Inventory of the five significant mechanisms of nephrotoxic drug effects

 The kidney is the main organ for the metabolism and excretion of various drugs, from minor to common anti-cold drugs, antibiotics, antivirals, and significant to anti-tumor drugs, all of which may cause kidney damage. In drug safety evaluation studies, the study of drug nephrotoxicity is a critical element.

The causes of kidney susceptibility to drug damage include physiological function aspects, anatomical structure and composition of material components, blood supply, and drug metabolism. The mechanism of nephrotoxic action of drugs can be divided into five major types according to the mode of action of renal damage of drugs.

Drug-induced kidney damage can be called drug-related kidney damage, which refers to the adverse reactions of the kidney to therapeutic doses of drugs and toxic reactions due to drug overdose or irrational application. For example, drug-induced acute tubular necrosis can manifest as irritable thirst, polyhydramnios, polyuria, and other non-oliguric symptoms, and examination shows a rapid increase in blood creatinine and urea nitrogen levels, decrease in urine specific gravity and urine osmolality, which can be accompanied by metabolic acidosis and electrolyte disorders.

The drug can also cause acute interstitial nephritis, which manifests as systemic allergic reactions: typical hypersensitivity triad (fever, drug rash, blood eosinophilia), lymph node enlargement, arthralgia, etc.; renal manifestations include abnormal urinalysis with aseptic leukocyturia, eosinophilia, hematuria, proteinuria (usually not more than 1g/24h), and in severe cases, acute renal failure. In drug safety evaluation studies, typical indicators that can indicate the risk of nephrotoxicity include urine volume, urine protein, serum creatinine (Cr), blood urea nitrogen (BUN), and histopathological observations.

1, Direct toxicity of drugs to the kidney

The degree of damage from direct toxicity of a drug is related to the dose and course of the drug. It is more likely to occur in the presence of high drug concentrations and active metabolism that can be transported to the proximal renal tubules where intracellular accumulation occurs. Direct toxicity of drugs can damage renal cells, such as disrupting cell membranes, altering membrane permeability and ion transport functions, or damaging cellular mitochondria and lysosomes.

The direct toxicity of some drugs can also inhibit protease activity and protein synthesis, etc. Drug toxicity is an essential factor affecting the development of new medicines. The kidney is the main target organ for the toxic effects of drugs, and predicting the nephrotoxicity of drugs is an essential part of drug safety assessment. Medicilon's drug safety evaluation center consists of a group of experienced and professional research teams that have established a drug safety evaluation system in line with international standards. The experimental studies follow ICH, CFDA/NMPA, FDA, and OECD guidelines, which can provide customers with high-quality data and a rapid study cycle for preclinical drug safety evaluation services.

2, Physical injury to the kidney caused by drugs

Physical injury to the kidney caused by drugs may be caused by drug-induced obstructive kidney injury, including drug-induced intrarenal obstruction and obstruction caused in the urinary tract. It may also be due to the hypertonic effect of drugs on the glomerulus and tubules caused by the damage.

3, Drugs affect the renal blood supply

Drug-induced hypotension, diffuse intravascular coagulation, decreased blood volume, renal artery constriction, and drug inhibition of prostate synthesis can cause reduced renal blood supply, reduced glomerular filtration rate (GFR), and manifestations of renal dysfunction such as oliguria or anuria. Drug-related kidney injury generally requires discontinuing drugs that damage the kidney, maintaining fluid balance, nutrition, correcting various electrolyte disorders, preventing infection, and renal replacement therapy, etc. The primary mechanism of nephropathy caused by non-steroidal antipyretic analgesics, for example, is by causing renal vasoconstriction, resulting in inadequate blood supply to the kidney. Kidney damage can be reduced by increasing renal blood flow through large amounts of rehydration.

4, Renal damage caused by a metamorphic reaction of drugs

Some drugs, as semi-antigens, enter the body and form antigen-antibody complexes, which cause kidney damage by deposition in the glomerulus. In addition, some drugs as semi-antigens into the body allergic reactions and lead to kidney damage, such as penicillin. Drug-induced allergic renal injury, the central lesion in the glomerulus, and the drug dose are not closely related, often accompanied by systemic manifestations of allergic reactions. There are significant individual differences, with good results with adrenocorticotropic hormone.

5, Metabolic disorders caused by drugs harm the kidneys

Kidneys as a critical metabolic organ in the body. When some drugs cause metabolic disorders in the body, such as diuretics' improper use caused by water-electrolyte diseases, glucocorticoids cause disorders of sugar and protein metabolism in the body, it is possible to cause some damage to the kidneys. Hypokalemia, hypomagnesemia, hypocalcemia, and nephrotoxicity are increased when aminoglycosides are taken. Metabolic acidosis or alkalosis affects urine pH and increases the nephrotoxicity of sulfadiazine, methotrexate, and aminopterin in acidic urine (pH < 5.5); and atazanavir, oral sodium phosphate solution, and ciprofloxacin in alkaline urine (pH > 6.0).

The kidney is the largest metabolism and detoxification organ, and most of the drugs people take must be metabolized by the kidney before being absorbed by the body. Hence, the nephrotoxicity of drugs needs to be evaluated in the preclinical drug safety evaluation. In clinical practice, if you take too many drugs blindly, it will add to the metabolic burden of the kidneys and make the kidneys suffer damage. In light cases, there will be dry mouth, frequent urination, and other uncomfortable symptoms; in severe cases, it will lead to nephritis and nephrotic syndrome, and in extreme cases, it will even threaten people's lives.