Kidney injury in COVID-19 patients, drug development and their renal complications: Review study.

Since December 2019, the world was encountered a new disease called coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although SARS-CoV-2 initially causes lung damage, it also affects many other organs, including the kidneys, and on average, 5-23% of people with COVID-19 develop the symptoms of acute kidney injury (AKI), including elevated blood creatinine and urea, hematuria, proteinuria, and histopathological damages. The exact mechanism is unknown, but the researchers believe that SARS-CoV-2 directly and indirectly affects the kidneys. The direct pathway is by binding the virus to ACE2 receptor in the kidney, damage to cells, the renin-angiotensin system disturbances, activating coagulation pathways, and damaging the renal vascular endothelium. The initial evidence from studying the kidney tissue in postmortem patients is more in favor of the direct pathway. The indirect pathway is created by increased cytokines and cytokine storm, sepsis, circulatory disturbances, hypoxemia, as well as using the nephrotoxic drugs. Using renal tissue biopsy and autopsy in the patients with COVID-19, recent studies found evidence for a predominant indirect pathway in AKI induction by SARS-CoV-2. Besides, some studies showed that the degree of acute tubular injury (ATI) in autopsies from COVID-19 victims is milder compared to AKI degree. We review the mechanism of AKI induction and the renal side effects of the most common drugs used to treat COVID-19 after the overview of the latest findings on SARS-CoV-2 pathogenicity.

Protective effect of piperine in ischemia-reperfusion induced acute kidney injury through inhibition of inflammation and oxidative stress.

BACKGROUND AND AIM: Renal ischemia-reperfusion is associated with inflammation and oxidative stress. As a major compound in black pepper, piperine has anti-inflammatory and anti-oxidative properties. In present study, the protective effects of oral administration of piperine in renal ischemia-reperfusion (IR) induced acute kidney injuries (AKI) were investigated. EXPERIMENTAL PROCEDURE: Male Wistar rats received piperine (10 or 20 mg/kg.bw) or vehicle for 10 days. The artery and vein of both kidneys were then clamped for 30 min, followed by a 24-h reperfusion period. Concentrations of creatinine and urea-nitrogen in descending aorta blood were measured, and malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP) levels were measured in kidney tissue to evaluate the oxidative stress. Inflammation was evaluated by measuring the TNF-α and ICAM-1 mRNA expression levels in renal cortical tissue using Real Time PCR method and counting leukocytes infiltration to interstitium. Further measured were tissue damages in H & E stained sections. RESULTS: Renal IR reduced FRAP, while increasing the plasma concentrations of creatinine and urea-nitrogen, tissue MDA level, TNF-α and ICAM-1 mRNA expressions, leukocyte infiltration and histopathologic injuries. Piperine administration significantly reduced the plasma concentrations of creatinine and urea-nitrogen, expression of pro-inflammatory factors, oxidative stress and renal histopathologic injuries. It is to be noted that 20 mg/kg dose was more effective. CONCLUSION: Our results suggest piperine protects the kidney against ischemia-reperfusion induced acute kidney injuries by its anti-inflammatory and anti-oxidative properties.

Piperine pretreatment attenuates renal ischemia-reperfusion induced liver injury.

BACKGROUND: Remote organ injury is one of the complications which are developed following ischemia-reperfusion induced acute kidney injury (AKI), dramatically increasing its mortality rate. The aim of the present study was to investigate the effect of piperine pretreatment on liver dysfunction following ischemia-reperfusion induced AKI. MATERIALS AND METHODS: Acute kidney injury was induced by 30 min-bilateral renal ischemia followed by 24 h of reperfusion. To investigate liver damages, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) enzymes were measured in plasma. In order to study oxidative stress, malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) levels were measured. Furthermore, the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA along with infiltration of leukocytes in the liver tissue was measured for inflammation assessment. Histopathological damages were studied through measuring the extent of cellular fibrosis, sinusoidal dilatation, and vascular congestion in liver tissue. RESULTS: Following acute kidney injury, AST, ALT, and ALP levels in plasma, MDA level and ICAM-1 expression in the liver tissue, infiltration of leukocytes into the interstitium, and hepatic histopathologic damages increased significantly, while FRAP decreased. Pretreatment with piperine at 10 and 20 mg/kg body weight was able to improve these damages, such that some of them reached its value in the sham group, though piperine in the 20 mg/kg was more effective. CONCLUSIONS: The results of this study suggest that ischemia-reperfusion induced AKI result in hepatic damages, and pretreatment with piperine can prevent development of these damages through its antioxidant and anti-inflammatory properties.

Amelioration of renal and hepatic function, oxidative stress, inflammation and histopathologic damages by Malva sylvestris extract in gentamicin induced renal toxicity.

BACKGROUND: Gentamycin, contrary to its wide range of antimicrobial effects, has a high potential for nephrotoxicity, and renal injury can have effects on other organs such as the liver. OBJECTIVES: The aim of the present study was to assess the effects of hydro alcoholic Malva sylvestris(MS) extract on nephrotoxicity induced by gentamicin, and also its remote organ injury in the liver. METHODS: Renal and hepatic functions were evaluated through measurement of creatinine, urea-nitrogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in plasma. Oxidative stress was assessed through measuring malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP) levels, and histopathologic injuries were evaluated using H & E stained sections. For evaluation of inflammation, TNF-α and ICAM-1 mRNA expression levels were measured in the renal tissue using Real-time PCR method. RESULTS: Gentamicin resulted in an increase in the levels of creatinine, urea-nitrogen, AST, ALT, and ALP in the plasma, as well as an increase in TNF-α and ICAM-1 mRNA expression levels in the renal tissue, renal and hepatic histopathologic injuries and MDA level, and a decrease in FRAP. Administration of MS led to improvement in the function of kidney and liver, a decrease in the expression levels of proinflammatory factors, reduction of oxidative stress, and also a decrease in tissue injuries. CONCLUSION: MS extract can protect the kidney against toxic effects of gentamicin, and thus, the degree of harmful effects of nephrotoxicity on remote organs including the liver will be decreased.

Reduction of cisplatin-induced renal and hepatic side effects in rat through antioxidative and anti-inflammatory properties of Malva sylvestris L. extract.

BACKGROUND: Cisplatin is widely used in the chemotherapy of solid organ cancers. However, its application is associated with serious side effects in various organs including the kidneys and liver. OBJECTIVES: The aim of this study was to investigate the effects of mallow extract on the side effects of cisplatin in the kidneys and liver. METHODS: Hydroalcoholic extract of mallow, at doses of 200, 400, and 600 mg/kg BW, was administered to the animals for seven days intraperitoneally (ip). Animals in the Cis + Mallow group received a dose of cisplatin (8 mg/kg, ip) on the third day. Renal and hepatic functional disturbances were evaluated by measuring concentrations of creatinine, urea-nitrogen, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in the plasma. In order to assess oxidative stress, malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) levels were measured in the kidney tissue. Then, degree of mRNA expressions of TNF-α and ICAM-1 were measured to examine renal inflammation. Hematoxylin and Eosin (H & E) staining of kidney and liver tissues was performed to study tissue damage and leukocyte infiltration. RESULTS: Cisplatin increased levels of plasma creatinine, urea-nitrogen, AST, and ALT; levels of tissue damage and leukocytes infiltration in the kidneys and liver; and MDA level and expression of pro-inflammatory factors in the kidney tissue. Meanwhile, it decreased FRAP level in the kidney tissue. Pretreatment by mallow extract resulted in significant improvement in all measured variables although 200-mg and 400-mg doses yielded better results. CONCLUSION: Results showed that mallow supplement protects the kidneys and liver against side effects of cisplatin, and reduces the resultant oxidative stress and inflammation.

Protective effect of Malva sylvestris L. extract in ischemia-reperfusion induced acute kidney and remote liver injury.

Mallow (Malva sylvestris L.) has had medicinal and therapeutic uses in addition to its oral consumption. The present study was conducted to examine the protective effect of Malva sylvestris L. extract on ischemia-reperfusion-induced kidney injury and remote organ injuries in the liver. Before ischemia-reperfusion, rats in the different groups received intraperitoneal normal saline or mallow extract at the doses of 200, 400 or 600 mg/kg of body weight. After 30-minutes of bilateral renal ischemia followed by 24-hours of reperfusion, tissue damage in the kidney and liver samples were determined through studying H&E-stained slides under a light microscope. The degree of leukocyte infiltration and tissue mRNA expressions of TNF- and ICAM-1 were then measured to examine the degree of renal inflammation. The renal tissue MDA and FRAP levels were measured for determining the amount of oxidative stress. Plasma concentrations of creatinine, urea, ALT and ALP were also measured. Ischemia-reperfusion led to a significant increase in plasma concentrations of creatinine, urea, ALT and ALP, and renal tissue MDA, and a significant decrease in renal tissue FRAP. The expression of pro-inflammatory factors in the kidney tissue, the level of leukocyte infiltration and the amount of tissue damage in the kidney and liver also increased. Pretreatment by mallow extract led to a significant improvement in all the variables measured. The 200- and 400-mg doses yielded better results in most parameters compared to the 600-mg dose. The findings showed that mallow extract protects the kidney against ischemia-reperfusion and reduces remote organ injury in the liver.

Therapeutic effects of curcumin on the functional disturbances and oxidative stress induced by renal ischemia/reperfusion in rats.

OBJECTIVE: Curcumin has anti-inflammatory and antioxidative properties. The objective of this study was to investigate the therapeutic effects of curcumin on functional disturbances, oxidative stress, and leukocyte infiltration induced by renal ischemia/reperfusion (I/R). MATERIALS AND METHODS: Animals were randomly divided into 9 groups. The groups with 24-h reperfusion consisted of sham-24h, I/R-24h, and three I/R groups treated with curcumin at 10, 20, or 30 mg kg(-1), i.p. after the ischemic period. The 72-h reperfusion groups also included Sham-72h, I/R-72h, I/R treated with curcumin at single dose of 20 mg kg(-1), i.p., and I/R group which received three doses of curcumin at 20 mg kg(-1), i.p., consecutively. Renal functional injury was assessed by measuring serum creatinine and urea-nitrogen concentrations. Oxidative stress was evaluated by assessment tissue malondialdehyde (MDA) and the ferric reducing/antioxidant power (FRAP) levels. Moreover, renal tissue leukocyte infiltration was measured by histopathology examination. RESULTS: Ischemia/reperfusion resulted in a significant increase in serum concentration of creatinine, urea-nitrogen, tissue MDA level, and leukocytes infiltration as well as reduced FRAP level. Treatment with curcumin in 24-h reperfusion groups could only lead to a significant change in the levels of MDA and FRAP. However, in 72-h reperfusion groups, curcumin was able to correct all functional disturbances, oxidative stress, and leukocytes infiltration with more effectiveness in groups that received three doses of curcumin. CONCLUSION: The administration of curcumin during 72-h reperfusion following 30 minutes of ischemia can decrease renal oxidative stress and leukocytes infiltration as well as improve kidney function. However, during first 24-h reperfusion, curcumin only decreased oxidative stress.