A novel pharmacological strategy using nanoparticles with glutathione and virgin coconut oil to treat gentamicin-induced acute renal failure in rats.

In acute renal failure (ARF), the glomerular filtration rate is reduced, and nitrogenous waste products accumulate persistently, which can last anywhere from a few hours to several days. There is hope for a reversal of the rapid loss of renal function caused by this condition. This study, with gentamicin-induced acute ARF as a prospective setting, sets out to examine the reno-protective benefits of virgin coconut oil (VCO) and GSH. Furthermore, the study evaluated the effect of medication nanoparticle compositions on several kidney function markers. The induction of ARF is achieved with the intraperitoneal injection of gentamicin. To assess renal function, rats underwent 24 h of dehydration and hunger before their deaths. The study examined various aspects, including kidney function tests, markers of oxidative stress, histology of kidney tissue, inflammatory cytokines, immunohistochemistry expression of nuclear factor-kappa B (NF-κB), and specific biomarkers for kidney tissue damage, such as kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). The results of our study indicated that the combination of VCO and GSH, using both regular and nanoparticle formulations, had a better protective impact on the kidneys compared to using either drug alone. The recovery of renal tissue and serum markers, which are symptomatic of organ damage, indicates improvement. This was also demonstrated by the reduction in tubular expression of TNF-α, IL-1ß, KIM-1, and NGAL. The immunohistochemical studies showed that the combination therapy, especially with the nanoforms, greatly improved the damaged cellular changes in the kidneys, as shown by higher levels of NF-κB. The study shows that VCO and GSH, when administered individually or combined, significantly improve ARF in a gentamicin-induced rat model, highlighting potential therapeutic implications. Notably, the combined nanoparticulate formulations exhibit substantial effectiveness.

In vivo assessment of the nephrotoxic effects of the synthetic cannabinoid AB-FUBINACA.

BACKGROUND: The widespread misuse of synthetic cannabinoids (SCs) has led to a notable increase in reported adverse effects, raising significant health concerns. SCs use has been particularly associated with acute kidney injury (AKI). However, the pathogenesis of SCs-induced AKI is not well-understood. METHODS: We investigated the nephrotoxic effect of acute administration of N-[(1S)- 1-(aminocarbonyl)-2-methylpropyl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (AB-FUBINKA) (3 mg/kg for 5 days) in mice. Various parameters of oxidative stress, inflammation, and apoptosis have been quantified. The expressions of mitochondrial complexes (I-V) in renal tissues were also assessed. RESULTS: Our findings showed that AB-FUBINACA induced substantial impairment in the renal function that is accompanied by elevated expression of renal tubular damage markers; KIM-1 and NGAL. Administration of AB-FUBINACA was found to be associated with a significant increase in the expression of oxidative stress markers (iNOS, NOX4, NOX2, NOS3) and the level of lipid peroxidation in the kidney. The expression of pro-inflammatory markers (IL-6, TNF-alpha, NF-kB) was also enhanced following exposure to AB-FUBINACA. These findings were also correlated with increased expression of major apoptosis regulatory markers (Bax, caspase-9, caspase-3) and reduced expression of mitochondrial complexes I, III, and IV. CONCLUSION: These results indicate that AB-FUBINACA can trigger oxidative stress and inflammation, and activate caspase-dependent apoptosis in the kidney, with these processes being possibly linked to disruption of mitochondrial complexes and could be an underlying mechanism of SCs-induced nephrotoxicity.

A translational model of chronic diabetic nephropathy in the Nile grass rat.

Diabetic nephropathy (DN) is a major healthcare challenge for individuals with diabetes and associated with increased cardiovascular morbidity and mortality. The existing rodent models do not fully represent the complex course of the human disease. Hence, developing a translational model of diabetes that reproduces both the early and the advanced characteristics of DN and faithfully recapitulates the overall human pathology is an unmet need. Here, we introduce the Nile grass rat (NGR) as a novel model of DN and characterize key pathologies underlying DN. NGRs spontaneously developed insulin resistance, reactive hyperinsulinemia, and hyperglycemia. Diabetic NGRs evolved DN and the key histopathological aspects of the human advanced DN, including glomerular hypertrophy, infiltration of mononuclear cells, tubular dilatation, and atrophy. Enlargement of the glomerular tufts and the Bowman's capsule areas accompanied the expansion of the Bowman's space. Glomerular sclerosis, renal arteriolar hyalinosis, Kimmelsteil-Wilson nodular lesions, and protein cast formations in the kidneys of diabetic NGR occurred with DN. Diabetic kidneys displayed interstitial and glomerular fibrosis, key characteristics of late human pathology as well as thickening of the glomerular basement membrane and podocyte effacement. Signs of injury included glomerular lipid accumulation, significantly more apoptotic cells, and expression of KIM-1. Diabetic NGRs became hypertensive, a known risk factor for kidney dysfunction, and showed decreased glomerular filtration rate. Diabetic NGRs recapitulate the breadth of human DN pathology and reproduce the consequences of chronic kidney disease, including injury and loss of function of the kidney. Hence, NGR represents a robust model for studying DN-related complications and provides a new foundation for more detailed mechanistic studies of the genesis of nephropathy, and the development of new therapeutic approaches.

A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization.

Insufficient therapeutic strategies for acute kidney injury (AKI) necessitate precision therapy targeting its pathogenesis. This study reveals the new mechanism of the marine-derived anti-AKI agent, piericidin glycoside S14, targeting peroxiredoxin 1 (PRDX1). By binding to Cys83 of PRDX1 and augmenting its peroxidase activity, S14 alleviates kidney injury efficiently in Prdx1-overexpression (Prdx1-OE) mice. Besides, S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production. Due to the limited druggability of S14 with low bioavailability (2.6%) and poor renal distribution, a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI. l-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1 (Kim-1)-overexpressed cells. The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly. By encapsulation with micelles, the AUC0‒t , half-life time, and renal distribution of S14 increase 2.5-, 1.8-, and 3.1-fold, respectively. The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase (UGT)-mediated biotransformation. In summary, this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology, thereby driving advancements in marine drug development for AKI.

L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice.

Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin. The aim of this study was to evaluate whether colistin can directly induce mitochondrial toxicity and, if so, uncover the underlying molecular mechanism. We found that colistin leads to a rapid permeability transition of mitochondria isolated from mouse kidney that was fully prevented by co-incubation of the mitochondria with desensitizers of the mitochondrial transition pore cyclosporin A or L-carnitine. The protective effect of L-carnitine was confirmed in experiments in primary cultured mouse tubular cells. Consistently, the relative risk of colistin-induced kidney damage, calculated based on histological analysis as well as by the early marker of tubular kidney injury, Kim-1, was halved under co-administration with L-carnitine in vivo. Notably, L-carnitine neither affected the pharmacokinetics of colistin nor its antimicrobial activity against relevant bacterial strains. In conclusion, colistin targets the mitochondria and induces permeability transition thereof. L-carnitine prevents colistin-induced permeability transition in vitro. Moreover, L-carnitine co-administration confers partial nephroprotection in mice treated with colistin, without interfering with its pharmacokinetics and antibacterial activity.

Urine Biomarkers of Kidney Tubule Health and Risk of Incident CKD in Persons Without Diabetes: The ARIC, MESA, and REGARDS Studies.

Rationale & Objective: Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD. Study Design: Prospective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS]). Setting & Participants: Adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and without diabetes in the ARIC, REGARDS, and MESA studies. Exposures: Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1. Outcome: Incident CKD or end-stage kidney disease. Analytical Approach: Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts. Results: 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m2. In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31). Limitations: Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts. Conclusions: In 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.

This study analyzed 3 cohorts (ARIC, MESA, and REGARDS) of adults without diabetes or prevalent chronic kidney disease (CKD) to determine the associations of 5 urinary biomarkers of kidney tubulointerstitial health with incident CKD, independent of traditional measures of kidney health. Meta-analysis of results from all 3 cohorts suggested that higher baseline levels of urine alpha-1-microglobulin were associated with incident CKD at follow-up. Results from individual cohorts suggested that in addition to alpha-1-microglobulin, monocyte chemoattractant protein-1, kidney injury molecule-1, and epidermal growth factor may also be associated with the development of CKD. These findings underscore the importance of kidney tubule interstitial health in defining risk of CKD independent of creatinine and urine albumin.

Nimbidiol protects from renal injury by alleviating redox imbalance in diabetic mice.

Introduction: Chronic hyperglycemia-induced oxidative stress plays a crucial role in the development of diabetic nephropathy (DN). Moreover, adverse extracellular matrix (ECM) accumulation elevates renal resistive index leading to progressive worsening of the pathology in DN. Nimbidiol is an alpha-glucosidase inhibitor, isolated from the medicinal plant, 'neem' (Azadirachta indica) and reported as a promising anti-diabetic compound. Previously, a myriad of studies demonstrated an anti-oxidative property of a broad-spectrum neem-extracts in various diseases including diabetes. Our recent study has shown that Nimbidiol protects diabetic mice from fibrotic renal dysfunction in part by mitigating adverse ECM accumulation. However, the precise mechanism remains poorly understood. Methods: The present study aimed to investigate whether Nimbidiol ameliorates renal injury by reducing oxidative stress in type-1 diabetes. To test the hypothesis, wild-type (C57BL/6J) and diabetic Akita (C57BL/6-Ins2Akita/J) mice aged 10-14 weeks were used to treat with saline or Nimbidiol (400 µg kg-1 day-1) for 8 weeks. Results: Diabetic mice showed elevated blood pressure, increased renal resistive index, and decreased renal vasculature compared to wild-type control. In diabetic kidney, reactive oxygen species and the expression levels of 4HNE, p22phox, Nox4, and ROMO1 were increased while GSH: GSSG, and the expression levels of SOD-1, SOD-2, and catalase were decreased. Further, eNOS, ACE2, Sirt1 and IL-10 were found to be downregulated while iNOS and IL-17 were upregulated in diabetic kidney. The changes were accompanied by elevated expression of the renal injury markers viz., lipocalin-2 and KIM-1 in diabetic kidney. Moreover, an upregulation of p-NF-κB and a downregulation of IkBα were observed in diabetic kidney compared to the control. Nimbidiol ameliorated these pathological changes in diabetic mice. Conclusion: Altogether, the data of our study suggest that oxidative stress largely contributes to the diabetic renal injury, and Nimbidiol mitigates redox imbalance and thereby protects kidney in part by inhibiting NF-κB signaling pathway in type-1 diabetes.

Elevated Serum KIM-1 in Sepsis Correlates with Kidney Dysfunction and the Severity of Multi-Organ Critical Illness.

The kidney injury molecule (KIM)-1 is shed from proximal tubular cells in acute kidney injury (AKI), relaying tubular epithelial proliferation. Additionally, KIM-1 portends complex immunoregulation and is elevated after exposure to lipopolysaccharides. It thus may represent a biomarker in critical illness, sepsis, and sepsis-associated AKI (SA-AKI). To characterise and compare KIM-1 in these settings, we analysed KIM-1 serum concentrations in 192 critically ill patients admitted to the intensive care unit. Irrespective of kidney dysfunction, KIM-1 serum levels were significantly higher in patients with sepsis compared with other critical illnesses (191.6 vs. 132.2 pg/mL, p = 0.019) and were highest in patients with urogenital sepsis, followed by liver failure. Furthermore, KIM-1 levels were significantly elevated in critically ill patients who developed AKI within 48 h (273.3 vs. 125.8 pg/mL, p = 0.026) or later received renal replacement therapy (RRT) (299.7 vs. 146.3 pg/mL, p < 0.001). KIM-1 correlated with markers of renal function, inflammatory parameters, hematopoietic function, and cholangiocellular injury. Among subcomponents of the SOFA score, KIM-1 was elevated in patients with hyperbilirubinaemia (>2 mg/dL, p < 0.001) and thrombocytopenia (<150/nL, p = 0.018). In univariate and multivariate regression analyses, KIM-1 predicted sepsis, the need for RRT, and multi-organ dysfunction (MOD, SOFA > 12 and APACHE II ≥ 20) on the day of admission, adjusting for relevant comorbidities, bilirubin, and platelet count. Additionally, KIM-1 in multivariate regression was able to predict sepsis in patients without prior (CKD) or present (AKI) kidney injury. Our study suggests that next to its established role as a biomarker in kidney dysfunction, KIM-1 is associated with sepsis, biliary injury, and critical illness severity. It thus may offer aid for risk stratification in these patients.

Comparison of the Impact of VRP-034 and Polymyxin B upon Markers of Kidney Injury in Human Proximal Tubule Monolayers In Vitro.

In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal model, aProximateTM. Freshly isolated primary proximal tubule cells (PTCs) were cultured in Transwell plates and treated with various concentrations of the formulations for up to 48 h. The functional expression of megalin-cubilin receptors in PTC monolayers was validated using FITC-conjugated albumin uptake assays. Polymyxin B and VRP-034 were evaluated at six concentrations (0.3, 1, 3, 10, 30, and 60 µM), and nephrotoxicity was assessed through measurements of transepithelial electrical resistance (TEER), intracellular adenosine triphosphate (ATP) levels, lactate dehydrogenase (LDH) release, and novel injury biomarkers [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and clusterin]. Additionally, histological analysis using annexin V apoptosis staining was performed. Our results indicated a significant decrease in TEER with polymyxin B at concentrations ≥10 µM compared to VRP-034. Toxic effects were observed from ATP and LDH release only at concentrations ≥30 µM for both formulations. Furthermore, injury biomarker release was higher with polymyxin B compared to VRP-034, particularly at concentrations ≥10 µM. Histologically, polymyxin B-treated PTCs showed increased apoptosis compared to VRP-034-treated cells. Overall, VRP-034 demonstrated improved tolerance in the aProximateTM model compared to polymyxin B, suggesting its potential as a safer alternative for renal protection.

Renal Biomarkers in Heart Failure: Systematic Review and Meta-Analysis.

Background: Cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule (KIM)-1 are renal biomarkers increasingly appreciated for their role in the risk stratification and prognostication of heart failure (HF) patients. However, very few have been adopted clinically, owing to the lack of consistency. Objectives: The authors aimed to study the association between cystatin C, NGAL, and KIM-1 and outcomes, mortality, hospitalizations, and worsening renal function (WRF) in patients with acute and chronic HF. Methods: We included peer-reviewed English-language articles from PubMed and EMBASE published up to December 2021. We analyzed the above associations using random-effects meta-analysis. Publication bias was assessed using funnel plots. Results: Among 2,631 articles, 100 articles, including 45,428 patients, met the inclusion criteria. Top-tertile of serum cystatin C, when compared to the bottom-tertile, carried a higher pooled hazard ratio (pHR) for mortality (pHR: 1.59, 95% CI: 1.42-1.77) and for the composite outcome of mortality and HF hospitalizations (pHR: 1.49, 95% CI: 1.23-1.75). Top-tertile of serum NGAL had a higher hazard for mortality (pHR: 2.91, 95% CI: 1.49-5.67) and composite outcome (HR: 4.11, 95% CI: 2.69-6.30). Serum and urine NGAL were significantly associated with WRF, with pHRs of 2.40 (95% CI: 1.48-3.90) and 2.01 (95% CI: 1.21-3.35). Urine KIM-1 was significantly associated with WRF (pHR: 1.60, 95% CI: 1.24-2.07) but not with other outcomes. High heterogeneity was noted between studies without an obvious explanation based on meta-regression. Conclusions: Serum cystatin C and serum NGAL are independent predictors of adverse outcomes in HF. Serum and urine NGAL are important predictors of WRF in HF.

Potential role of serum copeptin among smoker T2DM patients with emphasis to ACE I/D gene polymorphism predicting DN.

Diabetic nephropathy represents one of the main long-term complications in T2DM patients. Cigarette smoking represents one of modifiable renal risk factors to kidney damage due to lead (Pb) exposure in these patients. Our goal is to investigate serum copeptin and Kidney injury molecule-1 (KIM-1) and urinary lead (UPb) in type 2 diabetes mellitus (T2DM) patients even smokers and non-smokers groups and compared to corresponding health controls and assess its associations with Angiotensin-Converting enzyme Insertion/Deletion polymorphism [ACE (I/D)] polymorphism in diabetic nephropathy progression in those patients. In present study, 106 T2DM patients and 102 healthy control individuals were enrolled. Serum glucose, copeptin, KIM-1, total cholesterol (TChol), triglycerides (TG), estimated glomerular filtration rate (eGFR) and UPb levels and ACE (I/D) polymorphisms were assessed in both groups. Results mentioned to significant variations in all parameters compared to in T2DM group compared to control group. Serum copeptin and UPb demonstrated significant difference in diabetic smokers (DS) and diabetic non-smokers (DNS) groups while KIM-1 exhibited significant change between DNS and healthy control non-smokers (CNS) groups. Positive relation was recorded between serum glucose and KIM-1 while negative one was found between serum copeptin and TChol. D allele was associated with significant variation in most parameters in T2DM, especially insertion/deletion (ID) polymorphism. ROC curve analysis (AUC) for serum copeptin was 0.8, p < 0.044 and for Kim-1 was 0.54, p = 0.13 while for uPb was 0.71, p < 0.033. Serum copeptin and UPb might be a prognostic biomarker for renal function decline in smoker T2DM patients while KIM-1 was potent marker in non-smoker T2DM with association with D allele of ACE I/D gene polymorphism.

Longitudinal Trajectories of Biomarkers of Kidney Tubular Function in Type 1 Diabetes.

Introduction: Tubular biomarkers may shed insight into progression of kidney tubulointerstitial pathology complementary to traditional measures of glomerular function and damage. Methods: We examined trajectories of tubular biomarkers in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC Study) of type 1 diabetes (T1D). Biomarkers were measured in a subset of 220 participants across 7 time points over 26 years. Measurements included the following: kidney injury molecule 1 (KIM-1), soluble tumor necrosis factor 1 (sTNFR1) in serum or plasma, epidermal growth factor (EGF), monocyte chemoattractant protein-1 (MCP1) in timed urine, and a composite tubular secretion score. We described biomarker trajectories and examined how these were affected by intensive glucose-lowering therapy and glycemia. Results: At baseline, participants had a mean age of 28 years, 45% were women, and 50% were assigned to intensive glucose-lowering therapy. The mean estimated glomerular filtration rate (eGFR) was 125 ml/min per 1.73 m2 and 90% of participants had a urinary albumin excretion rate (AER) <30 mg/24h. Mean changes in biomarkers over time (percent/decade) were: KIM-1: 27.3% (95% confidence interval [CI]: 21.4-33.5), sTNFR1: 16.9% (14.5-19.3), MCP1: 18.4% (8.9-28.8), EGF: -13.5% (-16.7 to -10.1), EGF-MCP1 ratio: -26.9% (-32.2 to -21.3), and tubular secretion score -0.9% (-1.8 to 0.0), versus -12.0% (CI: -12.9 to -11.1) for eGFR and 10.9% (2.5-20.1) for AER. Intensive versus conventional glucose-lowering therapy was associated with slower increase in sTNFR1 (relative difference in change: 0.94 [0.90-0.98]). Higher HbA1c was associated with faster increases in sTNFR1 (relative difference in change: 1.06 per 1% higher HbA1c [1.05-1.08]) and KIM-1 (1.09 [1.05-1.14]). Conclusion: Among participants with T1D and normal eGFR at baseline, kidney tubular biomarkers changed significantly over long-term follow-up. Hyperglycemia was associated with larger increases in serum or plasma sTNFR1 and KIM-1, when followed-up longitudinally.

Therapeutic potential of Lactobacillus casei and Chlorella vulgaris in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD)-associated kidney damages: a stereological study.

BACKGROUND: The non-alcoholic fatty liver disease (NAFLD) is prevalent in as many as 25% of adults who are afflicted with metabolic syndrome. Oxidative stress plays a significant role in the pathophysiology of hepatic and renal injury associated with NAFLD. Therefore, probiotics such as Lactobacillus casei (LBC) and the microalga Chlorella vulgaris (CV) may be beneficial in alleviating kidney injury related to NAFLD. MATERIALS AND METHODS: This animal study utilized 30 C57BL/6 mice, which were evenly distributed into five groups: the control group, the NAFLD group, the NAFLD + CV group, the NAFLD + LBC group, and the NAFLD + CV + LBC group. A high-fat diet (HFD) was administered to induce NAFLD for six weeks. The treatments with CV and LBC were continued for an additional 35 days. Biochemical parameters, total antioxidant capacity (TAC), and the expression of kidney damage marker genes (KIM 1 and NGAL) in serum and kidney tissue were determined, respectively. A stereological analysis was conducted to observe the structural changes in kidney tissues. RESULTS: A liver histopathological examination confirmed the successful induction of NAFLD. Biochemical investigations revealed that the NAFLD group exhibited increased ALT and AST levels, significantly reduced in the therapy groups (p < 0.001). The gene expression levels of KIM-1 and NGAL were elevated in NAFLD but were significantly reduced by CV and LBC therapies (p < 0.001). Stereological examinations revealed reduced kidney size, volume, and tissue composition in the NAFLD group, with significant improvements observed in the treated groups (p < 0.001). CONCLUSION: This study highlights the potential therapeutic efficacy of C. vulgaris and L. casei in mitigating kidney damage caused by NAFLD. These findings provide valuable insights for developing novel treatment approaches for managing NAFLD and its associated complications.

The Human Phospholipase B-II Precursor (HPLBII-P) in Urine as a Novel Biomarker of Glomerular Activity in COVID-19 and Diabetes Mellitus.

Background: The human phospholipase B-II precursor (HPLBII-P) was originally purified from white blood cells but is also found in other cellular structures, such as kidney glomeruli and tubuli. The objective of this report was to investigate the relationship of HPLBII-P in urine to acute kidney injury in patients with COVID-19. Methods: Urine was collected at admission from 132 patients with COVID-19 admitted to the intensive care units (ICUs) because of respiratory failure. HPLBII-P was measured using a sensitive ELISA. For comparison, human neutrophil lipocalin (HNL) was measured in urine, using the ELISA configured with the monoclonal antibody 763/8F, as a sign of tubular affection in addition to routine biomarkers of kidney disease. Results: Overall, the concentrations of urinary HPLBII-P were almost 3-fold higher in patients with COVID-19 compared to healthy controls (p < 0.0001) and with significantly higher concentrations even in patients with COVID-19 without signs of acute kidney injury (AKI) (p < 0.001). HPLBII-P was further increased in patients with AKI (p < 0.02). HPLBII-P was significantly increased in patients with diabetes mellitus (p = 0.0008) and correlated to plasma glucose (r = 0.29, p = 0.001) and urine albumin concentrations (r = 0.55, p < 0.001). Conclusions: Urine concentrations of HPLBII-P are highly raised in the urine of patients with COVID-19 and relate to AKI and diabetes mellitus. HPLBII-P may reflect glomerular injury and/or increased glomerular cell activity in SARS-CoV-2 infections.

A Pilot Study of the Role of Selected Biomarkers of Kidney Injury in Dogs with Dilated Cardiomyopathy.

Heart and kidney diseases are among the most frequent medical conditions diagnosed in small animals. Due to the functional interconnection between these organs, the concept of the cardio-renal axis has been developed. In this context, renal disease or dysfunction often occurs secondary to heart diseases, such as dilated cardiomyopathy (DCM). DCM is the most common cardiomyopathy and a leading cause of mortality in large-breed dogs. Traditional biomarkers like creatinine or symmetric dimethylarginine concentration are not always effective, especially in the early stages of the disease, underscoring the need for more sensitive markers of renal impairment during heart failure (HF). This study aimed to evaluate the efficacy of selected biomarkers as indicators for early kidney damage in dogs with stage B2 DCM. We measured serum concentrations of cystatin C, KIM-1 (kidney injury molecule-1), and NGAL (neutrophil gelatinase-associated lipocalin) and their ratios to creatinine, analyzing their diagnostic values. Cystatin C was quantified using a sandwich enzyme immunoassay, while KIM-1 and NGAL were measured with enzyme-linked immunosorbent assay kits designed for canine diagnostics. The concentrations were indexed against serum creatinine. The study included 26 dogs: 9 with HF and 17 healthy controls. The mean ± standard deviation for healthy dogs for cystatin C, cystatin C/creatinine ratio, KIM-1, KIM-1/creatinine ratio, NGAL, and NGAL/creatinine ratio were 0.24 ± 0.04, 0.26 ± 0.07, 0.61 ± 0.07, 0.67 ± 0.13, 2.76 ± 1.8, and 2.79 ± 1.81, respectively. For DCM dogs, these values were 0.27 ± 0.1, 0.32 ± 0.12, 0.61 ± 0.08, 0.69 ± 0.17, 6.46 ± 5.22 (p = 0.02), and 7.99 ± 6.53 (p = 0.04). This study's findings suggest that during the asymptomatic phase of DCM, only NGAL concentration and the NGAL/creatinine ratio may serve as diagnostic markers for early-stage kidney injury.

Impacts of age, type 2 diabetes, and hypertension on circulating neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 after prolonged work in the heat in men.

PURPOSE: Prolonged work in the heat increases the risk of acute kidney injury (AKI) in young men. Whether aging and age-associated chronic disease may exacerbate the risk of AKI remains unclear. METHODS: We evaluated plasma neutrophil gelatinase-associated lipocalin (NGAL) and serum kidney injury molecule-1 (KIM1) before and after 180 min of moderate-intensity work (200 W/m2) in temperate (wet-bulb globe temperature [WBGT] 16 °C) and hot (32 °C) environments in healthy young (n = 13, 22 years) and older men (n = 12, 59 years), and older men with type 2 diabetes (T2D; n = 9, 60 years) or hypertension (HTN; n = 9, 60 years). RESULTS: There were no changes in NGAL or KIM1 concentrations following prolonged work in temperate conditions in any group. Despite a similar work tolerance, the relative change in NGAL was greater in the older group when compared to the young group following exercise in the hot condition (mean difference + 82 ng/mL; p < 0.001). Baseline concentrations of KIM1 were ~ 22 pg/mL higher in the older relative to young group, increasing by ~ 10 pg/mL in each group after exercise in the heat (both p ≤ 0.03). Despite a reduced work tolerance in the heat in older men with T2D (120 ± 40 min) and HTN (108 ± 42 min), elevations in NGAL and KIM1 were similar to their healthy counterparts. CONCLUSION: Age may be associated with greater renal stress following prolonged work in the heat. The similar biomarker responses in T2D and HTN compared to healthy older men, alongside reduced exercise tolerance in the heat, suggest these individuals may exhibit greater vulnerability to heat-induced AKI if work is prolonged.

Investigation of reno-protective efficacy of thymoquinone in a unilateral hydronephrosis model.

We aimed to evaluate the effects of the antioxidant thymoquinone on treated and untreated kidneys on histological and oxidative parameters as well as Kidney Injury Molecule (KIM-1) levels in an experimental unilateral ureteropelvic junction obstruction (UPJO) with resultant hydronephrosis (HN) model. In adherence to the Animal research: reporting of in vivo exepriments guidelines, 34 male Wistar rats were randomly divided into four groups which were named accordingly: "CO" (corn oil), "TQ" (thymoquinone and corn oil), "HNCO" (UPJO-HN and corn oil), "HNTQ" (UPJO-HN, thymoquinone and corn oil). Histologically, pelvic epithelial damage, glomerular shrinkage and sclerosis, tubular damage, interstitial edema-inflammation-fibrosis (IEIF), and vascular congestion were assessed. Biochemically, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione reductase (GR) and KIM-1 levels were assessed. Macroscopic HN developed in all obstructed kidneys. Ipsilateral obstructed kidneys deteriorated in all histological parameters. Thymoquinone attenuated glomerular shrinkage and sclerosis alterations but increased vascular congestion. Contralateral non-obstructed kidneys also showed histological deterioration. Thymoquinone had beneficial effects in terms of IEIF presence in contralateral kidneys but it increased vascular congestion. MDA and SOD results were inconclusive. UPJO caused decreased GR levels in the ipsilateral kidneys but not in the contralateral ones. This effect was not ameliorated by thymoquinone treatment. KIM-1 levels were increased in ipsilateral obstructed kidneys with a lower level in HNTQ group than in HNCO. KIM-1 level of the ipsilateral HNTQ group was higher than in both non-obstructed ipsilateral kidney groups. The effect of thymoquinone in ameliorating bilaterally observed histological alterations was limited and controversial. Oxidative damage detected by GR measurements was not prevented by thymoquinone. Thymoquinone partially decreased the damage as evidenced by reduced KIM-1 levels in thymoquinone-treated obstructed kidneys.

The Expression of Markers of Acute Kidney Injury Kim1 and NGAL after Administration of High Doses of Lithium Carbonate in Mice with Engrafted Skin Melanoma B16.

The expression of marker proteins of acute kidney injury after administration of high doses of lithium carbonate was assessed to evaluate the possibility of lithium use in neutron capture therapy. In mice with implanted skin melanoma B16, the expression of Kim1 (kidney injury molecule 1) and NGAL (neutrophil gelatinase-associated lipocalin) proteins in the kidneys was evaluated immunohistochemically 15, 30, 90, 180 min, and 7 days after peroral administration of lithium carbonate at single doses of 300 and 400 mg/kg. An increase in the expression of the studied proteins was found in 30 and 90 min after administration of 400 mg/kg lithium carbonate, however, 7 days after the drug administration, the expression returned to the level observed in the control group. It can be suggested that single administration of lithium carbonate in the studied doses effective for lithium neutron capture therapy will not significantly affect the renal function.

Diagnostic efficacy of urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 for early detection of acute kidney injury in dogs with leptospirosis or babesiosis.

This study evaluates the diagnostic efficacy of urinary biomarkers, Neutrophil Gelatinase-Associated Lipocalin (uNGAL), and Kidney Injury Molecule-1 (uKIM-1), in identifying Acute Kidney Injury (AKI) in dogs affected with leptospirosis or babesiosis. Acute kidney injury was diagnosed based on the increase in serum creatinine levels above 0.3 mg/dL within 48 h and dogs were categorized according to AKI grades based on International Renal Interest Society guidelines. Traditional biomarkers (serum creatinine and blood urea nitrogen) and novel biomarkers like urinary NGAL and urinary KIM-1 levels were measured and compared to concentrations obtained in control dogs. Statistical analysis assessed significant differences (P < 0.01) across AKI grades, specifically noting elevated urinary NGAL and KIM-1 in IRIS grade I AKI (P < 0.001). The study highlights the diagnostic significance of urinary NGAL and KIM-1 as early indicators of renal damage, particularly valuable in non-azotemic AKI cases, offering promising markers for early AKI diagnosis in veterinary clinical settings. These biomarkers demonstrate clinical utility and underscore their potential for improving AKI management in veterinary medicine. Further validation studies involving larger cohorts and diverse etiologies of AKI are needed to confirm the diagnostic accuracy and clinical utility of urinary NGAL and KIM-1 in veterinary practice.

Mitochondrial P-JNK target, SAB (SH3BP5), in regulation of cell death.

Cell death occurs in various circumstances, such as homeostasis, stress response, and defense, via specific pathways and mechanisms that are regulated by specific activator-induced signal transductions. Among them, Jun N-terminal kinases (JNKs) participate in various aspects, and the recent discovery of JNKs and mitochondrial protein SAB interaction in signal regulation of cell death completes our understanding of the mechanism of sustained activation of JNK (P-JNK), which leads to triggering of the machinery of cell death. This understanding will lead the investigators to discover the modulators facilitating or preventing cell death for therapeutic application in acute or chronic diseases and cancer. We discuss here the mechanism and modulators of the JNK-SAB-ROS activation loop, which is the core component of mitochondria-dependent cell death, specifically apoptosis and mitochondrial permeability transition (MPT)-driven necrosis, and which may also contribute to cell death mechanisms of ferroptosis and pyroptosis. The discussion here is based on the results and evidence discovered from liver disease models, but the JNK-SAB-ROS activation loop to sustain JNK activation is universally applicable to various disease models where mitochondria and reactive oxygen species contribute to the mechanism of disease.