2. Calcium and verapamil (isoptin) combined use: While using gentamicin, calcium gluconate 1g, 3 times a day, taken orally; verapamil (isoptin) 40mg, 3 times a day, taken orally; there is indeed a protective effect against gentamicin-induced nephrotoxic damage. The protective mechanism of calcium may be to reduce the uptake of gentamicin by renal tubular cells; the protective effect of verapamil (isoptin) may be related to interference with the binding of gentamicin to the brush border membrane or affecting the cell's phagocytic process.

　　3. Angiotensin-converting enzyme inhibitors: These preparations (such as Captopril, Enalapril, Benazepril, Perindopril, and others) can inhibit the formation of angiotensin II, block tubuloglomerular feedback, increase kininogenase, improve renal blood flow, and this measure has been used in clinical practice.

　　4. General symptomatic treatment: includes the active treatment of the primary disease, control of infection, blood volume supplementation, anti-shock, correction of water and electrolyte balance, close observation of blood pressure, urine volume, and cardiorespiratory status. If renal toxicity is suspected clinically, antibiotics should be discontinued immediately.

　　5. Diuretic therapy:

　　(1) Mannitol (25g) or 25% sorbitol 125-250ml can be administered intravenously as a rapid infusion.

　　(2) When furosemide is combined with mannitol, a better diuretic and natriuretic effect can sometimes be achieved. For patients with poor response to furosemide in clinical practice, consideration can be given to the administration of low-dose dopamine or atropine to enhance the diuretic effect.

　　Animal experiments have confirmed that mannitol and furosemide can improve renal hemodynamics and prevent the formation of renal tubular casts. The mechanism of action is that mannitol is filtered by the glomerulus and is not reabsorbed by the renal tubules, which has osmotic diuresis. Furosemide inhibits the reabsorption of water from the proximal tubule to the loop of Henle, preventing the formation of renal tubular protein casts. Osmotic diuresis reduces edema of renal tubular epithelial cells and renal interstitium, thus reducing tubular obstruction. Osmotic diuresis can increase the clearance of toxins and prevent the development of oliguria in non-oliguric acute renal failure.

　　(3) Atrial natriuretic peptide (ANP) combined with mannitol has been proven to improve renal function in ARF animal models; usually, fluid resuscitation, mannitol, and furosemide are considered as the three-step approach for the early prevention and treatment of ATN.

　　(4) Traditional Chinese Medicine Treatment: The purpose of using traditional Chinese medicine is mainly to promote blood circulation and remove blood stasis, including Chuanxiong, Danshen, and others. Studies have confirmed that Cordyceps sinensis can significantly promote the growth of renal tubular epithelial cells in vitro, can significantly alleviate the acute renal failure (ARF) caused by gentamicin in rats, prevent the nephrotoxicity caused by kanamycin in rats, and has a good protective effect on the nephrotoxicity caused by aminoglycoside antibiotics in clinical practice. It may also have a certain therapeutic effect on interstitial nephritis caused by antibiotics.

　　(5) Use of drugs that promote cell recovery and regeneration:

　　① Adenine nucleotide drugs: Adenine nucleotides promote the structural recovery and renal function recovery of damaged cells, which is achieved by stimulating DNA synthesis and the release of cell growth factors through adenosine, promoting the proliferation and repair of damaged renal cells, and causing the regeneration of renal tubular epithelial cells. In the ATN animal model, after intravenous administration of ATP-MgCl2 mixed solution, the obstruction of renal tubules is reduced, the back leakage of renal tubular fluid into the stroma is reduced, and the integrity of the renal unit tissue is restored.

　　② Oxygen free radical scavengers: Oxygen free radicals play a role in the mechanism of ATN caused by aminoglycoside antibiotics. The use of oxygen free radical scavengers (such as allopurinol, glutathione, ogunin, and vitamin E, etc.) can increase the clearance of oxygen free radicals, thereby protecting damaged renal cells.

　　③ Prostaglandin PGI or PGE can increase renal blood flow and glomerular filtration rate and can be appropriately selected.

　　Third, the treatment of acute renal failure

　　When ARF has already formed, it should be treated strictly according to acute renal failure, including the treatment of oliguria, polyuria, and recovery periods. Although there is still controversy over whether to perform prophylactic dialysis, dialysis is still the most important treatment method for ATN, and the most effective measure for the rescue of ATN acute renal failure. Dialysis treatment can not only replace the excretory function of the kidneys but also can dialyze out some drugs accumulated in the plasma, allowing patients to get through the oliguria period, reduce mortality, and shorten the course of the disease. In the 1950s, the mortality rate of ATN was as high as over 80%, and in recent years, the significant decrease in the mortality rate of ATN is due to the development of hemopurification technology. Therefore, most scholars advocate early dialysis.

　　Dialysis methods include hemodialysis and peritoneal dialysis. Hemodialysis is more commonly used, and in addition, CAVH (Continuous Arteriovenous Hemofiltration), CAVHD (Continuous Arteriovenous Hemodialysis Filtration), CVVH (Continuous Venovenous Hemofiltration), and HDF (Hemodialysis Filtration) are also used increasingly in the treatment of Acute Renal Failure (ARF) due to their many advantages that cannot be replaced by simple hemodialysis. However, for patients with low blood pressure, bleeding, and poor vascular conditions, peritoneal dialysis is more suitable. This therapy is simple, safe, and economical, and can be widely carried out.