RESUMO
Acute Kidney Injury (AKI) is a clinical condition with various etiologies. It is also known as acute renal failure, which is a sudden episode of kidney failure or kidney damage that happens within a few hours or a few days in patients. It causes an increase of waste products in blood and makes it hard for the patient kidneys to keep the right balance of fluid in the body. It can also affect other vital organs such as the brain, heart, and lungs. AKI is common in patients who are in the hospital, in intensive care units, and especially in older adults. It results in increased accumulation of a nitrogenous surplus in blood and a reduction in urine volume. The pathophysiology of various types of AKI is different. The earlier we can identify the causes the more effective treatment can be administered. This review attempts to identify changes on a molecular level during different stages of the disease and further discussed understanding the pathophysiology of AKI to find important molecules involved in various metabolic pathways, various phases and types of AKI, and the effect of drugs on kidneys and cellular level changes. This review article would help to design new drugs and the consequences of their metabolites to avoid Acute Kidney Injury.
RESUMO
Background: The need to identify causes of drug induced kidney failure has been underscored by International Conference on Harmonization (ICH) regulated agencies. In our earlier studies on adverse drug reaction (ADR) reported in Canada Vigilance Adverse Reaction Online Database it was observed that drugs azathioprine, clozaril/clozapine, diclofenac sodium, diflucan/ fluconazole, furosemide, indomethacin, metformin, micardis/ telmisartan, viread/tenofovir, and zyprexa/olanzapine lead to kidney failure. Method: Attempts have been made to understand the physiological process via bioinformatics perspective. This was done by active site identification for cytochrome P450 along with multidrug resistance protein 1 (MRP1). Docking against the drugs in these proteins that are categorically involved in drug binding based on their pharmacological actions are as per drug bank annotations. Results: Cytochrome P450 2C19 protein showed better interactions with drug indomethacin with a maximum score of -119.2 kcal/mol followed by drug clozaril with a score of -102.5 kcal/mol. This was finally followed by of drug zyprexa with a score of -101.0 kcal/mol. The residues which are actively involved with the drug indomethacin include Arg97 and Arg433. Drug clozaril shows interaction with Ala297. For drug zyprexa the residues like Arg97, Ala297 and Cys435 interact with the protein. For MRP1, even though it showed better binding scores for drugs azathioprine, indomethacin, diflucan and furosemide. But still, they are not able to interact within the pocket, leaving it empty during docking studies. Conclusion: Through this study, it was possible to identify active site pocket in the related proteins and the interacting amino acid residues of cytochrome P450 that may contribute to drug induced kidney failure.