Pediatric drug-induced kidney damage

　　1. Causes of disease

　　The reasons why the kidney is prone to drug-induced damage are that the kidney is particularly sensitive to the toxic reactions of drugs, and the main reasons include:

　　(1) Abundant renal blood flow: accounting for 20% to 25% of cardiac output, it is the organ with the largest blood flow per unit area. Therefore, a large amount of drugs can enter the kidney.

　　(2) Large surface area of renal capillaries: prone to the deposition of antigen-antibody complexes.

　　(3) Concentration of excretory substances: The concentration of excretory substances acting on the surface of renal tubules is high, which is due to the effect on the blood concentration system. In addition, the proximal tubules have secretory and reabsorptive effects on a variety of drugs, which also increases the opportunities for drugs to interact with renal tubular epithelial cells.

　　(4) High metabolic rate of renal tubules: During the process of secretion and reabsorption, drugs often concentrate on the surface of renal tubules or inside cells, making drug poisoning more likely to occur.

　　(5) Drug sensitivity: The kidney consumes a large amount of oxygen, is sensitive to ischemia and hypoxia, and therefore is sensitive to drugs that affect blood flow.

　　(6) Susceptibility: Renal disease increases susceptibility to drug damage, hypoalbuminemia increases the concentration of free drugs, and renal insufficiency prolongs the half-life of drugs. Renal disease and special populations such as infants, children, and the elderly have lower renal reserve function.

　　2. Common drugs that are likely to cause renal damage

　　(1) Antibiotics and sulfonamides: including: ① Aminoglycosides: gentamicin, amikacin (butyl kanamycin), streptomycin, kanamycin, neomycin, etc.; among them, neomycin, kanamycin, and gentamicin have the strongest toxic effects; ② Penicillins: various semi-synthetic penicillins can induce renal damage; ③ Cephalosporins: the first-generation cephalosporins are most prominent; ④ Polymyxins; ⑤ Tetracyclines: increase protein degradation, exacerbate azotemia; ⑥ Amphotericin B; ⑦ Vancomycin, and sulfonamide drugs.

　　(2) Non-steroidal anti-inflammatory drugs (NSAIDs): including aspirin (acetylsalicylic acid), ibuprofen, indomethacin, naproxen (methoxybenzylpropionic acid), indomethacin (anti-inflammatory pain), piroxicam (anti-inflammatory analgesic), Celebrex, etc.

　　(3) X-ray contrast agents: mainly iodinated contrast agents.

　　(4) Antitumor drugs: including cisplatin, methotrexate, streptomycin, nitrosoureas (carmustine, chloroethylcyclohexane, hexamethylmelamine).

　　(5) Diuretics: including osmotic diuretics and furosemide.

　　(6) Traditional Chinese herbal medicine: mainly including Aristolochia debilis, Coptis, Stephania tetrandra, Magnolia officinalis, Asarum sieboldii, Leonurus heterophyllus, etc.

　　(7) Other drugs: such as penicillamine, captopril, birth control pills, cyclosporine, adrenaline, etc.

　　Second, pathogenesis

　　1. Constricts renal blood vessels, affecting renal hemodynamics, reducing blood flow, which can decrease renal filtration and clearance function. At the same time, it can also lead to renal ischemia and hypoxia, causing further renal damage.

　　2. Direct nephrotoxic drugs can directly damage renal tubular epithelial cells when their concentration in the renal tubules reaches a toxic level. The extent of injury is related to the dose, and the mechanisms include:

　　(1) Directly injures the cell membrane, altering membrane permeability and ion transport function.

　　(2) Damages the cytoplasmic mitochondria, inhibits enzyme activity and protein synthesis, causes calcium influx, disrupts the cytoskeleton structure, and leads to the necrosis of epithelial cells.

　　(3) Produce oxygen free radicals.

　　(4) Acting on the DNA of epithelial cells, causing cross-linking, or inhibiting the activity of enzymes related to DNA replication, inhibiting the metabolism of renal tubular epithelial cells.

　　(5) High osmotic direct damage.

　　3, Immune-inflammatory reactions include:

　　(1) Cell-mediated immune mechanism: plays an important role in acute allergic interstitial nephritis.

　　(2) Induce the production of anti-renal tubular basement membrane antibodies, mediate immune injury.

　　(3) Interaction between drugs and renal tubular or renal interstitial proteins, making them become haptens or antigens, induce antibodies, form immune complexes, and trigger immune-inflammatory reactions.

　　(4) Idiopathic inflammatory response.

　　4, Obstructive renal lesions, sulfonamide crystals accumulate and block renal tubules, epithelial cell变性, necrosis, interstitial inflammation cell infiltration, high-dose methotrexate, and ultra-high-dose immunoglobulins can cause renal damage through obstruction.

　　5, Inducing and aggravating factors include:

　　(1) Renal function decline, drug half-life extension.

　　(2) Hypoproteinemia increases the freedom of drugs, making it easier for drugs to reach toxic doses. The above several kidney damage mechanisms can exist alone or coexist simultaneously triggered by a single drug.

　　Pediatric drug-induced renal damage can complicate acute and chronic renal failure, diabetes insipidus, allergic diseases, nephrotic syndrome, and other conditions. It seriously affects the health of patients and threatens their lives, so timely treatment is essential.

　　1, Acute renal failure (ARF):It is relatively common, and ARF caused by X-ray contrast agents usually appears within 48 hours after the contrast. ARF caused by kidney toxic drugs such as sulfonamides and aminoglycosides mainly occurs 5 to 7 days after medication or within 24 to 48 hours after a single large dose of medication. Allergic reactions caused by penicillin derivatives usually cause renal failure within 24 hours after medication.

　　2, Renal tubule-interstitial disease:Penicillin can cause acute allergic interstitial nephritis, manifested as hematuria, leukocyteuria, proteinuria, and a large number of eosinophils in the urine leukocytes (can be >30%), accompanied by renal insufficiency, fever, drug rash, elevated eosinophils in the blood. Chronic interstitial nephritis can be caused by non-steroidal anti-inflammatory drugs and traditional Chinese herbal medicines containing aristolochic acid, with a long duration of use often lasting for several months or more. Nephrotoxic antibiotics (aminoglycosides and cephalosporins) and antitumor agents (cisplatin), in addition to directly damaging renal tubular epithelial cells, can also cause chronic interstitial nephritis; in recent years, chronic interstitial nephritis caused by captopril has also gradually increased; in addition, amphotericin, tetracycline, and some traditional Chinese medicines can cause renal tubular acidosis, Fanconi syndrome, nephrogenic diabetes insipidus, and other renal tubular diseases.

　　3, Nephrotic syndrome:Manifested by large amounts of proteinuria, edema, hypoproteinemia, etc., penicillamine, NSAIDs, and other drugs can all lead to nephrotic syndrome.

　　4, Nephritis syndrome:Manifested as hematuria, proteinuria, and hypertension.

　　5, Simple hematuria and/or proteinuria:Can be caused by various nephrotoxic drugs such as aminoglycosides, cephalosporins, sulfonamides, NSAIDs, and antitumor drugs.

　　6, Chronic renal failure:Caused by traditional Chinese herbs containing aristolochic acid such as aristolochia, stephania, and motherwort, which can lead to progressive and irreversible renal function failure.

　　7, Obstructive renal damage:Primarily caused by the obstruction of renal tubules by large amounts of sulfonamide crystals, tumor chemotherapy drugs can also cause uric acid crystals to block renal tubules.

　　8, Hemolytic uremic syndrome (HUS):Contraceptives, cyclosporine, FK506, quinine, and others can lead to secondary HUS.

　　Emphasizing the importance of early diagnosis of drug-induced renal damage and increasing awareness of the disease. Due to the insufficient understanding of renal damage caused by drugs by clinical doctors, and because certain drugs often lack characteristic clinical manifestations of renal lesions, and the kidneys have a great capacity for reserve and compensation, drug-induced nephropathy is not easily discovered early. The toxic symptoms of drugs are often mistaken for symptoms of renal insufficiency and uremia, leading to delayed diagnosis and treatment, and even developing into irreversible end-stage renal failure. It is noteworthy that some drugs used to treat kidney diseases themselves have nephrotoxicity. Therefore, awareness of this disease should be increased, and careful observation, increased vigilance, early detection, early discontinuation of medication, and early treatment should be emphasized during the treatment process.

　　Understanding drug characteristics and rational medication use. Clinical doctors should be familiar with the pharmacological and pharmacokinetic characteristics of avoiding or reducing renal damage when using high-dose contrast agents. They should fully recognize the nephrotoxicity and other adverse reactions of drugs to reduce the occurrence of drug-induced renal dysfunction. This is especially important now, with the proliferation of new drug varieties, where clinical doctors often lack an understanding of the composition, metabolic processes, pharmacokinetic characteristics, and drug interactions of the drugs they use. This leads to improper medication use. Some doctors in grassroots hospitals use antibiotics, especially those with nephrotoxic effects, more随意ly and often combine two or more drugs with kidney toxicity, increasing the likelihood of renal damage. Clinical doctors should pay attention to strengthening the awareness of preventing this disease, mastering relevant drug knowledge, and using drugs rationally.

　　Many clinical doctors are mechanical and rigid in their use of medication, failing to provide individualized treatment based on the specific conditions of the patients. For example, patients with risk factors such as advanced age, insufficient blood volume, or chronic kidney damage have not had their drug dosages reduced or the intervals between medication extended. In the future, it should be emphasized that individualized treatment should be provided to reduce the occurrence of drug-induced renal damage.

　　The timing and treatment measures for drug-induced renal damage are crucial for prognosis. Generally speaking, if treated promptly and correctly, most patients with drug-induced renal damage can turn from danger to safety, and even their renal function can be expected to be completely restored. However, some medical units are not very proactive in handling drug-induced renal damage after it occurs, merely stopping the drug without seizing the opportunity to give necessary promoting excretion and kidney-protecting drugs. Lack of or failure to carry out timely hemodialysis treatment also affects the effectiveness of the treatment for drug-induced renal damage. Therefore, it is important to pay attention to timely handling and active treatment.

　　1. Blood:In allergic interstitial nephritis, an increase in blood eosinophils, IgG, and histamine may be observed; different clinical manifestation categories can lead to corresponding changes in blood biochemistry. Blood drug concentration monitoring has certain diagnostic value for cyclosporine-induced renal damage, aminoglycoside-induced renal damage, and the nephrotoxic effects of cisplatin. For example, the safe blood concentration of cyclosporine is less than 250ng/ml in whole blood, and the possibility of renal damage is greater if the concentration exceeds this level.

　　2. Urine:Depending on the type of manifestation, oliguria, proteinuria, hematuria, leukocyteuria, and changes in renal tubular function may occur. In cases of sulfonamide-induced renal damage, a large amount of sulfonamide crystals may appear in the urine; in allergic interstitial nephritis, eosinophils may appear in the urine. In addition, urine osmolality is often significantly lower than normal, reflecting that some small molecular proteins in renal tubular function, such as retinol-binding protein (RBP), β2-microglobulin, and lysozyme, are elevated. The level of N-acetyl-β-D-glucosaminidase (NAG) in urine also increases.

　　3. Radionuclide examination (SPECT):Static imaging of 67Ga in both kidneys shows uniform absorption and high concentration in interstitial nephritis, with the most absorption on the right side after 48 hours, which is of great help in diagnosing drug-induced interstitial nephritis. 99mTc diethylenetriamine pentaacetic acid (DTPA) dynamic imaging shows good renal perfusion but poor renal parenchymal absorption function in tubulointerstitial lesions. When renal tubular function is impaired, dynamic renal imaging with 131I-para-iodomethane acid sodium (OIH) is unclear and particularly sensitive, with a diagnostic accuracy rate of 95%.

　　4. X-ray:Persistent dense shadows on the X-ray film are a sensitive indicator of contrast agent-induced renal toxicity, but they lack specificity.

　　5. B-ultrasound:Acute interstitial nephritis caused by drugs often shows symmetrical enlargement of the kidneys on B-ultrasound.

　　6. Drug-specific lymphocyte transformation test:The principle is to use the specific antigen of the drug in vitro culture to stimulate the transformation of the patient's sensitized lymphocytes. According to the level of drug antigen to which the lymphocytes respond, it can be determined whether the patient is allergic to this drug. This test is an in vitro experiment, which has no adverse effects on the patient. Another advantage is that it has a high specificity, with rare false positives. However, a negative result cannot exclude the possibility of being allergic to a certain drug. Generally, a stimulation index ≥2 is considered positive, and <1.9 is considered negative.

　　I. Treatment

　　1. Discontinuing the drug causing kidney damage: Once suspected of drug-induced kidney damage, the medication should be reduced or even stopped immediately. The renal function of children often recovers rapidly, and the changes in urine gradually disappear.

　　2.水利尿磺胺, when crystalline damage to the kidney occurs due to antitumor drugs, large amounts of drinking water and furosemide (速尿) 2mg/kg each time can be used to clear the crystalline obstruction in the renal tubules. However, children with renal failure should not drink large amounts of water to avoid increasing the volume load.

　　3. Adrenal cortical hormones can be used for acute allergic interstitial nephritis caused by penicillin antibiotics, antineoplastic drugs, and NSAIDs. Glucocorticoids such as prednisone 1-2mg/(kg·d) can be used, with a course of 1-2 weeks, which can significantly improve renal function. Adrenal cortical hormones can also be used appropriately for drug-induced kidney damage manifested as nephrotic syndrome or glomerulonephritis syndrome.

　　4. Immunosuppressants are used for interstitial nephritis caused by NSAIDs, and when the treatment effect of adrenal cortical hormones is not satisfactory.

　　5. Renal tubular epithelial cell protection and cell regeneration promoting drugs include Cordyceps extract, high-dose vitamin E 100-200mg/time, 3 times/d, hepatocyte growth factor and epidermal growth factor, etc. Some people also report that calcium channel blockers such as nimodipine, verapamil (isoptin) and others have a preventive and therapeutic effect on tubular epithelial cell necrosis caused by drugs (aminoglycosides).

　　6. Dialysis therapy: Hemodialysis or peritoneal dialysis is used in acute renal failure, and dialysis also helps to clear drugs.

　　II. Prognosis

　　The prognosis of drug-induced kidney damage is good. If diagnosed and treated in time, the renal function of most patients with drug-induced kidney damage can return to normal, and the patients can recover completely. However, in some severe cases of renal failure, the condition is complex, or there is pre-existing renal insufficiency and elderly patients often have difficulty recovering renal function, showing progressive renal insufficiency, eventually developing into end-stage renal failure. In addition, the prognosis of this disease is related to the drug causing it. There are reports that antineoplastic drugs such as carmustine and semustine, and certain polypeptide antibiotics can cause irreversible or progressive renal damage.