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Purpose: To evaluate the benefits of allicin, a vital garlic component, against streptozotocin-induced diabetic kidney damage in rats. Methods: A total of thirty male albino Wistar rats were divided into five groups of six rats each, with groups II – IV induced with diabetes using a single intraperitoneal administration of streptozotocin (55 mg/kg). Group I served as normal control while Group II was untreated diabetic control, receiving vehicle injections. Diabetic rats in Groups III and IV were treated with allicin (diallyl thiosulfinate, DATS, 20 mg/kg/day orally for 15 days) and aminoguanidine (AG, 100 mg/kg/day orally for 15 days), respectively, while Group V rats served as normal control rats receiving DATS only. Various biochemical, and kidney marker assessments and histological examinations were conducted at the end of treatment. Results: Streptozotocin-induced diabetic rats exhibited significant (p < 0.05) alterations in body weight, kidney metrics, kidney markers and renal histopathology compared to normal control (Group I). Treatment with DATS showed significant improvements in body weight, kidney metrics and biochemical markers (p < 0.05) indicating potential nephroprotective effect against diabetic nephropathy by significantly restoring kidney weight, protein levels, albumin, potassium, sodium and other urinary markers (p < 0.05). Furthermore, DATS effectively reversed STZ-induced renal damage with outcomes comparable to standard drug (aminoguanidine). Conclusion: Administration of DATS in rats with nephropathy from diabetes may have kidney protective benefits. The study highlights allicin’s potential as a therapeutic agent in managing diabetic complications, particularly diabetic nephropathy, prompting further exploration prior to future use. [ABSTRACT FROM AUTHOR]

Aim: Previous studies have shown that fenofibrate improves outcomes such as albuminuria and estimated glomerular filtration rate decline. We hypothesize that fenofibrate has renoprotective effects and prevents or delays the development of end‐stage renal disease. The objective of this study is to investigate the risk of incident end‐stage renal disease in relation to fenofibrate treatment in patients who are already taking statins. Materials and Methods: We performed a nationwide population‐based cohort study using data from the Korea National Health Information Database from 2010 to 2017. Among adults using statins, 413 715 fenofibrate users were compared with 413 715 fenofibrate non‐users after 1:1 age, sex and triglyceride matching. The endpoint of this study was incident end‐stage renal disease. Results: During a median 3.96‐year follow‐up, the incidence per 1000 person years of end‐stage renal disease was lower in fenofibrate users than in fenofibrate non‐users (0.885 vs. 0.960, p < 0.0001). The hazard ratio for end‐stage renal disease was lower (0.763, 95% confidence interval 0.710–0.821) in fenofibrate users. This association was significant in patients with hypertension, proteinuria and an estimated glomerular filtration rate <60 mL/min/1.732. Conclusions: Fenofibrate use in patients taking statins with either hypertension, proteinuria, or decreased estimated glomerular filtration rate is associated with a low risk of incident end‐stage renal disease. To confirm the renoprotective effect of fenofibrate in chronic kidney disease, a randomized controlled trial is warranted. [ABSTRACT FROM AUTHOR]

Introduction: From 2008 and following the withdrawal of rosiglitazone, obligatory cardiovascular outcomes trials are performed for glucose lowering drugs introduced to the market to ensure their cardiovascular (CV) safety. Paradoxically, these studies have demonstrated CV safety but also shown additional cardio-reno-vascular protection of some therapeutic agents. Additionally, nonsteroidal mineralocorticoid receptor antagonists (ns-MRA) have emerged as novel drugs for cardio – and renoprotection in type 2 diabetes (T2D) and chronic kidney disease (CKD). In addition to atherosclerotic CV disease, heart failure (HF) and CKD are important clinical problems in T2D leading to poor quality of life and premature death as such cardio-reno-vascular protection is an important clinical issue. Areas covered: We provide new insights into pharmacotherapeutic cardio-reno-vascular protection in T2D based on the new glucose lowering drugs and ns-MRA. PUB MED/CINAHL/Web of Science/Scopus were searched (May 2024). Expert opinion: The conventional glucose lowering approach alone which was implemented for decades is now replaced by the use of disease modifying drugs which lower the rates of CV events, HF decompensation, hospitalization due to HF, slow progression of CKD and all-cause mortality. Indeed, the choice of medications in T2D should be focused on underlying co-morbidities with cardio-reno-vascular protection rather than a gluco-centric approach. [ABSTRACT FROM AUTHOR]

Background and Aims Contrast-induced nephropathy (CIN), also known as contrast-associated acute kidney injury (CA-AKI) underlies a significant proportion of the morbidity and mortality following coronary angiographic procedures in high-risk patients and remains a significant unmet need. In pre-clinical studies inorganic nitrate, which is chemically reduced in vivo to nitric oxide, is renoprotective but this observation is yet to be translated clinically. In this study, the efficacy of inorganic nitrate in the prevention of CIN in high-risk patients presenting with acute coronary syndromes (ACS) is reported. Methods NITRATE-CIN is a double-blind, randomized, single-centre, placebo-controlled trial assessing efficacy of inorganic nitrate in CIN prevention in at-risk patients presenting with ACS. Patients were randomized 1:1 to once daily potassium nitrate (12 mmol) or placebo (potassium chloride) capsules for 5 days. The primary endpoint was CIN (KDIGO criteria). Secondary outcomes included kidney function [estimated glomerular filtration rate (eGFR)] at 3 months, rates of procedural myocardial infarction, and major adverse cardiac events (MACE) at 12 months. This study is registered with ClinicalTrials.gov : NCT03627130. Results Over 3 years, 640 patients were randomized with a median follow-up of 1.0 years, 319 received inorganic nitrate with 321 received placebo. The mean age of trial participants was 71.0 years, with 73.3% male and 75.2% Caucasian; 45.9% had diabetes, 56.0% had chronic kidney disease (eGFR <60 mL/min) and the mean Mehran score of the population was 10. Inorganic nitrate treatment significantly reduced CIN rates (9.1%) vs. placebo (30.5%, P <.001). This difference persisted after adjustment for baseline creatinine and diabetes status (odds ratio 0.21, 95% confidence interval 0.13–0.34). Secondary outcomes were improved with inorganic nitrate, with lower rates of procedural myocardial infarction (2.7% vs. 12.5%, P =.003), improved 3-month renal function (between-group change in eGFR 5.17, 95% CI 2.94–7.39) and reduced 1-year MACE (9.1% vs. 18.1%, P =.001) vs. placebo. Conclusions In patients at risk of renal injury undergoing coronary angiography for ACS, a short (5 day) course of once-daily inorganic nitrate reduced CIN, improved kidney outcomes at 3 months, and MACE events at 1 year compared to placebo. [ABSTRACT FROM AUTHOR]

Dina Kutbi,1,2 Riyadh S Almalki3 1Department of Pharmacy, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia; 2Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm AL-Qura University, Makkah, Saudi ArabiaCorrespondence: Dina Kutbi, Department of Pharmacy, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia, Email dina.t.kutbi@gmail.comBackground: Methotrexate (MTX) is a folic acid antagonist, commonly administered for the treatment of a variety of cancers. However, methotrexate toxicity including bone marrow suppression and hepatic and renal toxicity limits its use. Angiotensin AT1 receptor blockers including Valsartan (Val) possess the ability to ameliorate MTX-induced toxicity through various mechanisms. In this study, we explored the potential reno-protective effects of Val against MTX-induced acute kidney injury in rats.Methods: Twenty-four Wistar rats were randomly segregated into 3 groups. Group 1 served as the control group and received an oral dose of 1mL/kg of normal saline. Group 2 received a single dose of 20 mg/kg of MTX intraperitoneally (IP) for 5 days. Group 3 received a single IP dose of 20 mg/kg of MTX followed by an oral dose of 10 mg/kg of Valsartan for 5 days. At the end of the experiment, the levels of serum kidney biomarkers, inflammatory and oxidative stress markers were accessed. Furthermore, the effect of MTX on kidney tissue histology was examined.Results and discussion: Our results showed that MTX treatment increased the level of serum kidney and inflammatory biomarkers and decreased the level of antioxidants SOD and GSH while increasing the lipid peroxidation contents. Furthermore, MTX treatment caused structural changes to kidney histology. However, the administration of Val significantly prevented these changes.Conclusion: Valsartan possesses nephroprotective potential and might serve as a potential therapeutic strategy against MTX-induced kidney injury.Keywords: acute kidney injury, inflammation, methotrexate, oxidative stress, renal toxicity, renoprotection

Acute kidney injury (AKI) is a serious health concern with high morbidity and high mortality worldwide. Recently, sexual dimorphism has become increasingly recognized as a factor influencing the severity of the disease. This study explores the gender-specific renoprotective pathways in αMUPA transgenic mice subjected to AKI. αMUPA transgenic male and female mice were subjected to ischemia–reperfusion (I/R)-AKI in the presence or absence of orchiectomy, oophorectomy, and L-NAME administration. Blood samples and kidneys were harvested 48 h following AKI for the biomarkers of kidney function, renal injury, inflammatory response and intracellular pathway sensing of or responding to AKI. Our findings show differing responses to AKI, where female αMUPA mice were remarkably protected against AKI as compared with males, as was evident by the lower SCr and BUN, normal renal histologically and attenuated expression of NGAL and KIM-1. Moreover, αMUPA females did not show a significant change in the renal inflammatory and fibrotic markers following AKI as compared with wild-type (WT) mice and αMUPA males. Interestingly, oophorectomized females eliminated the observed resistance to renal injury, highlighting the central protective role of estrogen. Correspondingly, orchiectomy in αMUPA males mitigated their sensitivity to renal damage, thereby emphasizing the devastating effects of testosterone. Additionally, treatment with L-NAME proved to have significant deleterious impacts on the renal protective mediators, thereby underscoring the involvement of eNOS. In conclusion, gender-specific differences in the response to AKI in αMUPA mice include multifaceted and keen interactions between the sex hormones and key biochemical mediators (such as estrogen, testosterone and eNOS). These novel findings shed light on the renoprotective pathways and mechanisms, which may pave the way for development of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is reported as one of the most serious microvascular diabetic complications and the trigger of end-stage renal disease (ESRD), underscoring the concern of any therapeutic intervention directed at ameliorating the development and progression of DN. The current study explored the renoprotective impact of montelukast (Mon) against streptozotocin (STZ)-induced DN in rats compared to a standard anti-hyperglycemic insulin (Ins) treatment. Diabetes was induced by a single dose of STZ (55 mg/kg). Diabetic rats were treated with Mon (10 and 20 mg/kg, oral gavage) for eight weeks. Mon administration for 8 weeks after induction of diabetes conferred significant dose-dependent renoprotection, independent of blood glucose levels (unlike Ins), as evidenced by the improvement in serum creatinine, and blood urea nitrogen (BUN), and ameliorated STZ-induced renal necrotic, inflammatory alterations, and renal fibrosis. Additionally, Mon treatment in diabetic rats significantly restored redox hemostasis as evidenced by malondialdehyde (MDA) and total antioxidant capacity (TAC) levels; significantly reduced the renal expression of high mobility group box (HMGB) 1, toll-like receptor (TLR) 4, nuclear factor kappa B (NF-κB) (in the nucleus), NOD-like receptor family pyrin domain containing (NLRP) 3, and interleukin (IL)-1β. Moreover, Mon administration ameliorated the dysregulation in autophagy as evidenced by p62 and microtubule-associated protein 1A/1B-light chain 3 (LC3)-II levels. In conclusion, the renoprotective effect of Mon is potentially associated with its modulatory effect on inflammatory cytokines, antioxidant properties, and autophagy. Renoprotective effect of montelukast and its underlying pathway: Hyperglycemia and advanced glycation end products (AGEs) stimulate the release of high mobility group box (HMGB) 1 from necrotic and inflammatory cells. HMGB1 is considered as one of the endogenous ligands of toll-like receptor (TLR) 4, and the interaction of HMGB1 with TLR4 results in a subsequent translocation of nuclear factor kappa B (NF-κB) from the cytoplasm into the nucleus inducing an inflammatory response. NF-κB is a key mediator of the priming signal responsible for the activation of NOD-like receptor family pyrin domain containing (NLRP) 3 inflammasome by stimulating the expression of both NLRP3 and pro- interleukin (IL)-1β, which is then converted to IL-1β by to mediate inflammation. NLRP3 can induce reactive oxygen species production, while autophagy inhibits AGEs and NLRP3 accumulation. Montelukast show an inhibitory effect on HMGB1, TLR4, NF-κB, NLRP3, and IL-1β and has autophagy stimulating characteristics indicating its potential renoprotective effect. [ABSTRACT FROM AUTHOR]

Background: The growing prevalence of cancer and the concomitant rise in chemotherapy use have led to an increased incidence of kidney-related diseases, including nephrotoxicity. Cisplatin (CP) is a widely used and potent anticancer drug, but nephrotoxicity limits its clinical application. Purpose: Our study aimed to determine the phytochemicals and median lethal dose of Cucumeropsis mannii seed oil (CMSO) using standard methods and to further investigate the effects of CMSO on CP-induced nephrotoxicity in male Wistar rats. Methods: Twenty-one rats (100 to 150 g) were randomly divided into seven groups (n = 3) and treated with CMSO or normal saline for ten days. Group A received 1.0 mL of normal saline, irrespective of the body weight (b.w.). Groups B-D received 2500, 5000, and 7500 mg/kg b.w., respectively, of the CMSO and a single intraperitoneal dose of CP (8 mg/kg) on the seventh day. Groups E and F were administered 2500 mg/kg and 7500 mg/kg b.w., respectively, of the CMSO without CP administration. Group G received a single intraperitoneal dose (8 mg/kg b.w.) of CP on the seventh day without CMSO treatment. Results: The analysis of CMSO revealed the presence of various phytochemicals such as hydrogen cyanide, glycosides, saponins, steroids, tannins, alkaloids, terpenoids, phenols, and flavonoids. Acute toxicity testing demonstrated the safety of CMSO up to 5000 mg/kg b.w. We discovered that the CP administration increased serum creatinine (sCr), urea, blood urea nitrogen (BUN), and malondialdehyde (MDA) levels in rats and markedly decreased renal superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and glutathione (GSH) levels. CMSO attenuated kidney dysfunction, oxidative stress, and lipid peroxidation. Interestingly, CMSO prominently decreased sCr, urea, and BUN levels, boosted the activity of SOD, CAT, and GPx, increased GSH levels, and significantly (p < 0.05) decreased MDA levels. Histological assessment corroborated these biochemical findings. Conclusion: Our findings highlight the potential of CMSO as a protective agent against CP-induced nephrotoxicity. The observed effects are attributable to the rich phenolic and flavonoid content of CMSO. These findings have significant implications for developing complementary therapies to mitigate chemotherapy-associated kidney damage, potentially enhancing the safety and efficacy of cisplatin-based cancer treatments. Further investigation is needed to explore the clinical applications of CMSO for cancer patients.

Background: Diabetic nephropathy is a progressive condition and a leading cause of end-stage renal disease. Oxidative stress and inflammation play an important role in its pathogenesis. In pre-clinical studies, Montelukast had shown renoprotective and anti-oxidant properties, hence the study was planned to evaluate the effect of Montelukast in a Streptozotocin (STZ) induced model of diabetic nephropathy. Methods: 40 Wistar rats of either sex were randomly divided into four groups viz. 1. Vehicle control group, 2. Enalapril (5 mg/kg), 3. Montelukast low-dose (10 mg/kg) and 4. High-dose (20 mg/kg) group. On day 1, diabetes was induced using a single dose of STZ (60 mg/kg) intraperitoneally. Diabetes induction was verified based on fasting blood glucose (FBG) levels on day 7 and from day 8 to day 42, rats were given study drugs. FBG, serum creatinine, blood urea nitrogen (BUN) and urine microalbumin levels were assessed pre-study and post-study. Assessments of kidney malondialdehyde (MDA), reduced glutathione (GSH) and renal histopathology were carried out at the end of the study. Results: Montelukast 10 mg/kg group showed significantly lower urine microalbumin levels compared to the vehicle control group (p < 0.05). Montelukast 20 mg/kg group showed significantly lower levels of FBG, serum creatinine, BUN and urine microalbumin compared to the vehicle control group (p < 0.05). In addition, Montelukast 20 mg/kg group also showed better effects on kidney MDA and GSH levels (p < 0.05) and histopathological scores compared to the vehicle control group. Conclusion: Montelukast showed a protective effect in the model of diabetic nephropathy because of its antioxidant effect.

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are considered to have the potential to maintain renal function by correcting glomerular hypertension in patients with diabetic kidney disease (DKD). The aim of this study is to demonstrate the renoprotective effect of SGLT2i by measuring renal hemodynamics, including glomerular filtration fraction (FF), in type 2 diabetic patients with moderate renal dysfunction. Methods Renoprotective effect of canagliflozin derived from test of renal hemodynamics in diabetic kidney disease (FAGOTTO) study is a 12-week multicenter, open-label, randomized (1:1), parallel-group trial of type 2 diabetic patients with diabetic kidney disease (30 ≤ estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2). A total of 110 patients are to be randomly allocated to receive once-daily canagliflozin 100 mg or control (standard therapy). FF will be calculated by dividing the measured GFR (mGFR) by the effective renal plasma flow (eRPF). mGFR and eRPF will be measured by the clearance of inulin and para-aminohippuric acid (PAH), respectively. The primary endpoint of this trial is the percentage change in FF after 4 weeks of treatment in the canagliflozin and control groups. Discussion The FAGOTTO study will elucidate the mechanism of the renoprotective action of SGLT2i. The background, rationale, and study design of this trial are presented. To date, > 80 patients have been enrolled in this trial. The study will end in 2025. Trial registration jRCT (Japan Registry Of Clinical Trials) jRCTs041200069. Date of registration: November 27, 2020.

Introduction: Although sirtuin 3 (SIRT3) is known to be involved in dexmedetomidine (DEX)‐mediated alleviation of renal ischemia and reperfusion injury, the influence of the association between DEX and SIRT3 on nephritis development remains unclear. In this study, the role of SIRT3 in DEX‐mediated amelioration of inflammation and oxidative stress in nephritis as well as the possible underlying mechanism were explored in vivo and in vitro. Methods: An animal model of glomerulonephritis was generated by injecting mice with interferon‐alpha (IFNα)‐expressing adenoviruses, and periodic acid–Schiff staining was then used to reveal pathogenicity‐related changes in the renal tissue. Additionally, human embryonic kidney cells (HEK293) and renal mesangial cells (RMCs) were treated with IFNα to establish cell models of inflammation in vitro. Results: DEX administration alleviated glomerulonephritis in the animal model and upregulated SIRT3 expression in the renal tissue. SIRT3 knockdown inhibited the renoprotective effects of DEX against nephritis. IFNα induced inflammation, oxidative stress, and apoptosis in the RMCs and HEK293 cells and reduced their growth, as evidenced by the evaluation of cytokine levels (enzyme‐linked immunosorbent assay), reactive oxygen species generation, catalase and superoxide dismutase activities, nuclear factor‐erythroid factor 2‐related factor 2/heme oxygenase‐1 signal transduction, apoptotic cell proportion, and cell viability. In addition to promoting SIRT3 expression, DEX inhibited IFNα‐induced inflammation, oxidative stress, and apoptosis in these cells and promoted their viability. SIRT3 knockdown partially reversed the beneficial effects of DEX on RMCs and HEK293 cells. Conclusions: Our results suggest that DEX exhibits renoprotective activity during nephritis progression, protecting renal cells against inflammatory injury by promoting SIRT3 expression. [ABSTRACT FROM AUTHOR]

Background: Diabetic nephropathy is a progressive condition and a leading cause of end-stage renal disease. Oxidative stress and inflammation play an important role in its pathogenesis. In pre-clinical studies, Montelukast had shown renoprotective and anti-oxidant properties, hence the study was planned to evaluate the effect of Montelukast in a Streptozotocin (STZ) induced model of diabetic nephropathy. Methods: 40 Wistar rats of either sex were randomly divided into four groups viz. 1. Vehicle control group, 2. Enalapril (5 mg/kg), 3. Montelukast low-dose (10 mg/kg) and 4. High-dose (20 mg/kg) group. On day 1, diabetes was induced using a single dose of STZ (60 mg/kg) intraperitoneally. Diabetes induction was verified based on fasting blood glucose (FBG) levels on day 7 and from day 8 to day 42, rats were given study drugs. FBG, serum creatinine, blood urea nitrogen (BUN) and urine microalbumin levels were assessed pre-study and post-study. Assessments of kidney malondialdehyde (MDA), reduced glutathione (GSH) and renal histopathology were carried out at the end of the study. Results: Montelukast 10 mg/kg group showed significantly lower urine microalbumin levels compared to the vehicle control group (p < 0.05). Montelukast 20 mg/kg group showed significantly lower levels of FBG, serum creatinine, BUN and urine microalbumin compared to the vehicle control group (p < 0.05). In addition, Montelukast 20 mg/kg group also showed better effects on kidney MDA and GSH levels (p < 0.05) and histopathological scores compared to the vehicle control group. Conclusion: Montelukast showed a protective effect in the model of diabetic nephropathy because of its antioxidant effect. [ABSTRACT FROM AUTHOR]

Renal ischemia-reperfusion injury (IRI) is a critical health concern that aggravates the pathophysiology of acute kidney injury (AKI), leading to high mortality rates in intensive care units. Cardamonin is a natural compound with anti-inflammatory and antioxidant properties. The current study aimed to evaluate the renoprotective impact of cardamonin against AKI induced by renal IRI. Male rats (n=5 per group) were divided into four groups: the sham group underwent anesthesia and abdominal incision only; the control group experienced bilateral renal artery clamping for 30 minutes followed by 2 hours of reperfusion; the vehicle group received the cardamonin vehicle 30 minutes before ischemia induction; and the cardamonin group was administered 5 mg/kg of cardamonin 30 minutes before ischemia. Blood urea nitrogen (BUN) and creatinine were measured to assess the renal function. Tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin-6 (IL-6), caspase 3, and F2-isoprostane were assessed in renal tissues. Kidney injury was examined using the hematoxylin and eosin stain method. Compared to the sham group, the control group exhibited significantly higher levels of BUN, creatinine, TNF-α, IL-1β, IL-6, F2-isoprostane, and caspase 3 in renal tissues, along with severe kidney injury as evidenced by histological analysis. Compared to the control group, pretreatment with cardamonin resulted in a significant reduction in these biomarkers and alleviated renal damage. Cardamonin had renoprotective effects against renal ischemia and reperfusion injury via modulating inflammation, oxidative stress, and apoptosis pathways. [ABSTRACT FROM AUTHOR]

Renal ischemia-reperfusion (I-R) injury is a complex pathophysiologic condition characterized by oxidative stress, inflammation and apoptosis. We investigated the potential renoprotective effect of nebivolol, a β1 adrenergic receptor blocker, against renal I-R injury. We focused on the role of nebivolol in activating p38 mitogen-activated protein kinase (MAPK) signaling, Akt (protein kinase B) and nuclear factor-κB (NFκB) transcription factors, which contribute to oxidative stress, inflammation and apoptosis during renal I-R. We divided 20 adult male Wistar albino rats into three experimental groups. Group 1 was a sham control in which only laparotomy was performed. Group 2 was the I-R group in which both kidneys were made ischemic for 45 min, then reperfused for 24 h. Group 3 was the I-R + nebivolol group in which 10 mg/kg nebivolol was administrated by gavage for 7 days before I-R. We measured Inflammation, oxidative stress and active caspase-3 as well as activation of p38 MAPK, Akt (protein kinase B) and NFκB transcription factor. Nebivolol significantly reduced oxidative stress and increased superoxide dismutase levels during renal I-R. We found that nebivolol significantly decreased interstitial inflammation, and TNF-α and interleukin-1β mRNA expression. Nebivolol significantly reduced active caspase-3 and kidney injury molecule-1 (KIM-1) expressions. Nebivolol also significantly decreased activation of p38 MAPK signaling and NFκB, and induced Akt activation during renal I-R. Our findings suggest that nebivolol may be useful for management of renal I-R injury. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic kidney disease (CKD) is a worldwide public health problem affecting millions of people. Probiotics and postbiotics are associated with valuable compounds with antibacterial, anti-inflammatory, and immunomodulatory effects, preserving renal function in CKD patients. The current study is aimed to evaluate the efficacy of Limosilactobacillus fermentum (L. fermentum) and its postbiotic in an animal model of cisplatin-induced CKD. Methods The animals were divided into four experimental groups (normal mice, CKD mice with no treatment, CKD mice with probiotic treatment, and CKD mice with postbiotic treatment). CKD mice were induced by a single dose of cisplatin 10 mg/kg, intraperitoneally. For 28 days, the cultured probiotic bacteria and its supernatant (postbiotic) were delivered freshly to the related groups through their daily water. Then, blood urea nitrogen (BUN) and creatinine (Cr) of plasma samples as well as glutathione (GSH), lipid peroxidation, reactive oxygen species, and total antioxidant capacity of kidneys were assessed in the experimental mice groups. In addition, histopathological studies were performed on the kidneys. Results Application of L. fermentum probiotic, and especially postbiotics, significantly decreased BUN and Cr (P

Abstract Background The ischemia–reperfusion (IR) environment during deep hypothermic circulatory arrest (DHCA) cardiovascular surgery is a major cause of acute kidney injury (AKI), which lacks preventive measure and treatment. It was reported that cold inducible RNA-binding protein (CIRP) can be induced under hypoxic and hypothermic stress and may have a protective effect on multiple organs. The purpose of this study was to investigate whether CIRP could exert renoprotective effect during hypothermic IR and the potential mechanisms. Methods Utilizing RNA-sequencing, we compared the differences in gene expression between Cirp knockout rats and wild-type rats after DHCA and screened the possible mechanisms. Then, we established the hypothermic oxygen–glucose deprivation (OGD) model using HK-2 cells transfected with siRNA to verify the downstream pathways and explore potential pharmacological approach. The effects of CIRP and enarodustat (JTZ-951) on renal IR injury (IRI) were investigated in vivo and in vitro using multiple levels of pathological and molecular biological experiments. Results We discovered that Cirp knockout significantly upregulated rat Phd3 expression, which is the key regulator of HIF-1α, thereby inhibiting HIF-1α after DHCA. In addition, deletion of Cirp in rat model promoted apoptosis and aggravated renal injury by reactive oxygen species (ROS) accumulation and significant activation of the TGF-β1/p38 MAPK inflammatory pathway. Then, based on the HK-2 cell model of hypothermic OGD, we found that CIRP silencing significantly stimulated the expression of the TGF-β1/p38 MAPK inflammatory pathway by activating the PHD3/HIF-1α axis, and induced more severe apoptosis through the mitochondrial cytochrome c-Apaf-1-caspase 9 and FADD-caspase 8 death receptor pathways compared with untransfected cells. However, silencing PHD3 remarkably activated the expression of HIF-1α and alleviated the apoptosis of HK-2 cells in hypothermic OGD. On this basis, by pretreating HK-2 and rats with enarodustat, a novel HIF-1α stabilizer, we found that enarodustat significantly mitigated renal cellular apoptosis under hypothermic IR and reversed the aggravated IRI induced by CIRP defect, both in vitro and in vivo. Conclusion Our findings indicated that CIRP may confer renoprotection against hypothermic IRI by suppressing PHD3/HIF-1α-mediated apoptosis. PHD3 inhibitors and HIF-1α stabilizers may have clinical value in renal IRI.

Background: Sodium-glucose transporter 2 (SGLT-2) inhibitors provide additional benefits besides glycemic control. Aim: This study aims to compare the clinical outcomes of dapagliflozin and empagliflozin. Methods: This retrospective study evaluated data retrieved from medical records of patients who were under follow-up with the diagnosis of type 2 diabetes mellitus (T2DM) and were started on dapagliflozin or empagliflozin treatment between January 1, 2017, and June 1, 2020. Demographic features, comorbidities, clinical features, duration of diabetes, baseline, and follow-up laboratory test results were recorded. The significance level was set at p < 0.05. Results: This study comprised 342 patients who are on the treatment with dapagliflozin (n = 228) or empagliflozin (n = 114). The glycosylated hemoglobin a1c (HBA1C) level was significantly decreased in both the dapagliflozin (8.18–7.59, p < 0.001) and empagliflozin (8.35–7.58, p < 0.001) groups. The urine albumin-to-creatinine ratio (ACR) was also decreased in both groups. A decrease in urine ACR was observed independent of using a renin–angiotensin–aldosterone system (RAAS) blocker both in the whole group and in patients with diabetic nephropathy. The time to addition of a new anti-diabetic agent to the treatment was shorter in the dapagliflozin group (14.4 months vs 17.7 months, p = 0.041, respectively). Conclusion: Dapagliflozin and empagliflozin are the drugs to choose for renoprotection in diabetics independent of the use of a RAAS blocker. Even the time to addition of a new anti-diabetic agent is longer in the empagliflozin group, head-to-head comparative trials are needed to asess the potential differences in this regard. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are considered to have the potential to maintain renal function by correcting glomerular hypertension in patients with diabetic kidney disease (DKD). The aim of this study is to demonstrate the renoprotective effect of SGLT2i by measuring renal hemodynamics, including glomerular filtration fraction (FF), in type 2 diabetic patients with moderate renal dysfunction. Methods: Renoprotective effect of canagliflozin derived from test of renal hemodynamics in diabetic kidney disease (FAGOTTO) study is a 12-week multicenter, open-label, randomized (1:1), parallel-group trial of type 2 diabetic patients with diabetic kidney disease (30 ≤ estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2). A total of 110 patients are to be randomly allocated to receive once-daily canagliflozin 100 mg or control (standard therapy). FF will be calculated by dividing the measured GFR (mGFR) by the effective renal plasma flow (eRPF). mGFR and eRPF will be measured by the clearance of inulin and para-aminohippuric acid (PAH), respectively. The primary endpoint of this trial is the percentage change in FF after 4 weeks of treatment in the canagliflozin and control groups. Discussion: The FAGOTTO study will elucidate the mechanism of the renoprotective action of SGLT2i. The background, rationale, and study design of this trial are presented. To date, > 80 patients have been enrolled in this trial. The study will end in 2025. Trial registration: jRCT (Japan Registry Of Clinical Trials) jRCTs041200069. Date of registration: November 27, 2020. [ABSTRACT FROM AUTHOR]

Abstract Background The renal burden imposed by diclofenac sodium (DS) remedy is a significant concern and limits the extension in its clinical application. Curcumin (Cur) can be used as a promising natural phytochemical in rescuing chemotherapy-associated renal dysfunction owing to its redox stabilizing and cytoprotective nature. Thus, the current experiment aims to highlight the possible ameliorative impact of Cur on DS-induced renal damage and its mediating mechanisms in adult male mice. Methods A total number of eighteen healthy adult mice of the male sex were classified into 3 groups for 21 days. The first group served as a control, whereas the second one received DS at 10 mg/kg body weight by intraperitoneal route of administration daily during the last 14 days of the experiment. The third group was supplemented with Cur at 100 mg/kg body weight during the entire duration of the intervention in conjunction with the DS burden. At the end of the experimental protocol, kidney functions, redox parameters, histopathological investigation and TUNEL assay were performed. Results Cur succeeded in restoring the typical histomorphometric features and reducing the apoptosis in the kidney. The redox disturbances in the kidney of DS-challenged mice rebalanced were manifested by normalizing the level of renal reduced glutathione and immunostaining of glutathione reductase and superoxide dismutase 2. No marked alteration in plasma urea level in the DS group could be noticed compared to the control. Nevertheless, an obvious reduction in plasma urea level was observed in the DS+Cur group relative to the control and DS groups. The comparison between all experimental groups revealed the absence of significant difference in plasma creatinine and renal lipid peroxide levels. Conclusions Cur might exert its renoprotective action through its cytoprotective, anti-apoptotic and antioxidant characteristics. The findings of this study shed light on using natural phytochemicals to alleviate the adverse influences of chemotherapies.

Background. Clinical studies of urate-lowering therapy (ULT) use in multimorbid patients, including those with chronic kidney disease (CKD), are important in modern medical science. The purpose was to determine the efficacy and safety of ULT in patients with hyperuricemia and comorbid conditions, including people with chronic kidney disease, in real clinical practice. Materials and methods. This prospective comparative clinical study “Liquestia: comparative efficacy and safety in gouty arthritis patients with comorbid diseases and in patients with hyperuricemia and chronic kidney disease” was conducted in real clinical practice with the involvement of 124 patients with hyperuricemia, who were prescribed either febuxostat (Liquestia, JSC “Farmak”/Adenuric, Berlin Chemie) or allopurinol as ULT. Results. Individuals who received febuxostat significantly more often and faster reached the target levels of uric acid compared to patients who underwent treatment by allopurinol, regardless of glomerular filtration rate (GFR), except those from dialysis subgroup, and the presence of comorbidities. Patients in febuxostat subgroups during the study showed an increase in GFR after 6 months of treatment — at the level of the trend in the group with baseline GFR ≥ 60 ml/min and at a statistically significant level — in CKD stage 3–4, which could be the evidence of renoprotective effect of febuxostat with reduced GFR, while people receiving allopurinol tended to further decrease of GFR in 31.8 % of cases. Conclusions. The use of Liquestia for the treatment of patients with hyperuricemia and various comorbid conditions is no less effective than the use of Adenuric and more effective than allopurinol and helps achieve the target levels of uric acid in 90 % of cases within 6 months of treatment, which accompanied by a statistically significant increase in GFR in patients with CKD stage 3–4.

Kidney disease is a growing public health problem worldwide, including both acute and chronic forms. Existing therapies for kidney disease target various pathogenic mechanisms; however, these therapies only slow down the progression of the disease rather than offering a cure. One of the potential and emerging approaches for the treatment of kidney disease is mesenchymal stromal/stem cell (MSC) therapy, shown to have beneficial effects in preclinical studies. In addition, extracellular vesicles (EVs) released by MSCs became a potent cell-free therapy option in various preclinical models of kidney disease due to their regenerative, anti-inflammatory, and immunomodulatory properties. However, there are scarce clinical data available regarding the use of MSC-EVs in kidney pathologies. This review article provides an outline of the renoprotective effects of MSC-EVs in different preclinical models of kidney disease. It offers a comprehensive analysis of possible mechanisms of action of MSC-EVs with an emphasis on kidney disease. Finally, on the journey toward the implementation of MSC-EVs into clinical practice, we highlight the need to establish standardized methods for the characterization of an EV-based product and investigate the adequate dosing, safety, and efficacy of MSC-EVs application, as well as the development of suitable potency assays. [ABSTRACT FROM AUTHOR]

Background: Based on their anti-oxidative and anti-fibrotic properties, Angelica sinensis (Oliv.) Diels roots [Apiaceae; Radix Angelicae sinensis] (Danggui [abbreviated as S in the context]), Astragalus membranaceus (Fisch.) Bunge [Fabaceae; Astragalus membranaceus] (Huangqi [A]), Rheum palmatum L. [Polygonaceae; Rheum palmatum] (Dahuang [R]), and Salvia miltiorrhiza Bunge [Lamiaceae; Salvia miltiorrhiza Bunge radix et rhizoma] (Danshen [D]) are potential renoprotective Chinese herbal medicines (CHMs). Renoprotection using ARD alone for the treatment of chronic kidney disease (CKD) has been documented in pre-clinical, clinical, and meta-analysis research; however, only pre-clinical data are available for the use of S alone. Moreover, with an increasing number of CKD patients taking prescribed CHMs, hyperkalemia risk remains unclear. Methods: This study retrospectively analyzed national health insurance claims data in 2001-2017. Propensity score matching was used to analyze renal and survival outcomes and the dose-response effects of S without ARD use in 18,348 new S users, 9,174 new ARD users, and 36,696 non-users. Cox proportional hazard regression was used to investigate adjusted hazard ratios (aHRs) for end-stage renal disease (ESRD) in the presence of competing mortality and death. The additive effect of the S herb in single form to compounds was also analyzed. Additionally, to analyze hyperkalemia risk, an exact match on each covariate was used to include 42,265 new CHM users and non-users, while Poisson regression was used to estimate adjusted incidence rate ratios (aIRRs) of hyperkalemia of prescribed CHMs. Results: S users and ARD users were associated with aHRs of 0.77 (95% confidence interval; 0.69-0.86) and 1.04 (0.91-1.19), respectively, for ESRD and 0.55 (0.53-0.57) and 0.71 (0.67-0.75), respectively, for death. The renal and survival benefits of S use were consistent in several sensitivity analyses. The dose- and timedependent renoprotection and dose-dependent survival benefits were observed for S use. The top two additive renoprotective collocations of the S herb in compounds were Xue-Fu-Zhu-Yu-Tang and Shen-Tong-Zhu-Yu-Tang, followed by Shu-Jing-Huo-Xue-Tang and Shen-Tong-Zhu-Yu-Tang. Moreover, CHM users were associated with aIRRs of 0.34 (0.31-0.37) for hyperkalemia. Conclusion: This study suggests dose- and time-dependent renoprotection and dose-dependent survival benefits of the S herb in compounds and no increased hyperkalemia risk of the prescribed CHMs in CKD patients. [ABSTRACT FROM AUTHOR]

The authors conducted a study on 35 white Wistar outbred rats to investigate the possibility of correcting acute kidney damage induced by the administration of phenylhydrazine at a dose of 100 mg/kg by introducing a mixture of sodium chloride and sodium bicarbonate solutions into the body. The research results identified changes in the kidneys upon phenylhydrazine administration, including the loss of some capillary glomeruli, eosinophilic deposits in Bowman's spaces and tubular lumens, and lymphoid infiltration in the interstitium. Rats receiving a mixture of sodium chloride and sodium bicarbonate solutions in their drinking water showed positive changes in their kidneys: no loss of capillary glomeruli was observed, and eosinophilic deposits were absent in most tubules. Lymphocyte aggregation was only observed around some renal vessels. The authors suggest that the intake of additional sodium and bicarbonate into the body, along with alkalinization of the primary urine, promotes the excretion of hemolysis products caused by phenylhydrazine, which contributes to renoprotection and preservation of renal parenchyma.

Acetaminophen (APAP) is the most commonly used nonprescription antipyretic-analgesic drug. This medication is thought to be safe at the suggested dosage (4 g/24 h), but its overdose (up to 2.5 g/kg) can cause severe injuries to the human body, including renal injury. APAP has various toxic effects on nephrons, as it leads to an excessive free radical generation that, in turn, results in a disturbance in the redox homeostasis of cells, causing oxidative stress. To replenish this oxidative stress, there is an ultimate urge for natural therapies that can retain the cellular homeostasis of nephrons by diminishing the overdose impression of acetaminophen. The principle objective of this work is to appraise nephrotoxicity due to APAP and its amelioration through the antioxidant properties of aqueous extracts of selected medicinal plants: Urtica dioica, Capsella bursa-pastoris, and Inula racemosa (UD, CBP, and IR, respectively). The pH stability of the nutraceuticals used was examined by determining the impact of pH 4, pH 7 and pH 9 on the DPPH radical scavenging activity of aqueous plant extracts. Gas chromatography-Mass spectroscopy (GC–MS) analytical technique was performed to determine the volatile organic phytochemical profiles of all three medicinal plants. Male Swiss albino mice were used for the present investigation. The animals were distributed into five groups of (n = 6), a total of 30 mice, for in vivo analysis. Group 1 served as the control group; group 2 received a single IP dose of APAP (600 mg/kg); group 3 received APAP pretreated with UD (300 mg/kg); group 4 received APAP pretreated with CBP (300 mg/kg); and group 5 received APAP pretreated with IR (300 mg/kg). Overdose of the APAP- induced a significant (p < 0.05) alterations in the total protein concentration, weight and the nephrological architecture in renal tissue, as observed through biochemical assays and histopathological examinations. Due to nephrotoxicity, there was a substantial (p < 0.05) drop in body weight and total protein contents in the APAP alone group when compared to the treatment groups. There was remarkable protection against APAP-induced alterations in the total protein of renal homogenate in the treatment groups. Histopathological analysis (H&E staining) of the mice kidneys indicated severe deterioration in the APAP alone group, whereas the therapy groups showed considerable nephroprotection towards APAP-induced abnormalities. The biochemical findings and histopathological study of the kidneys revealed that the herbal extracts (UD, CBP, and IR) have a nephroprotective potential against APAP-induced nephropathy. The trend of efficacy was observed as UD > CBP > IR. However, extensive study is needed to determine the likely ameliorative mechanism of these nutraceuticals. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is one of frequent complications of sepsis with high mortality. Mitochondria is the center of energy metabolism participating in the pathogenesis of sepsis-associated AKI, and SIRT1/PGC1-α signaling pathway plays a crucial role in the modulation of energy metabolism. Erythropoietin (EPO) exerts protective functions on chronic kidney disease. We aimed to assess the effects of EPO on cell damage and energy metabolism in a cell model of septic AKI. Renal tubular epithelial cells HK-2 were treated with LPS and human recombinant erythropoietin (rhEPO). Cell viability was detected by CCK-8 and mitochondrial membrane potential was determined using JC-1 fluorescent probe. Then the content of ATP, ADP and NADPH, as well as lactic acid, were measured for the assessment of energy metabolism. Oxidative stress was evaluated by detecting the levels of ROS, MDA, SOD and GSH. Pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, were measured with ELISA. Moreover, qRT-PCR and western blot were performed to detect mRNA and protein expressions. shSIRT1 was used to knockdown SIRT1, while EX527 and SR-18292 were applied to inhibit SIRT1 and PGC1-α, respectively, to investigate the regulatory mechanism of rhEPO on inflammatory injury and energy metabolism. In LPS-exposed HK-2 cells, rhEPO attenuated cell damage, inflammation and abnormal energy metabolism, as indicated by the elevated cell viability, the inhibited oxidative stress, cell apoptosis and inflammation, as well as the increased mitochondrial membrane potential and energy metabolism. However, these protective effects induced by rhEPO were reversed after SIRT1 or PGC1-α inhibition. EPO activated SIRT1/PGC1-α pathway to alleviate LPS-induced abnormal energy metabolism and cell damage in HK-2 cells. Our study suggested that rhEPO played a renoprotective role through SIRT1/PGC1-α pathway, which supported its therapeutic potential in septic AKI. [ABSTRACT FROM AUTHOR]

Recent clinical trials in people with type 2 diabetes have demonstrated beneficial actions on heart and kidney outcomes following treatment with GLP-1RAs. In part, these actions are consistent with improved glucose control and significant weight loss. But GLP-1RAs may also have additive benefits by improving postprandial dysmetabolism. In diabetes, dysregulated postprandial nutrient excursions trigger inflammation, oxidative stress, endothelial dysfunction, thrombogenicity, and endotoxemia; alter hormone levels; and modulate cardiac output and regional blood and lymphatic flow. In this perspective, we explore the actions of GLP-1RAs on the postprandial state and their potential role in end-organ benefits observed in recent trials. Treatment with GLP-1RAs has been associated with beneficial actions on heart and kidney outcomes in recent clinical trials. Beyond improvements in glucose control and significant weight loss, Thomas et al. argue that the GLP-1RAs may also have additive benefits by improving postprandial dysmetabolism in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: The renal burden imposed by diclofenac sodium (DS) remedy is a significant concern and limits the extension in its clinical application. Curcumin (Cur) can be used as a promising natural phytochemical in rescuing chemotherapy-associated renal dysfunction owing to its redox stabilizing and cytoprotective nature. Thus, the current experiment aims to highlight the possible ameliorative impact of Cur on DS-induced renal damage and its mediating mechanisms in adult male mice. Methods: A total number of eighteen healthy adult mice of the male sex were classified into 3 groups for 21 days. The first group served as a control, whereas the second one received DS at 10 mg/kg body weight by intraperitoneal route of administration daily during the last 14 days of the experiment. The third group was supplemented with Cur at 100 mg/kg body weight during the entire duration of the intervention in conjunction with the DS burden. At the end of the experimental protocol, kidney functions, redox parameters, histopathological investigation and TUNEL assay were performed. Results: Cur succeeded in restoring the typical histomorphometric features and reducing the apoptosis in the kidney. The redox disturbances in the kidney of DS-challenged mice rebalanced were manifested by normalizing the level of renal reduced glutathione and immunostaining of glutathione reductase and superoxide dismutase 2. No marked alteration in plasma urea level in the DS group could be noticed compared to the control. Nevertheless, an obvious reduction in plasma urea level was observed in the DS+Cur group relative to the control and DS groups. The comparison between all experimental groups revealed the absence of significant difference in plasma creatinine and renal lipid peroxide levels. Conclusions: Cur might exert its renoprotective action through its cytoprotective, anti-apoptotic and antioxidant characteristics. The findings of this study shed light on using natural phytochemicals to alleviate the adverse influences of chemotherapies. [ABSTRACT FROM AUTHOR]

Cisplatin is a first-line antitumor drug which is applied in the therapeutic field of numerous kinds of cancers. The main dose-dependent adverse effect of cisplatin is nephrotoxicity in approximately one-third of patients, who received this drug during their treatment. Oxidative stress is one of the most significant mechanisms in cisplatin nephrotoxicity. Cisplatin-induced oxidative stress stimulates apoptosis, inflammation, mitochondrial damage within cells, and endoplasmic reticulum (ER) stress. The administration of an antioxidant in this context could be a suitable approach for preventing of cisplatin nephrotoxicity. Antioxidants are categorized into four classes: dietary antioxidants, free radical scavengers, thiol-containing compounds, and iron chelators.

Background: Due to the toxicity issues of synthetic compounds, herbal medicines are preferred in treating or curing many diseases in recent times. Because of limited treatment options for chronic kidney disease (CKD), the use of traditional herbal medication to alleviate urogenital problems is the alternate therapeutic selection. Purpose: Here, we summarized the research outcomes for the use of herbal medicine in the treatment of CKD and hurdles in the way for further research. Methods: A relevant literature based on combinations of keywords such as herbal medicines, Chinese herbal medicine, CKD, chronic renal failure, nephroprotection, renoprotection, vegetable-based diet, and plant-based diets was searched using Pub med, Google Scholar, and Science Direct databases. The original articles published from 2006 to 2021 were taken into consideration. The literature was evaluated by studying the abstract or full text, all irrelevant studies were ignored. Results: About 54 studies were found to describe the utilization of herbal drugs in the treatment of CKD in both human and laboratory animals, 17 studies described the clinical application of about 13 medicinal plants used against CKD in humans and 37 studies demonstrated the beneficial use of 24 medicinal plants in animal models and in vitro studies for CKD treatment explaining possible mechanisms of their action. The herbal treatment displayed anti-inflammatory, antioxidant, chemopreventive, and immune-mediated properties. The anti-inflammatory action is well implicated via regulation of cyclooxygenase-2, signal transducer, and activation of transcription 3 and IκB kinase β pathways. These pathways are being hypothesized to produce convincing results in CKD. The CKD and gut microbiota is known to be closely related through inflammatory, renal, cardiovascular, and endocrine processes. The various concerns encountered during the use of herbal therapy in CKD are unpredictable pharmacokinetics, herbal and physiological interactions, electrolytic imbalance, and interaction with co-morbid conditions. The combined use of Chinese herbal medicine and Western medicine for the treatment of advanced-stage CKD was found to be effective in delaying dialysis initiation and reducing dialysis incidence. Conclusions: A large number of medicinal plants have shown promising beneficial effects against several diseases including cancer, but only a handful of studies are available on CKD. Several studies explained the possible mechanisms of herbal medications in CKD for therapeutic use; however, the focussed molecular studies for identification of active components of medicinal herbs with their mechanism of action and safety standard are still awaited. The demand for well-designed clinical trials and rigorous pharmacological studies as well as a surge for combined use of herbal medicine and Western medicine for the treatment of CKD has been noticed. The nephrotoxicity issues of medicinal plants should not be ignored.

Background: For localized disease, partial nephrectomy of small tumors continues to be the gold-standard treatment. However, temporary clamping is routinely performed during this process to control renal blood flow, which can cause renal ischemic/reperfusion injury. We evaluated whether dexmedetomidine postconditioning (DPOC) can reduce renal ischemic/reperfusion injury for patients receiving laparoscopic partial nephrectomy (LPN). Methods: This randomized double-blind controlled trial included 77 patients who were scheduled for LPN at our hospital. Patients were randomly allocated to the DPOC or control group. DPOC was performed via intravenous administration of dexmedetomidine at 0.6 µgkg-1 for 10 min immediately after unclamping the renal artery. In the control group, saline was administered in place of dexmedetomidine under the same protocol. All participants underwent a 6-month follow-up. The primary outcome were the values of 99mTc-DTPA-GFR in the affected kidney at one and 6 months post-LPN. Result: The GFR values in the DPOC group (35.65 ± 4.89 ml min-1.1.73 m-2) were significantly higher than those the control group (33.10 ± 5.41 ml min-1.1.73 m-2; p = 0.022) at 1 month after LPN. There was no statistically significant difference in GFR value between the two groups at 6 months after LPN. Conclusion: DPOC provides therapeutic benefits to LPN patients, at least on a short-term basis, by alleviating renal ischemic/reperfusion injury. [ABSTRACT FROM AUTHOR]

Background. Clinical studies of urate-lowering therapy (ULT) use in multimorbid patients, including those with chronic kidney disease (CKD), are important in modern medical science. The purpose was to determine the efficacy and safety of ULT in patients with hyperuricemia and comorbid conditions, including people with chronic kidney disease, in real clinical practice. Materials and methods. This prospective comparative clinical study “Liquestia: comparative efficacy and safety in gouty arthritis patients with comorbid diseases and in patients with hyperuricemia and chronic kidney disease” was conducted in real clinical practice with the involvement of 124 patients with hyperuricemia, who were prescribed either febuxostat (Liquestia, JSC “Farmak”/ Adenuric, Berlin Chemie) or allopurinol as ULT. Results. Individuals who received febuxostat significantly more often and faster reached the target levels of uric acid compared to patients who underwent treatment by allopurinol, regardless of glomerular filtration rate (GFR), except those from dialysis subgroup, and the presence of comorbidities. Patients in febuxostat subgroups during the study showed an increase in GFR after 6 months of treatment — at the level of the trend in the group with baseline GFR ≥ 60 ml/min and at a statistically significant level — in CKD stage 3–4, which could be the evidence of renoprotective effect of febuxostat with reduced GFR, while people receiving allopurinol tended to further decrease of GFR in 31.8 % of cases. Conclusions. The use of Liquestia for the treatment of patients with hyperuricemia and various comorbid conditions is no less effective than the use of Adenuric and more effective than allopurinol and helps achieve the target levels of uric acid in 90 % of cases within 6 months of treatment, which accompanied by a statistically significant increase in GFR in patients with CKD stage 3–4. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion injury (IRI) during kidney transplantation is a serious clinical problem with a high mortality rate and a lack of therapy. Therefore, there is a need to improve the ability of the kidney to tolerate IRI during transplantation. This study aimed to investigate the possible protective effect of vinpocetine; a derivative of vincamine alkaloid; against renal IRI in rats with the elucidation of the involved mechanisms. Vinpocetine (25 mg/kg; i.p.) was administered for 10 successive days before the induction of ischemia by bilateral clamping of both renal pedicles for 45 min followed by 24 h of reperfusion. Blood and renal tissue samples were then collected for biochemical, molecular, and histopathological investigations. Vinpocetine significantly reduced serum creatinine and blood urea nitrogen levels in rats subjected to IRI. It also reduced mRNA expression of NADPH oxidase and renal content of malondialdehyde, while enhanced Nrf2 protein expression and renal content of reduced glutathione. The suppression of the provoked inflammatory response was evident by the downregulation of IKKβ and NF‐κB p65 protein expressions, as well as their downstream inflammatory markers; tumor necrosis factor‐α, interleukin‐6, and myeloperoxidase. In addition, vinpocetine reduced protein expression of the apoptotic executioner cleaved caspase‐3. These nephroprotective effects were confirmed by the improvement in histopathological features. Collectively, the protective effect of vinpocetine against IRI could be attributed to modulation of NADPH oxidase/Nrf2, IKKβ/NF‐κB p65, and cleaved caspase‐3 expressions. Thus, vinpocetine could improve oxidant/antioxidant balance, suppress triggered inflammatory response, and promote renal cell survival after IRI. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a pathological characteristic of the endpoint of chronic kidney disease (CKD), which remains a major public health problem. None of the current therapies is effective in stopping kidney fibrosis progression. In light of our novel detection of a potential antifibrosis of microcystins (MCs), we investigate the renoprotection effect of MCs with UUO-induced renal fibrosis. The treatment of MCs was initiated in model animals in advance of UUO operation. After determining that the antifibrotic effect of MCs was independent of its toxicity, our study focused on the renoprotection of microcystin-RR (MC-RR), a lower toxic congener of MCs, in UUO mice and the cell models in vitro. The co-immunoprecipitation assay and recombination plasmid transfection were used in the investigation of the mechanism of antifibrosis of MC-RR. The data show that MC-RR substantially exerts an effect on renoprotection with suppression of the expression of TGF-β1/Smad signaling molecules and a blockage in epithelial dedifferentiation and myofibroblast activation in UUO model animals. MC-RR shows a binding directly to pyruvate kinase M2 (PKM2), downregulates PKM2-HIF-1α signaling, restores the inhibited expression of MMP-7 and MMP-13, and reduces the upregulated expression of MMP-9 in UUO renal tissues. The current study demonstrates a novel effect of MC-RR on renoprotection in kidney damage, which could be conducted in therapeutics for chronic kidney disease. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a pathological characteristic of the endpoint of chronic kidney disease (CKD), which remains a major public health problem. None of the current therapies is effective in stopping kidney fibrosis progression. In light of our novel detection of a potential antifibrosis of microcystins (MCs), we investigate the renoprotection effect of MCs with UUO-induced renal fibrosis. The treatment of MCs was initiated in model animals in advance of UUO operation. After determining that the antifibrotic effect of MCs was independent of its toxicity, our study focused on the renoprotection of microcystin-RR (MC-RR), a lower toxic congener of MCs, in UUO mice and the cell models in vitro. The co-immunoprecipitation assay and recombination plasmid transfection were used in the investigation of the mechanism of antifibrosis of MC-RR. The data show that MC-RR substantially exerts an effect on renoprotection with suppression of the expression of TGF-β1/Smad signaling molecules and a blockage in epithelial dedifferentiation and myofibroblast activation in UUO model animals. MC-RR shows a binding directly to pyruvate kinase M2 (PKM2), downregulates PKM2-HIF-1α signaling, restores the inhibited expression of MMP-7 and MMP-13, and reduces the upregulated expression of MMP-9 in UUO renal tissues. The current study demonstrates a novel effect of MC-RR on renoprotection in kidney damage, which could be conducted in therapeutics for chronic kidney disease.

Aim: The aim of this study was to validate the potential of teneligliptin in managing type 2 diabetes mellitus (T2DM) with renal impairment and to evaluate its effect on renal parameters in Indian subjects. Patients and Methods: The prospective observational study included 86 subjects aged >40 years with suboptimal control of T2DM (HbA1c >7.5). The demographic details of the selected subjects were recorded. The patients were continued on existing oral hypoglycemic agents (OHAs) and antihypertensives. The following clinical and anthropometric parameters were measured at baseline, 4 months, 8 months, and 12 months during the treatment using 20 mg of teneligliptin per day: HbA1c, eGFRs, UACR, FBG, and PPBG levels. Comparisons of anthropometric and laboratory parameters were carried out using analysis of variance (ANOVA) and t test for normal data, Kruskal–Wallis for nonnormal data, and chi-square test for counts data. Results: The mean age of the subjects was 54.28 ± 6.8 years and the male-to-female ratio noted was 1:0.65. The mean values of FBG (mg/dL ± SD) at 4, 8, and 12 months were found to be statistically significant (P < 0.001, 117.12 ± 30.51, 109.69 ± 43.66, and 113.16 ± 56.93, respectively). t test carried out for PPBG indicated that the levels at respective intervals were significantly reduced as opposed to baseline (P < 0.05). The difference in HbA1c (%) across baseline, 4, 8, and 12 months was found to be statistically significant (P < 0.001) and the mean levels noted were 8.09 ± 2.26, 7.57 ± 1.84, 6.95 ± 1.80, and 6.46 ± 1.81, respectively. The difference in UACR across different intervals was found to be statistically significant (P < 0.001) and the corresponding mean UACRs (mg/g ± SD) noted were 417.21 ± 182.87, 291.82 ± 98.30, 296.84 ± 109.48 and 284.18 ± 103.26. Conclusion: Teneligliptin monotherapy is well tolerated with a persistent reduction in HbA1C and significant improvement in renal function.

Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors represent novel hypoglycemic drugs for the treatment of adult diabetes that have shown considerable potential for cardioprotection and renoprotection. This new drug can inhibit SGLT2 at the proximal tubule, increase glucosuria and natriuresis, and thus decreases the serum glucose level and blood pressure. Furthermore, the tubuloglomerular feedback activated by the natriuresis can decrease glomerular hyperfiltration, acknowledged as the main foundation of renoprotection. Several studies have confirmed the protective effects of SGLT2 inhibitors on the kidneys of adult diabetic patients and those with non‐diabetic nephropathy; however, limited researches are seen in paediatric patients. In this review, we have summarized the mechanisms of action of SGLT2 inhibitors, the current experiences in adults, results of exploratory studies in children, and adverse events & obstacles of paediatric use. We further explore the potential and possible future research direction of SGLT2 inhibitors in paediatric diseases. SUMMARY AT A GLANCE: With limited data of SGLT2 inhibitors in paediatric patients, this review summarizes the efficacy and safety of SGLT2 inhibitors in children and outlines future research direction on the use of these agents in paediatric diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Ischaemia/reperfusion (I/R) injury is associated with renal tissue damage during deceased donor renal transplantation. The effect of mannitol to reduce I/R injury during graft reperfusion in renal transplant recipients is based on weak evidence. We evaluated the effect of mannitol to reduce renal graft injury represented by 16 serum biomarkers, which are indicators for different important pathophysiological pathways. Our primary outcome were differences in biomarker concentrations between the mannitol and the placebo group 24 h after graft reperfusion. Additionally, we performed a linear mixed linear model to account biomarker concentrations before renal transplantation. Methods Thirty-four patients undergoing deceased donor renal transplantation were randomly assigned to receive either 20% mannitol or 0.9% NaCl placebo solution before, during, and after graft reperfusion. Sixteen serum biomarkers (MMP1, CHI3L1, CCL2, MMP8, HGF, GH, FGF23, Tie2, VCAM1, TNFR1, IGFBP7, IL18, NGAL, Endostatin, CystC, KIM1) were measured preoperatively and 24 h after graft reperfusion using Luminex assays and ELISA. Results Sixteen patients in each group were analysed. Tie2 differed 24 h after graft reperfusion between both groups (p = 0.011). Change of log2 transformed concentration levels over time differed significantly in four biomarkers (VCAM1,Endostatin, KIM1, GH; p = 0.007; p = 0.013; p = 0.004; p = 0.033; respectively) out of 16 between both groups. Conclusion This study showed no effect of mannitol on I/R injury in patients undergoing deceased renal transplantation. Thus, we do not support the routinely use of mannitol to attenuate I/R injury. Trial registration NCT02705573 . Registered on 10th March 2016.

Diabetic kidney disease (DKD) is defined as a clinical syndrome consisting of persistent macroalbuminuria, progressive decline in glomerular filtration rate (GFR), hypertension, increased cardiovascular disease events, and the associated mortality of these conditions. The disease evolves from the microvascular complications of poorly controlled Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). The pathogenic pathways comprise renal haemodynamic changes, ischaemia and inflammation, and overactive renin–angiotensin–aldosterone system (RAAS), through which several events cascade down from hyperglycaemia to renal fibrosis. Conventional and novel renoprotective strategies target modifiable DKD risk factors and specific stages of the pathogenic pathways, respectively. Although these strategies may slow DKD progression to end-stage kidney disease (ESKD), novel drugs are still undergoing trials for validation in human participants. This narrative review appraises these renoprotective strategies and highlights the current clinical staging and pathogenesis of the disease.

Acetaminophen (APAP) is the most commonly used nonprescription antipyretic-analgesic drug. This medication is thought to be safe at the suggested dosage (4 g/24 h), but its overdose (up to 2.5 g/kg) can cause severe injuries to the human body, including renal injury. APAP has various toxic effects on nephrons, as it leads to an excessive free radical generation that, in turn, results in a disturbance in the redox homeostasis of cells, causing oxidative stress. To replenish this oxidative stress, there is an ultimate urge for natural therapies that can retain the cellular homeostasis of nephrons by diminishing the overdose impression of acetaminophen. The principle objective of this work is to appraise nephrotoxicity due to APAP and its amelioration through the antioxidant properties of aqueous extracts of selected medicinal plants: Urtica dioica, Capsella bursa-pastoris, and Inula racemosa (UD, CBP, and IR, respectively). The pH stability of the nutraceuticals used was examined by determining the impact of pH 4, pH 7 and pH 9 on the DPPH radical scavenging activity of aqueous plant extracts. Gas chromatography-Mass spectroscopy (GC–MS) analytical technique was performed to determine the volatile organic phytochemical profiles of all three medicinal plants. Male Swiss albino mice were used for the present investigation. The animals were distributed into five groups of (n = 6), a total of 30 mice, for in vivo analysis. Group 1 served as the control group; group 2 received a single IP dose of APAP (600 mg/kg); group 3 received APAP pretreated with UD (300 mg/kg); group 4 received APAP pretreated with CBP (300 mg/kg); and group 5 received APAP pretreated with IR (300 mg/kg). Overdose of the APAP- induced a significant (p < 0.05) alterations in the total protein concentration, weight and the nephrological architecture in renal tissue, as observed through biochemical assays and histopathological examinations. Due to nephrotoxicity, there was a substantial (p < 0.05) drop in body weight and total protein contents in the APAP alone group when compared to the treatment groups. There was remarkable protection against APAP-induced alterations in the total protein of renal homogenate in the treatment groups. Histopathological analysis (H&E staining) of the mice kidneys indicated severe deterioration in the APAP alone group, whereas the therapy groups showed considerable nephroprotection towards APAP-induced abnormalities. The biochemical findings and histopathological study of the kidneys revealed that the herbal extracts (UD, CBP, and IR) have a nephroprotective potential against APAP-induced nephropathy. The trend of efficacy was observed as UD > CBP > IR. However, extensive study is needed to determine the likely ameliorative mechanism of these nutraceuticals.

Number of patients with progressive chronic kidney disease (CKD) is increasing all over the world. One of the risk factors for CKD development and progression is increased serum uric acid (sUA) level. Possibly, control of hyperurcemia with urate lowering therapy drugs can slow the decline in kidney function. The objective: to determine efficacy and safety of allopurinol and febuxostat in treatment of patients with CKD and hyperurcemia to reduce the sUA level and analyze its influence on glomerular filtration rate (GFR). Materials and methods. The study included 45 CKD patients (stages 3b-5) without other severe/decompensated diseases and contraindications to the allopurinol/febuxostat. All patients underwent a comprehensive clinical and laboratory examination, and were divided into the study groups: Group I (28 patients, 61.3±3.2 y.o., CKD3b-12, CKD4-10, on hemodialysis-6 patients) received febuxostat, Group II (24 patients, 60.7±4.1 y.o., CKD3b-9, CKD4-10, on hemodialysis – 5 patients) took allopurinol. Results. Achievement of the target level of sUA was significantly often registered in Group I: after 1 month – in 45.5% (in group II – in 15.9%, p<0.001); after 3 months – in 67.5% (in group II – 21.2% p<0.01); after 6 months, these figures were 90% and 37.1%, respectively (p<0.01). sUA level <300 µmol/l was accompanied by significant positive GFR changes in group I patients; in group II there was a gradual progression of GFR deterioration in 31.8% of patients. Conclusions. In patients with pre-dialysis stages of CKD febuxostat demonstrates renoprotective abilities. Use of febuxostat in patients with CKD stage 3b-4 and in patients on hemodialysis is safe and more effective for target sUA level achievement than the use of allopurinol. [ABSTRACT FROM AUTHOR]

Chronic kidney disease is an increasingly serious public health problem worldwide. Our recent studies have shown that Huangjinsan has a renal protective effect on chronic kidney disease, but the specific mechanism by which this effect occurs is not clear. To study the therapeutic effect of Huangjinsan on chronic kidney disease and to explore its possible mechanism of action through nontargeted metabolomics methods, a chronic kidney disease rat model was induced by adenine, and the Huangjinsan extract was given by oral gavage. Body weight, the kidney index, pathological sections, and a series of biochemical indicators were measured. High‐performance liquid chromatography quadrupole time‐of‐flight mass spectrometry was used to analyze the changes in the plasma metabolome. Huangjinsan significantly reduced indicators of kidney damage, including total protein, albumin, the total protein to creatinine ratio, and the albumin to creatinine ratio in urine, as well as IL‐2, MCP‐1α, and blood urea levels in plasma. Based on nontargeted metabolomics, 13 metabolites related to chronic kidney disease were discovered. These metabolites are closely related to glycerophospholipid metabolism, arginine and proline metabolism, and sphingolipid metabolism. We found that Huangjinsan can restore the renal function of adenine‐induced chronic kidney disease by regulating the metabolic profile. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a relatively novel class of drug for treating type 2 diabetes mellitus (T2DM) that inhibits glucose reabsorption in the renal proximal tubule to promote glycosuria and reduce blood glucose levels. SGLT2i has been clinically indicated for treating T2DM, with numerous recent publications focussing on both primary and secondary prevention of cardiovascular and renal events in Type 2 diabetic patients. The most recent clinical trials showed that SGLT2i have moderately significant beneficial effects on atherosclerotic major adverse cardiovascular events (MACE) in patients with histories of atherosclerotic cardiovascular disease. In this review and analysis, SGLT2i have however demonstrated clinically significant benefits in reducing hospitalisation for heart failure and worsening of chronic kidney disease (CKD) irrespective of pre-existing atherosclerotic cardiovascular disease or previous heart failure history. A meta-analysis suggests that all SGLT2 inhibitors demonstrated the therapeutic benefit on all-cause and cardiovascular mortality, as shown in EMPAREG OUTCOME study with a significant decrease in myocardial infarction, without increased stroke risk. All the above clinical trial recruited type 2 diabetic patients. This article aims to postulate and review the possible primary prevention role of SGLT2i in healthy individuals by reviewing the current literature and provide a prospective overview. The emphasis will include primary prevention of Type 2 Diabetes, Heart Failure, CKD, Hypertension, Obesity and Dyslipidaemia in healthy individuals, whom are defined as healthy, low or intermediate risks patients.

Summary: Background: Reduced kidney function has been associated with worse clinical outcomes in patients with myeloproliferative neoplasms (MPN). Statins and angiotensin-converting enzyme inhibitors (ACE-i) have renoprotective properties and their pleiotropic effects might also affect the malignant MPN clone; however, whether concomitant use of statins and ACE‑i has a positive effect on estimated glomerular filtration rate (eGFR) in polycythemia vera (PV) patients is currently unknown. Methods: This multicenter retrospective study investigated effects of statins and ACE‑i on 12-month eGFR dynamics in 75 PV patients. Results: Of the patients 25 (33.3%) had a 10% or more increase in eGFR at 12 months. Univariately, statins (55.5% vs. 16.3%; p = 0.022), ACE‑i (61% vs. 24.6%; p = 0.004), male sex (54.3%, vs. 15%; p < 0.001) and the absence of chronic kidney disease (CKD, 45.5% vs. 16.1%; p = 0.008) were statistically significantly associated with an improvement in eGFR. ACE‑i (p = 0.008), CKD (p < 0.001), male sex (p = 0.004) and higher baseline eGFR (p = 0.007) remained statistically significantly associated with an improvement in eGFR in the multivariate logistic regression model also including statins, hydroxyurea, high-risk disease, cardiovascular risk factors, chronic heart failure and baseline hematocrit. Conclusion: The ACE‑i might have renoprotective properties in PV. Further studies are needed to elucidate whether the use of these drugs could also affect other MPN-related outcomes. [ABSTRACT FROM AUTHOR]

Introduction: People with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD) have increased morbidity and mortality risk. Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) are recommended to slow kidney function decline in DKD. This representative, real-world data analysis of patients with T2DM was performed to detect onset of DKD and determine methods and timing of DKD diagnosis and time to initiation of ACEi/ARB therapy.Methods: Patients diagnosed with T2DM before January 1, 2016 who developed DKD between January 1, 2017 and June 30, 2019 were identified from a longitudinal ambulatory electronic health record (EHR) dataset (Veradigm Inc). Each record was analyzed using the CLinical INTelligence engine (CLINT™, HealthPals, Inc.) to identify delays and gaps in diagnosing DKD. DKD was diagnosed through two reduced estimated glomerular filtration rate (eGFR; < 60 mL/min/1.73 m2) measurements at least 90 days apart, a single elevated urine albumin-to-creatinine ratio (UACR; > 30 mg/g) measurement, or ICD-9/10 diagnosis codes for DKD and/or albuminuria. Time to diagnose (TTD), time to treat (TTT), and diagnosis to treatment time were assessed.Results: Of 6,499,409 patients with T2DM before January 2016, 245,978 developed DKD between January 1, 2017 and June 30, 2019. In this DKD cohort, ca. 50% were first identified through EHR diagnosis and ca. 50% by UACR or eGFR lab-based diagnosis. In patients who had UACR/eGFR assessed, more than 90% exhibited DKD-level results on the first diagnostic test. Average TTD after eGFR labs was 2 years; average TTT with ACEi/ARB was 6-9 months after DKD lab evidence. The majority of patients who developed DKD received ACEi/ARB therapy 6-7 months after diagnosis.Conclusion: In a contemporary, large national cohort of patients with T2DM, progression to DKD was common but likely underrepresented. The low rate of DKD-screening labs, along with sizable delays in diagnosis of DKD and initiation of ACEi/ARB therapy, indicates that many patients who progress to DKD are not being properly treated. [ABSTRACT FROM AUTHOR]

Regular exercise training can lead to several health benefits, reduce mortality risk, and increase life expectancy. On the other hand, a sedentary lifestyle is a known risk factor for chronic diseases and increased mortality. Acute kidney injury (AKI) and chronic kidney disease (CKD) represent a significant global health problem, affecting millions of people worldwide. The progression from AKI to CKD is well-recognized in the literature, and exercise training has emerged as a potential renoprotective strategy. Thus, this article aims to review the main molecular mechanisms underlying the renoprotective actions of exercise training in the context of AKI and CKD, focusing on its antioxidative, anti-inflammatory, anti-apoptotic, anti-fibrotic, and autophagy regulatory effects. For that, bibliographical research was carried out in Medline/PubMed and Scielo databases. Although the pathophysiological mechanisms involved in renal diseases are not fully understood, experimental studies demonstrate that oxidative stress, inflammation, apoptosis, and dysregulation of fibrotic and autophagic processes play central roles in the development of tissue damage. Increasing evidence has suggested that exercise can beneficially modulate these mechanisms, potentially becoming a safe and effective non-pharmacological strategy for kidney health protection and promotion. Thus, the evidence base discussed in this review suggests that an adequate training program emerges as a valuable tool for preserving renal function in experimental animals, mainly through the production of antioxidant enzymes, nitric oxide (NO), irisin, IL-10, and IL-11. Future research can continue to explore these mechanisms to develop specific guidelines for the prescription of exercise training in different populations of patients with kidney diseases. [Display omitted] [ABSTRACT FROM AUTHOR]