Search Results (319)

Background: Intravenous vancomycin remains a key agent in the treatment of complex orthopedic infections, particularly those involving methicillin-resistant Staphylococcus aureus (MRSA). However, its use is associated with significant risks, most notably nephrotoxicity. Despite guideline recommendations, standardized dosing and monitoring protocols are often absent in orthopedic settings, leading to inconsistent therapeutic drug exposure and preventable adverse events. This study evaluated the clinical impact of implementing a structured standard operating procedure (SOP) for intravenous vancomycin therapy in orthopedic inpatients. Methods: We conducted a single-center, pre-post cohort study at a university orthopedic department. The intervention consisted of a standard operating procedure (SOP) for intravenous vancomycin therapy, which mandated weight-based loading doses, renal function-adjusted maintenance dosing, trough level monitoring, and defined dose adjustments. Patients treated before SOP implementation (n = 58) formed the control group; those treated under the SOP (n = 56) were prospectively included. The primary outcome was the incidence of vancomycin-associated acute kidney injury (VA-AKI) defined by KDIGO Stage 1 criteria. Secondary outcomes included therapeutic trough level attainment and infusion-related or ototoxic adverse events. Results: All patients in the post-SOP group received a loading dose (100% vs. 31% pre-SOP, p < 0.001). The range of measured vancomycin trough levels narrowed substantially after SOP implementation (7.1–36.2 mg/L vs. 4.0–80.0 mg/L). The proportion of patients reaching therapeutic trough levels increased, although this was not statistically significant. Most notably, VA-AKI occurred in 17.2% of patients in the control group, but in none of the patients after SOP implementation (0%, p = 0.0013). No cases of ototoxicity were observed in either group. Infusion-related reactions decreased after the implementation of the SOP, though not significantly. Conclusions: The introduction of a structured vancomycin protocol significantly reduced adverse drug events and improved dosing control in orthopedic inpatients. Incorporating such protocols into routine practice represents a feasible and effective strategy to strengthen antibiotic stewardship and clinical quality in surgical disciplines. Full article

Type 2 diabetes mellitus (T2DM) demands safer and more effective therapies to control postprandial hyperglycemia. Here, we report the synthesis and in vitro evaluation of ten salicylic acid-derived Schiff base derivatives (4a–4j) as α-glucosidase inhibitors. Compounds 4e, 4g, 4i, and 4j exhibited potent enzyme inhibition, with IC₅₀ values ranging from 14.86 to 18.05 µM—substantially better than acarbose (IC₅₀ = 45.78 µM). Molecular docking and 500 ns molecular dynamics simulations revealed stable enzyme–ligand complexes driven by π–π stacking, halogen bonding, and hydrophobic interactions. Density Functional Theory (DFT) calculations and molecular electrostatic potential (MEP) maps highlighted key electronic factors, while ADMET analysis confirmed favorable drug-like properties and reduced nephrotoxicity. Structure–activity relationship (SAR) analysis emphasized the importance of halogenation and aromaticity in enhancing bioactivity. Full article

Drug-induced nephrotoxicity is a common and serious problem in clinical practice. We conducted a systematic review of studies reporting nephrotoxicity events associated with antibiotics approved since 2018. The agents assessed included aztreonam/avibactam, cefepime/enmetazobactam, cefiderocol, ceftobiprole, contezolid, gepotidacin, imipenem/cilastatin/relebactam, lascufloxacin, lefamulin, levonadifloxacin, plazomicin, and sulbactam/durlobactam. Literature searches were conducted in PubMed, Scopus, Web of Science, and major pharmacovigilance databases (Vigibase, FAERS, EudraVigilance, EMA, FDA, NMPA, PMDA, and CDSCO) in May 2025, along with reference citation tracking. Studies were included if they reported safety or adverse event data. The risk of bias was assessed using validated tools in accordance with the study design. Out of 2105 potentially relevant records, 74 studies met inclusion criteria, comprising 52 clinical trials, 17 observational studies, 1 registry-based study, 3 case series, and 1 case report. Nephrotoxicity was rarely reported for any of the newly approved antibiotics. No renal adverse events were found in the available studies for aztreonam/avibactam, levonadifloxacin, and contezolid. Most studies were of moderate to high quality; two were classified as low quality. However, nephrotoxicity was inconsistently assessed, with variable definitions and methodologies used. Although current data suggest a low frequency of nephrotoxicity, limitations in study design and reporting preclude firm conclusions. There is a need for post-marketing studies to better characterize renal safety. Clinicians should remain vigilant and continue to monitor for and report renal-related adverse events. Full article

Magnesium (Mg²⁺) has gained oncologists’ attention due to its wide range of biological functions and frequent use as a complementary or integrative agent. This review outlines Mg’s actions, its complex role in carcinogenesis and tumor risk, and clinical issues. Mg²⁺ is essential in numerous biochemical processes, including adenosine triphosphate production, cellular signal transduction, DNA, RNA and protein synthesis, and bone formation. Pertinent full-text articles were thoroughly examined, and the most relevant ones were selected for inclusion in this review. There is conflicting scientific evidence about the relationship between Mg²⁺ changes and cancer risk, apart from colorectal cancer. Chronic Mg²⁺ deficiency leads to immune dysfunctions and enhanced baseline inflammation associated with oxidative stress related to various age-associated morbidities and cancer. On the other hand, Mg²⁺ deficiency is associated with drug or chemotherapy-related hypomagnesemia, postoperative pain, cachexia, opioid-induced constipation, normal tissue protection from radiation damage, and prevention of nephrotoxicity. A balanced diet usually provides sufficient Mg²⁺, but supplementation may be necessary in some clinical settings. Full article

Acetaminophen, or paracetamol (PCM), is a common painkiller used to treat aches, pain, and fever. Nevertheless, PCM has been reported to be hepatotoxic and nephrotoxic in humans. Thus, there is a need to identify how this side effect can be treated. Previous studies have shown that Leea species possess antioxidative, anthelmintic, anti-cytotoxic, hepatoprotective, and nephroprotective properties. However, the role of Leea guineensis (LG) in modulating PCM-induced hepatotoxicity or nephrotoxicity remains unknown. Herein, we investigate the possibility of Leea guineensis leaf extract (LGE) to ameliorate PCM toxic effects, evaluate hepatic and renal function, oxidative stress markers, and safety, and perform molecular docking to predict affinities of Leea guineensis extract compounds for their targets compared to PCM. An in vivo rat model was used for Leea guineensis extract or silymarin (SLM, standard drug) at various concentrations, and it was co-administered with PCM. We observed that Leea guineensis extract is rich in phytochemical constituents, and its treatment in rats did not significantly affect body weight. Our data showed that PCM increased bilirubin, creatinine, uric acid, Alanine aminotransferase (ALT), and cholesterol levels but decreased Aspartate aminotransferase (AST) in plasma. Moreover, it increased lipid peroxidation (MDA) levels in the liver and kidneys, while the total protein was elevated in the latter. Interestingly, Leea guineensis extract and SLM abrogated the elevated parameters due to PCM toxicity. Importantly, histopathological examination showed that Leea guineensis extract demonstrated the potential to ameliorate hepatic and renal lesions caused by PCM intoxication, thus demonstrating its safety. Furthermore, comparative molecular binding affinities of the study ligands binding the target corroborate the experimental findings. Our study shows that L. guineensis leaf extract, through its rich phytochemicals, can protect the liver and kidneys against the toxic effects of paracetamol in a dose-dependent manner. Full article

Cisplatin (Cis) is a widely used chemotherapy drug, but its nephrotoxicity limits its clinical application. Acute kidney injury (AKI) is a common complication, restricting long-term use. This study investigates the mechanisms of cisplatin-induced AKI and explores potential therapeutic targets. C57BL/6J mice were intraperitoneally injected with 20 mg/kg cisplatin to establish an AKI model. Serum creatinine, urea nitrogen, and tubular injury biomarkers (NGAL, KIM-1) progressively increased, indicating kidney dysfunction. Mitochondrial ATP levels significantly decreased, along with reduced mitochondrial fission and fusion, suggesting mitochondrial dysfunction. Increased oxidases and reduced antioxidants indicated redox imbalance, and metabolic reprogramming was observed, with lipid deposition, impaired fatty acid oxidation (FAO), and enhanced glycolysis in proximal tubular epithelial cells (PTECs). Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcriptional regulator of redox homeostasis and mitochondrial function. We found NRF2 levels increased early in AKI, followed by a decrease in vivo and in vitro, suggesting activation in the stress response. Nfe2l2 knockout mice showed aggravated kidney injury, characterized by worsened kidney function and histopathological damage. Mechanistically, Nfe2l2 knockout resulted in redox imbalance, reduced ATP synthesis, mitochondrial dysfunction and metabolic dysregulation. Furthermore, we activated NRF2 using dimethyl fumarate (DMF), observing a reduction in kidney damage and lipid deposition in mice. In conclusion, activating NRF2-dependent antioxidant pathways plays a crucial role in protecting against cisplatin-induced AKI. NRF2 may serve as a potential target for developing therapeutic strategies to prevent cisplatin nephrotoxicity. Full article

Background: Immune checkpoint inhibitors (ICIs) have significantly modified the management of metastatic cancers; however, their nephrotoxic potential remains underappreciated. While acute kidney injury (AKI) is a known immune-related adverse event, the subacute spectrum of kidney injury—termed acute kidney disease (AKD)—has not been adequately explored in this setting. Methods: We conducted a retrospective cohort study in 226 adult patients with metastatic solid tumors who received ICIs between 2017 and 2023 at a single tertiary care center. AKD was defined according to the 2024 “Kidney Disease: Improving Global Outcomes” (KDIGO) criteria. Multivariable logistic regression was used to identify predictors of AKD. Results: AKD occurred in 46 patients (20.4%) within 90 days of ICI initiation, with 16 (7.1%) experiencing persistent dysfunction beyond 30 days. Independent predictors of AKD included higher body surface area (OR 8.17, p = 0.03) and baseline use of nonsteroidal anti-inflammatory drugs (OR 29.74, p = 0.014). Baseline antibiotics showed a trend toward association (p = 0.054). Concurrent chemotherapy was associated with a trend toward protection. The predictive model showed good discrimination (AUC 0.778). No significant differences in other grade ≥2 immune-related adverse events were observed between the AKD and non-AKD groups. Conclusions: AKD is a frequent and underrecognized renal complication in patients receiving ICIs, with implications for both renal and oncological outcomes. Identifying high-risk patients and integrating longitudinal renal monitoring into immunotherapy care pathways may improve safety and treatment continuity. Full article

Background: Renal injury is a critical health issue in pet dogs, often exacerbated by drug-induced nephrotoxicity such as gentamicin (GM). This study investigated the protective effects of ergosterol (Erg), a natural compound from edible mushrooms, against GM-induced damage in Madin–Darby canine kidney (MDCK) cells. Methods: MDCK cells were treated with GM (0.5–3 mmol/L) for 12 h to establish injury. Erg (1 to 32 μg/mL) was pretreated for 12 h before GM exposure (2 mmol/L). Cell viability, nitric oxide (NO), lactate dehydrogenase (LDH), oxidative stress markers (SOD, GSH, CAT, MDA), inflammatory cytokines (IL-1β, IL-6, TNF-α), renal function indicators (Scr, BUN), and autophagy/apoptosis-related proteins (ATG5, Beclin1, P62, BAX, BCL-2) were assessed via CCK-8, ELISA, fluorescence staining, and Western blot. Statistical significance (p < 0.05) was determined by ANOVA and LSD post hoc tests. Results: GM (2 mmol/L) significantly reduced cell viability (p < 0.01) and elevated NO and LDH levels (p < 0.01). Erg pretreatment (4–8 μg/mL) restored cell viability (p < 0.01), suppressed NO (p < 0.01) and LDH release (p < 0.01), and enhanced antioxidant enzyme activities (SOD, GSH, CAT; p < 0.01). Erg attenuated GM-induced reactive oxygen species (ROS) overproduction (p < 0.01) and decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α; p < 0.01). Renal markers Scr and BUN were reduced (p < 0.01). Mechanistically, Erg upregulated autophagy proteins ATG5 and Beclin1 (p < 0.01), reduced P62 accumulation (p < 0.01), and lowered the BAX/BCL-2 ratio (p < 0.01). Conclusions: Erg protects MDCK cells from GM-induced nephrotoxicity by restoring autophagy flux, suppressing mitochondrial apoptosis, and mitigating oxidative stress and inflammation. These findings highlight Erg’s potential as a natural therapeutic agent for canine renal injury. Further in vivo studies are needed to validate its clinical efficacy. Full article

Cisplatin (CIS) is a widely used chemotherapeutic agent that is highly effective against various cancers. However, its clinical application is frequently limited by its substantial nephrotoxic side effects. The gastrin-releasing peptide receptor (GRPR), a critical regulator in inflammatory diseases, has been identified as a promising therapeutic target. Our previous studies have demonstrated that the GRPR antagonists PD176252 and RH-1402 can mitigate CIS-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, we designed and synthesized a series of 2-arylpropanoic acid-L-tryptophan derivatives to enhance the therapeutic effects. Among these compounds, 3m exhibited superior renal protection by significantly improving mouse renal tubular epithelial cell (mRTEC) viability from 50.2 ± 2.6% to 80.5 ± 3.9%, surpassing PD176252 (70.8 ± 1.4%) and RH-1402 (73.9 ± 3.7%). Moreover, compound 3m markedly reduced the expression of kidney injury molecule-1 (KIM-1) and inflammatory cytokines [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1)]. Finally, molecular docking results revealed that 3m exhibited a high binding affinity for GRPR. Computational predictions using SwissADME further indicated that 3m possesses favorable drug-like properties, thereby supporting its potential as a promising candidate for mitigating CIS-induced nephrotoxicity. Full article

Background/Objectives: Acute kidney injury (AKI) remains an unsolved medical problem due to the lack of effective treatments, high mortality, and increased susceptibility to progression to chronic kidney disease (CKD), especially in the elderly. Cellular senescence has been described in AKI, CKD, and aging and has been proposed as a promising therapeutic target. The senolytic drug combination of dasatinib plus quercetin (D&Q) is beneficial in some pathological conditions, including experimental CKD, but there are no data for AKI. Methods: The effect of D&Q combination was tested in folic acid-induced nephrotoxicity (FAN-AKI), a murine AKI model. Results: D&Q pretreatment did not prevent renal dysfunction in the acute phase of FAN-AKI, as determined by serum creatinine and BUN levels at 48 h. Moreover, gene expression of the kidney damage biomarkers Lcn2 and Havcr1, the Cdkn1a gene, which encodes p21, and some genes encoding components of the senescent cell secretome were significantly increased in response to D&Q treatment. The number of senescent p21-positive cells in injured kidneys was similar in untreated or D&Q-treated FAN mice. In addition, D&Q did not prevent the downregulation of the antiaging factor Klotho in damaged kidneys. Conclusions: D&Q treatment was not protective in FAN-AKI, exacerbating some deleterious responses. These results suggest caution when exploring the clinical translation of D&Q senolytic activity. Full article

Background/Objectives: Vancomycin, a glycopeptide antibiotic used for gram-positive infections, is associated with acute kidney injury (AKI). Therapeutic drug monitoring (TDM) is recommended to minimize this risk while ensuring therapeutic efficacy. This study evaluated whether AUC-guided monitoring improved patient safety compared to traditional trough-guided monitoring. Methods: A retrospective observational cohort study was conducted at the University Medical Centre Maribor, Slovenia, involving patients receiving intravenous vancomycin. One cohort was managed using trough-guided monitoring (n = 85), while the other was monitored using the AUC-guided approach (n = 139). The primary outcome was AKI incidence, and secondary outcomes included renal replacement therapy and mortality. Risk factors for AKI were identified, and pharmacokinetic parameters were evaluated at vancomycin therapy initiation and steady state. Results: The incidence of AKI was 20% in the trough-guided group and 18% in the AUC-guided group (p = 0.727). Secondary outcomes were similar in both cohorts. Risk factors for AKI included older age (OR 1.04; p = 0.042), higher steady-state AUC (OR 1.01; p < 0.001), longer duration of concomitant nephrotoxic therapy (OR 1.06; p = 0.019), and concomitant use of loop diuretics (OR 2.46; p = 0.045). Steady-state AUC values and trough levels (AUC_0–24ss, AUC_24–48ss, AUC_0–48ss, and C_min48ss) were significantly lower in the AUC-guided group, which was further reflected in the lower percentage of patients exceeding the AUC > 600 mg·h/L threshold at steady state. Conclusions: Although AKI incidence was lower in the AUC-guided group, the difference did not reach statistical significance. However, lower AUC values and trough levels in the AUC-guided group at steady state suggest a trend toward reduced vancomycin exposure and toxicity. Full article

Cisplatin is a highly cytotoxic drug used for the treatment of head, neck, and soft tissue cancers; however, it has nephrotoxic effects that can lead to acute kidney injury. Protocatechuic acid (PCA) is a natural widely available antioxidant found in many fruits such as kiwi, mango, and berries. We have recently shown that PCA reduced renal injury in a mouse model of unilateral ureteral obstruction. The current study aims to investigate the protective effects of PCA in Cisplatin-induced inflammation in vitro in Boston University Mouse Proximal Tubular (BUMPT) cells. BUMPT cells were cultured in complete DMEM. Confluent BUMPT cells were then treated with 20 μM Cisplatin ± PCA 50 or 100 μM for 24 h. PCA treatment showed a dose-depending increase in % cell viability in Cisplatin-treated BUMPT cells. PCA treatment also dose-dependently decreased Cisplatin-induced increases in oxidative stress (ROS and TBARS), inflammation (p-NF-κB and IL-6), and apoptosis (cleaved caspase-3 and % of TUNEL⁺ cells) compared to Cisplatin-only treatment. The reduction in oxidative stress, inflammation, and apoptosis with PCA treatment in Cisplatin-treated BUMPT cells was associated with decreases in tubular physical barrier resistance and the expression of the tight junction protein zonula occludens-1 (ZO-1) when compared to BUMPT cells treated with Cisplatin alone. The current findings suggest that PCA treatment improves tubular barrier function in Cisplatin-treated BUMPT cells via reductions in oxidative stress, inflammation, and apoptosis. Full article

Background: Progress in the treatment of childhood oncological diseases has led to the prolonged survival of patients with this severe diagnosis. On the other hand, the prolonged chemotherapy courses that achieve this outcome also bring a number of complications, with acute kidney injury being one of them. Its occurrence in patients not only affects their quality of life but also prolongs and increases the cost of hospitalization, burdens the body with additional treatment, and impacts the ability to manage the underlying disease. Aim: The aim of this study is to determine the frequency of acute kidney injury among children hospitalized in the Pediatric Oncohematology Unit in Plovdiv during the period 2016–2020, as well as to identify the risk factors for its occurrence, its severity, and its dependence on tumor type, gender, and age. Patients and Methods: During the five-year period under review, a total of 213 newly diagnosed children with hematological diseases were admitted to our Pediatric Oncohematology Unit—122 boys and 91 girls. Results: Acute kidney injury was identified in 94 (44.1%) of the children—54 with solid tumors and 40 with malignant hemopathies. The main cause of acute kidney injury diagnosed was drug-induced nephrotoxicity, especially due to nephrotoxic chemotherapeutic agents. No statistically significant association was found between the type of tumor and the occurrence of acute kidney injury. Of the children with documented episodes of AKI, 11 were found to have CKD according to the KDIGO criteria. Conclusions: Acute kidney injury is a common complication that occurs during the medical treatment of children with malignant diseases. Full article

Background/Objectives: Acute kidney injury (AKI) is a significant global health issue with a high morbidity and mortality. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines identify various exposures and susceptibilities as risk factors for AKI. However, the predictive significance of these factors in heterogeneous emergency department (ED) populations remains unclear. We hypothesized that assessing KDIGO-listed exposures and susceptibilities for AKI, alone and in combination, would provide an insight into their predictive value for AKI. Furthermore, we investigated whether adding biomarkers, plasma neutrophil gelatinase-associated lipocalin (pNGAL) and C-reactive protein (CRP), could enhance AKI risk prediction. Methods: Data were analyzed from the prospective longitudinal “NGAL study” conducted at North Zealand University Hospital in Denmark. A total of 344 ED patients were included, with AKI diagnosed using KDIGO’s creatinine-based criteria. Patient data, including medical history, exposures, and susceptibilities, were extracted and analyzed. Predictive performance was evaluated using a receiver operating characteristic (ROC) analysis on individual and combined risk factors. Additional models incorporated pNGAL and CRP to assess their impact on prediction accuracy. Results: Individual exposures and susceptibilities showed a poor predictive performance, with nephrotoxic drugs and advanced age demonstrating the highest sensitivity but a low positive predictive value (PPV). Combining multiple risk factors improved AKI prediction, with models clustering into those optimizing sensitivity or PPV. The inclusion of pNGAL significantly enhanced predictive performance, achieving the highest combined sensitivity and PPV. Although less than pNGAL, CRP also improved prediction, while requiring fewer variables than pNGAL-inclusive models. Conclusions: No individual KDIGO-listed exposure or susceptibility could reliably predict AKI in the ED setting. Combining multiple exposures and susceptibilities improved the predictive accuracy, but the models excelled either at screening or confirmation, not both. The addition of pNGAL and CRP significantly enhanced AKI prediction, emphasizing the need for biomarker integration in risk stratification models. These findings highlight the limitations of clinical parameters alone and underscore the importance of a multifaceted approach to AKI risk assessment. Full article

The kidneys are integral to homeostasis but are susceptible to nephrotoxic compounds. Proximal tubular epithelial cells (PTECs) mediate drug metabolism and transport and are widely used in preclinical studies. However, commercial PTECs are limited in availability and physiological relevance. This study aimed to develop a novel, reliable protocol for isolating and culturing PTECs from human kidney biopsies. Primary PTECs were isolated from kidney biopsies of two patients (MFUM-RPTEC-1 and MFUM-RPTEC-2). Their morphology, population doubling time, transepithelial electrical resistance (TEER), and phenotypic markers were evaluated. Polarization and transporter expression were analyzed using cells cultured on Transwell inserts. Colonies formed within 24–48 h, with confluence reached by 8–10 days and dome (hemicyst) formation by day 13. TEER values peaked at 190 Ω/cm² after 7–14 days, confirming tight junction formation. Immunostaining identified characteristic markers (e.g., SGLT2, OAT1/3, OCT2, P-gp, MRP4, MATE1, N-cadherin, ZO-1, CK-18). Cells cultured on Transwell plates exhibited native polarization, expressing transporters crucial for drug excretion on apical and basolateral surfaces. We present two robust protocols for isolating and characterizing PTECs, offering a scalable method to obtain functional, polarized cells from scarce biopsy material. The isolated PTECs, therefore, present a valuable platform for preclinical studies, especially for drug excretion testing through the expressed transporters. Drug competition for these transporters during tubular secretion is also a common cause of nephrotoxicity. Full article