Nephrotoxic Potential Research Articles

Advances in the clinical treatment of multidrug-resistant pathogens using polymyxins.

Polymyxins are a vital class of antibiotics used to combat multidrug-resistant Gram-negative bacteria. However, their use is limited due to potential nephrotoxicity and the availability of alternative antibiotics. This review aims to examine the properties of polymyxins and the clinical advances in their use for treating infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB). This review analyses literature on polymyxin properties and various clinical approaches, including intravenous drip infusion, nebulized or dry powder inhalation, and ointment application. Treatment efficacy in terms of bacterial eradication, cure rate and mortality rate are reviewed and evaluated. Polymyxins have been reintroduced to treat critical infections due to the increasing prevalence of CR-GNB. Clinical trials and studies have confirmed that polymyxins can effectively treat CR-GNB infections when the formulation and administration are appropriate, with acceptable levels of nephrotoxicity. In the future, the development of polymyxin formulations will aim to improve their clinical effectiveness while reducing toxicity and side effects and preventing the emergence of polymyxin-resistant strains. Enhanced efficacy and minimized potential side effects can be achieved by developing new polymyxin-delivery systems that provide a smart and controlled release or customized patient administration.

Nephrotoxicity of Cylindrospermopsin (CYN) and Microcystin-LR (MC-LR) on Mammalian Kidney: Wistar Rat as a Model Assessment

Naturally derived cyanotoxins, cylindrospermopsin (CYN), and microcystin-LR (MC-LR) have shown hepatotoxic and nephrotoxic effects in several studies. The present study aimed to determine the possible nephrotoxicity of MC-LR and CYN on mammalian kidneys using male Wistar rats as an animal model. Potential nephrotoxicity was evaluated at different doses of CYN (0.175 μg.kg-1, 0.140 μg.kg-1, 0.105 μg.kg-1) and MC-LR (0.105 μg.kg-1, 0.070 μg.kg-1, 0.035 μg.kg-1) was observed. Water samples from dug wells contaminated with CYN (0.161 μg.kg-1) and MC-LR (0.091 μg.kg-1) from the Padaviya area in Anuradhapura, Sri Lanka were used as environmental samples. The control groups were treated with distilled water. The exposure time of rats to the toxin was 90 days. Evaluation of urinary creatinine, serum creatinine, and Kidney Injury Molecule-1 (KIM-1) were estimated using standard protocols. A significant increase in serum creatinine levels was observed in all CYN and MC-LR treated groups (p<0.05) after 7 and 42 days of exposure, respectively, compared to control. It was found a decrease of urine creatinine when rats were treated with different concentrations of CYN and MC-LR (p<0.05) after 7 days compared to the control. The highest KIM-1 concentrations were recorded at 0.175 μg.kg-1 of CYN and 0.105 μg.kg-1 of MC-LR. The concentrations of KIM-1 in the control groups for CYN-treated and MC-LR-treated were not detected. Luminal protein, nuclear pyknosis, mild tubular epithelial swelling, vascular congestion, and interstitial inflammation in CYN and MC-LR treated groups were common. No predominant changes were observed in the control groups treated with CYN and MC-LR. The results of the present study confirm that the consumption of CYN and MC-LR-contaminated water may lead to kidney injury in Wistar rats.

Drug-Related Glomerular Phenotypes: A Global Pharmacovigilance Perspective.

Introduction: Adverse drug reactions are a significant problem in modern society, stemming from the increase in prescribed medications, over-the-counter drugs, and overall polypharmacy. Glomerular disorders are one of the frequently reported renal conditions associated with medication use. VigiBase is a significant tool for evaluating events associated with drug use, and, to the authors' knowledge, no study has yet assessed this database to identify the primary medications associated with glomerular disorders. Materials and Methods: We collected data from VigiBase for 54 years and evaluated data based on global frequencies, disproportionality (IC025 values), nephrotoxic potential, and physiopathological mechanisms. Results: Over the evaluation period, 33.932.051 spontaneous notifications of adverse drug reactions reported in VigiBase were assessed, from which 106.775 notifications of drug-associated glomerular disorders were extracted. The isolated medications were classified as 'potential nephrotoxins' (47.0%), with 40% of the medications lacking scientific references to report any association with the development of glomerular disorders. Among the evaluated medications, Inotersen (IC025 of 8.3), Penicillamine (IC025 6.8), Bevacizumab (IC025 5.9) and Lenvatinib (IC025 5.4) were identified as having the strongest association with these glomerular disorders. For medications classified as 'non-nephrotoxic', a high disproportionality index was observed, suggesting drugs that might be considered as new potential nephrotoxins. Conclusions: Drug-induced glomerular disorders were significantly associated with medications that had no established nephrotoxic role but demonstrated a high disproportionality index in VigiBase. These newly alleged nephrotoxic drugs warrant further evaluation in dedicated studies to assess their true nephrotoxic potential.

Unveiling the nephrotoxic profile of BCR-ABL tyrosine kinase inhibitors: A real-world experience in Africa.

The efficacy of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating chronic myelogenous leukemia and other malignancies is well-documented. However, concerns about potential nephrotoxicity have raised questions. This study, conducted at Tikur Anbesa Specialized Hospital (TASH) in Addis Ababa, Ethiopia, aimed to investigate the association between TKIs and renal toxicities. A hospital-based cross-sectional design was used to enroll 260 TASH patients actively receiving BCR-ABL TKIs. Demographic information, diagnoses, treatment details, and laboratory test results were collected for each participant's Electronic Medical Record. The primary goal was to assess adverse renal events, a combination of events of a decrease in estimated glomerular filtration rate (eGFR) exceeding 30% from baseline, significant proteinuria, and a diagnosis of acute kidney injury (AKI) or chronic kidney disease (CKD). A logistic regression model was used to analyze the data and identify factors associated with developing adverse renal events. Our analysis revealed a statistically significant decrease in eGFR following treatment with TKIs. However, the observed rate of adverse renal events (13.1%) was lower than reported in some previous studies. Factors significantly associated with adverse renal events included longer TKI duration, male sex (protective), hypertension, HIV infection, and achieving complete molecular remission and/or a complete hematologic response. No significant associations were found with diabetes mellitus, age, angiotensin-converting enzyme inhibitors use, or baseline creatinine level. While this study found that BCR-ABL TKIs can lead to a decline in eGFR, AKI, and CKD, it also demonstrated that they were relatively safer in our study population.

Plant Organic Acids as Natural Inhibitors of Foodborne Pathogens

Background: Foodborne infections affect approximately 600 million people annually. Simultaneously, many plants contain substances like organic acids, which have antimicrobial activity. The aim of this study was to examine the effects of 21 organic acids, naturally occurring in plants, on four foodborne bacteria (Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella enterica Typhimurium) and two fungi (Geotrichum candidum and Penicillium candidum). Methods: The minimal inhibitory concentrations (MIC) of the organic acids against foodborne bacteria and in silico toxicity prediction of acids were investigated. Results: Benzoic and salicylic acids exhibit the best activity against foodborne bacteria (mean MIC < 1 mg/mL). Acetic, chlorogenic, formic, malic, nicotinic, and rosmarinic acids demonstrate slightly weaker activity (mean MICs 1–2 mg/mL). Other acids have moderate or poor activity. The effectiveness of organic acids against foodborne fungi is weaker than against bacteria. Most acids require high concentrations (from 10 to >100 mg/mL) to inhibit fungal growth effectively. The predicted LD50 of organic acids ranges from 48 to 5000 mg/kg. Those potentially safe as food preservatives (MIC < LD50) include ascorbic, chlorogenic, malic, nicotinic, rosmarinic, salicylic, succinic, tannic, and tartaric acids. The studied organic acids are not carcinogenic but many can cause adverse effects such as skin sensitization, eye irritation, and potential nephrotoxicity, hepatotoxicity, or neurotoxicity. Conclusions: Most of the investigated plant-derived organic acids exhibit good antibacterial activity and moderate or poor antifungal effects. Among 21 acids, only 9 appear to be safe as food preservatives (MIC < LD50). The relationship between MIC and LD50 is crucial in determining the suitability of organic acids as food preservatives, ensuring that they are effective against bacteria or fungi at concentrations that are not harmful to humans.

New Predictive Equation for the Estimation of Plasma Concentrations of Formed Colistin in Patients Treated With Colistimethate Sodium for Multidrug-Resistant Gram-Negative Bacterial Infections.

The clinical use of colistin methanesulphonate (CMS) is limited by potential nephrotoxicity. The selection of an efficient and safe CMS dose for individual patients is complicated by the narrow therapeutic window and high interpatient pharmacokinetic variability. In this study, a simple predictive equation for estimating the plasma concentration of formed colistin in patients with multidrug and extremely drug-resistant gram-negative bacterial infections was developed. The equation was derived from the largest clinical cohort of patients undergoing therapeutic drug monitoring (TDM) of colistin for over 8 years in a tertiary Spanish hospital. All variables associated with C ss,avg were selected in a multiple linear regression model that was validated in a second cohort of 40 patients. Measured C ss,avg values were compared with those predicted by our model and a previous published algorithm for critically ill patients. In total, 276 patients were enrolled [the mean age was 67.2 (13.7) years, 203 (73.6%)] were male, and the mean (SD) C ss,avg was 1.12 (0.98) mg/L. Age, gender, estimated glomerular filtration rate, CMS dose and frequency, and concomitant drugs were included in the model. In the external validation, the previous algorithm appeared to yield more optimized colistin plasma concentrations when all types of C ss,avg values (high and low) were considered, while our equation yielded a more optimized prediction in the subgroup of patients with low colistin plasma concentrations (C ss,avg <1.5 mg/L). The proposed equation may help clinicians to better use CMS among a wide variety of patients, to maximize efficacy and prevent nephrotoxicity. A further prospective PK study is warranted to externally validate this algorithm.

Renal dysfunction in HIV-infected patients commencing antiretroviral therapy in a treatment centre in southern Nigeria

Objective: As HIV becomes a more manageable chronic condition, with increasing life expectancy and an ageing population, kidney disease due to HIV or antiretroviral therapy (ART) have become more prominent. Moreover, the nephrotoxic potential of some frontline antiretroviral drugs has become established. The study aimed to evaluate the prevalence and risk factors for renal dysfunction among HIV-infected patients commencing ART at a southern Nigerian tertiary hospital. Methods: A cross-sectional prospective study involving 263 HIV-infected treatment-naïve patients commencing ART at the University of Port Harcourt Teaching Hospital, Port Harcourt. Blood and urine samples were taken from randomly recruited patients for appropriate laboratory analysis. The MDRD formulae were used for evaluating renal function while renal dysfunction was defined as an estimated glomerular filtration rate ≤ 60mls/min/1.73m2 and /or proteinuria. Results: The average age of enrolled patients was 36.3±10.15 with 59.3% women. 33.8% had proteinuria and 6.5% had eGFR&lt;60mls/min/1.73m2. The prevalence of renal dysfunction was 37.6%. Age &gt; 50 years, anaemia and use of Traditional medicine were independent predictors of renal dysfunction. Conclusion: In this cohort of treatment naïve HIV patients, a high prevalence of renal dysfunction exists. Older age, anaemia and traditional medicine use were predictors of renal dysfunction. There is a need for clinicians to monitor these variables, especially the use of Traditional medicine which is easily overlooked in practice.

Nephrotoxicity of organophosphate flame retardants in patients with chronic kidney disease: A 2-year longitudinal study

Humans are extensively exposed to organophosphate flame retardants (OPFRs), an emerging group of organic contaminants with potential nephrotoxicity. Nevertheless, the estimated daily intake (EDI) and prognostic impacts of OPFRs have not been assessed in individuals with chronic kidney disease (CKD). In this 2-year longitudinal study of 169 patients with CKD, we calculated the EDIs of five OPFR triesters from urinary biomonitoring data of their degradation products and analyzed the effects of OPFR exposure on adverse renal outcomes and renal function deterioration. Our analysis demonstrated universal OPFR exposure in the CKD population, with a median EDIΣOPFR of 360.45 ng/kg body weight/day (interquartile range, 198.35–775.94). Additionally, our study revealed that high tris(2-chloroethyl) phosphate (TCEP) exposure independently correlated with composite adverse events and composite renal events (hazard ratio [95 % confidence interval; CI]: 4.616 [1.060–20.096], p = 0.042; 3.053 [1.075–8.674], p = 0.036) and served as an independent predictor for renal function deterioration throughout the study period, with a decline in estimated glomerular filtration rate of 4.127 mL/min/1.73 m2 (95 % CI, −8.127–−0.126; p = 0.043) per log ng/kg body weight/day of EDITCEP. Furthermore, the EDITCEP and EDIΣOPFR were positively associated with elevations in urinary 8-hydroxy-2’-deoxyguanosine and kidney injury molecule-1 during the study period, indicating the roles of oxidative damage and renal tubular injury in the nephrotoxicity of OPFR exposure. To conclude, our findings highlight the widespread OPFR exposure and its possible nephrotoxicity in the CKD population.

Complex Assessment of the Functional State of the Urinary System in Preclinical Studies. Part 1. Instrumental and Laboratory Assessment Methods (Review)

INTRODUCTION. Functional examination of the urinary system, and particularly the kidneys, is an important challenge in preclinical studies. Currently, there is no generally recognised and detailed approach to drug-induced nephrotoxicity detection in vivo, nor are there clear criteria for its assessment.AIM. This study aimed to analyse and systematise instrumental and laboratory methods for the assessment of urinary system function in laboratory animals and to identify the basic principles for studying drug-induced nephrotoxic effects.DISCUSSION. The study analysed the advantages and limitations of the methods used to study the nephrotoxicity of medicinal products, with considerations for the use of these methods in small and large laboratory animals. The effects of a test substance on the urinary system should first be evaluated using minimally invasive methods. One of these methods is urinalysis. For urinalysis, important considerations include the sampling technique, the volume of the biomaterial, and the turnaround time between urine collection and analysis. Ultrasonography is the most accessible instrumental method in preclinical studies. Ultrasonography can assess organ position, size, structure, and echogenicity and detect abnormalities and changes in real time. Dif ferent method settings are preferred for each species of laboratory animal. Further analysis can include macroscopic examination of organs, measurement of their masses, and microscopic analysis of tissues. Visual assessment should cover the size, colour, and consistency of the ureters, bladder, and kidneys. Nephrotoxicity may manifest as increased apoptosis, vacuolation of renal tubular epithelial cells, epithelial degeneration or dystrophy, oedema, diapedesis-associated haemorrhages, acute tubular and papillary necrosis, necrosis of the Bowman–Schumlansky capsule, casts and crystals in the tubular lumen, glomerulopathy with the corresponding changes, and inflammatory and vascular reactions.CONCLUSIONS. The study analysed and systematised instrumental and laboratory methods for assessing the functional state of the urinary system in preclinical studies. The authors outlined the basic principles for a structured and comprehensive study of the potential nephrotoxicity of novel medicines. The assessment of nephrotoxicity should start with simple and minimally invasive laboratory and instrumental methods, which include general urinalysis and microscopic examination of urine sediment. These methods can detect organ dysfunction that has not yet presented with an associated anatomical lesion. A more in-depth analysis should involve histological and immunohistochemical methods to examine the urinary tissues of laboratory animals.

Maintaining calcium homeostasis as a strategy to alleviate nephrotoxicity caused by evodiamine

Evodiamine (EVO), the main active alkaloid in Evodia rutaecarpa, was shown to exert various pharmacological activities, especially anti-tumor. Currently, it is considered a potential anti-cancer drug due to its excellent anti-tumor activity, which unfortunately has adverse reactions, such as the risk of liver and kidney injury, when Evodia rutaecarpa containing EVO is used clinically. In the present study, we aim to clarify the potential toxic target organs and toxicity mechanism of EVO, an active monomer in Evodia rutaecarpa, and to develop mitigation strategies for its toxicity mechanism. Transcriptome analysis and related experiments showed that the PI3K/Akt pathway induced by calcium overload was an important step in EVO-induced apoptosis of renal cells. Specifically, intracellular calcium ions were increased, and mitochondrial calcium ions were decreased. In addition, EVO-induced calcium overload was associated with TRPV1 receptor activation. In vivo TRPV1 antagonist and calcium chelator effects were observed to significantly reduce body weight loss and renal damage in mice due to EVO toxicity. The potential nephrotoxicity of EVO was further confirmed by an in vivo test. In conclusion, TRPV1-mediated calcium overload-induced apoptosis is one of the mechanisms contributing to the nephrotoxicity of EVO due to its toxicity, whereas maintaining body calcium homeostasis is an effective measure to reduce toxicity. These studies suggest that the clinical use of EVO-containing herbal medicines should pay due attention to the changes in renal function of patients as well as the off-target effects of the drugs.

Development of normal reference intervals for renal function in pregnancy: a secondary analysis of clinical trial data

Background Due to its potential nephrotoxicity, screening for pre-existing renal function disorders has become a routine clinical assessment for initiating Tenofovir diphosphate fumarate (TDF)-containing antiretroviral treatment (ART) or pre-exposure prophylaxis (PrEP) in pregnant and non-pregnant adults. We aimed to establish reference values for commonly used markers of renal function in healthy pregnant women of African origin. Methods Pregnant women ≥18 years, not living with HIV, and at 14–28 weeks gestation were enrolled in a PrEP clinical trial in Durban, South Africa between September 2017 and December 2019. Women were monitored 4-weekly during pregnancy until six months postpartum. We measured maternal weight and serum creatinine (sCr) at each visit and calculated creatinine clearance (CrCl) rates using the Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae. Reference ranges for sCr and CrCl by CG and MDRD calculations were derived from the mean ± 2SD of values for pregnancy and postdelivery. Results Between 14-–and 40 weeks gestation, 249 African women not exposed to TDF-PrEP contributed a total of 1193 renal function values. Postdelivery, 207 of these women contributed to 800 renal function values. The normal reference range for sCr was 30–57 and 32–60 umol/l in the 2nd and 3rd trimesters of pregnancy. Normal reference ranges for CrCl using the MDRD calculation were 129–282 and 119–267 ml/min/1.73m2 for the 2nd and 3rd trimesters, respectively. Using the CG method of calculation, normal reference ranges for CrCl were 120—304 and 123–309 ml/min/1.73m2 for the 2nd and 3rd trimesters respectively. In comparison, the normal reference range for sCr, CrCl by MDRD and CG calculations postpartum was 40–77 umol/l, 92–201, and 90–238 ml/min/1.73m2, respectively. Conclusions In African women, the Upper Limit of Normal (ULN) for sCr in pregnancy is approximately 20% lower than 6 months postnatally. Inversely, the Lower Limit of Normal (LLN) for CrCl using either MDRD or CG equation is approximately 35% higher than 6 months postnatally. We provide normal reference ranges for sCr and CrCl for both methods of calculation and appropriate for the 2nd and 3rd trimesters of pregnancy in African women.

Feline Leishmaniasis: Evidence-based Treatments and Challenges to be Solved.

Leishmaniasis is a neglected tropical disease caused by protozoa parasites from the Leishmania genus. Vertebrate hosts acquire the infection through the bite of a female sandfly, initiating a complex parasite development cycle. Contrary to previous beliefs regarding cats' resistance, these animals have recently been identified as potential reservoirs for leishmaniasis. Clinical symptoms in cats can manifest in diverse forms, including cutaneous, mucocutaneous, and visceral manifestations. The diagnosis of feline leishmaniasis is complicated by nonspecific symptoms and the relatively lower specificity of serological tests. The recommended treatment for feline leishmaniasis involves the administration of medications; however, success varies in each cat. This review aims to present cases of feline leishmaniasis, highlighting clinical symptoms, diagnostic methods, therapy schedules, and outcomes. Among the 24 cases documented in the available literature, 12 achieved successful treatment without relapses, resulting in a reduced parasite load and improved symptoms. Three cases responded well but presented persistent sequelae. Two feline leishmaniasis cases initially had treatment success but later experienced recurrences. Finally, no response was observed in seven cases, leading to the euthanasia of cats due to ineffectiveness or irregularities along the therapy. Conventional treatments, despite potential hepatotoxicity and nephrotoxicity, exhibit a high efficacy in reducing parasitic load, thereby improving clinical symptoms and increasing the life expectancy of affected cats. Nevertheless, consistent adherence is crucial, as interruptions may render the therapy ineffective and contribute to parasite resistance. Therefore, addressing the challenges associated with feline leishmaniasis treatment necessitates the development of new strategies to ensure a more effective and sustained approach.

Evaluating the Safety of Herbal Medicine on Renal Function: A Comprehensive Analysis from Six Randomized Controlled Trials Conducted with Four Formulations from Traditional Korean Medicine.

The growing popularity of herbal medicine raises concerns about potential nephrotoxicity risks, while limited evidence hinders a comprehensive impact assessment. This study aims to investigate the overall risk features of herbal medicine on kidney injury. We conducted a retrospective analysis on renal function changes, including blood urea nitrogen (BUN), serum creatinine, and estimated glomerular filtration rate (eGFR), through data from six randomized controlled trials (RCTs) in South Korea. A total of 407 participants (142 males, 265 females) received either one of four different herbal medicines (240 participants) or a placebo (167 participants). When comparing changes in eGFR regarding the mean, 90th-percentile value, and 20% reduction after treatment, there was no significant difference between the herbal-treated and placebo groups. This study provided a helpful reference for examining the safety issues of herbal remedies, especially regarding kidney function.

Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids

High-throughput drug screening is crucial for advancing healthcare through drug discovery. However, a significant limitation arises from available in vitro models using conventional 2D cell culture, which lack the proper phenotypes and architectures observed in three-dimensional (3D) tissues. Recent advancements in stem cell biology have facilitated the generation of organoids—3D tissue constructs that mimic human organs in vitro. Kidney organoids, derived from human pluripotent stem cells, represent a significant breakthrough in disease representation. They encompass major kidney cell types organized within distinct nephron segments, surrounded by stroma and endothelial cells. This tissue allows for the assessment of structural alterations such as nephron loss, a characteristic of chronic kidney disease. Despite these advantages, the complexity of 3D structures has hindered the use of organoids for large-scale drug screening, and the drug screening pipelines utilizing these complex in vitro models remain to be established for high-throughput screening. In this study, we address the technical limitations of kidney organoids through fully automated 3D imaging, aided by a machine-learning approach for automatic profiling of nephron segment-specific epithelial morphometry. Kidney organoids were exposed to the nephrotoxic agent cisplatin to model severe acute kidney injury. An U.S. Food and Drug Administration (FDA)-approved drug library was tested for therapeutic and nephrotoxicity screening. The fully automated pipeline of 3D image acquisition and analysis identified nephrotoxic or therapeutic drugs during cisplatin chemotherapy. The nephrotoxic potential of these drugs aligned with previous in vivo and human reports. Additionally, Imatinib, a tyrosine kinase inhibitor used in hematological malignancies, was identified as a potential preventive therapy for cisplatin-induced kidney injury. Our proof-of-concept report demonstrates that the automated screening process, using 3D morphometric assays with kidney organoids, enables high-throughput screening for nephrotoxicity and therapeutic assessment in 3D tissue constructs.

Perioperative regional anaesthesia in kidney transplantation

Background. Postoperative analgesia in kidney transplant recipients is challenging due to potential nephrotoxicity of nonsteroidal anti-inflammatory drugs and the reduced clearance of opioid metabolites during transient renal impairment. Opioid-sparing multimodal postoperative analgesia using regional analgesia methods could provide better pain control and early activation after kidney transplantation.Aim. To evaluate the clinical results of treatment using regional pain management methods in kidney transplant recipients.Material and methods. A single-center study was conducted at Republican Research Center of Emergency Medicine from 2020 to 2022. The study included 97 patients who underwent heterotopic kidney transplantation from a living related donor. Patients were divided into 3 groups. In group 1 (31 patients), general anesthesia was used. For postoperative analgesia opioid analgesics in combination with metamizole 1000 mg were used. In group 2 (33 recipient patients), a combination of general anesthesia and open transversus abdominis plane block was used. In group 3 (33 recipient patients), a combination of general anesthesia and erector spine plane block was performed. Opioid analgesics were used as a "rescue analgesia" when necessary. The primary study end points were the pain intensity assessed by a visual analogue scale and opioid consumption on the first day after surgery. Secondary endpoints were the time of intestinal motility recovery, the presence of nausea and vomiting, the Intensive Care Unit length of stay and the hospital length of stay.Results. Pain intensity 6 hours after surgery in patients of group 1 was 13.5% and 24.6% higher than in patients of group 2 and 3, respectively. In group 2, pain intensity was 12.8% higher compared to group 3 (p=0.0017). At 12 hours after surgery, the pain intensity was 42% higher in group 1 compared to group 2 and group 3 (p&lt;0.0001). After 18 hours, the pain score in group 3 was 48.5% and 35.7% lower compared to groups 1 and 2, respectively (p&lt;0.0001 and p=0.0016). 24 hours after surgery, the sensation of pain was 18.6% and 65.3% higher in group 1 compared to groups 2 and 3 (p&lt;0.0001). The mean dose of narcotic analgesic equivalent to morphine in group 1 was 22.6±8.6 mg, which was 18.5% higher than in group 2 patients. In group 3, it was 12.0±4.3 mg and was 47% lower compared to group 1 (p&lt;0.0001) and 34.7% lower compared to group 2 (p&lt;0.0001) (all comparisons are statistically significant). The adequacy of analgesia and less opioid consumption contributed to the absence of postoperative nausea and vomiting in 75% of cases, early restoration of intestinal motility in 63% compared with the group of patients where opioid analgesics were used for postoperative pain relief.Conclusion. The combined use of general anesthesia and erector spine plane block may be recommended as a method of effective perioperative analgesia in kidney transplantation.

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability.

Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 μM) and glucose transporter 9 (GLUT9, IC50 = 18.21 μM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

Potential Nephrotoxicity of Combination of Vancomycin and Piperacillin-Tazobactam: Recommendations from the AG ABS of the DGPI supported by experts of the GPN

The combination of vancomycin and piperacillin/tazobactam (V+P/T) is used for empirical antibiotic treatment of severe infections, especially in immunocompromised patients and those colonized with multidrug-resistant bacteria. Nephrotoxicity is a frequently observed adverse effect of vancomycin. Its risk can be reduced by therapeutic drug monitoring and adjusted dosing. Piperacillin/tazobactam (P/T) rarely causes interstitial nephritis. The results of retrospective cohort studies in children predominantly show a low, clinically irrelevant, additive nephrotoxicity (defined as an increase in creatinine in the serum) of both substances. Due to the limitations of the existing publications, the ABS working group of the DGPI and experts of the GPN do not recommend against the use of P/T plus vancomycin. Preclinical studies and a prospective study with adult patients, which evaluated different renal function tests as well as clinical outcomes, do not support previous findings of additive nephrotoxicity. Time-restricted use of V+P/T can minimize exposure and the potential risk of nephrotoxicity. Local guidelines, developed in collaboration with the antibiotic stewardship team, should define the indications for empirical and targeted use of P/T and V+P/T. When using combination therapy with V+P/T, kidney function should be monitored through clinical parameters (volume status, balancing, blood pressure) as well as additional laboratory tests such as serum creatinine and cystatin C.

Renal proximal tubule-on-a-chip in PDMS: fabrication, functionalization, and RPTEC:HUVEC co-culture evaluation

‘On-a-chip’ technology advances the development of physiologically relevant organ-mimicking architecture by integrating human cells into three-dimensional microfluidic devices. This method also establishes discrete functional units, faciliting focused research on specific organ components. In this study, we detail the development and assessment of a convoluted renal proximal tubule-on-a-chip (PT-on-a-chip). This platform involves co-culturing Renal Proximal Tubule Epithelial Cells (RPTEC) and Human Umbilical Vein Endothelial Cells (HUVEC) within a polydimethylsiloxane microfluidic device, crafted through a combination of 3D printing and molding techniques. Our PT-on-a-chip significantly reduced high glucose level, exhibited albumin uptake, and simulated tubulopathy induced by amphotericin B. Remarkably, the RPTEC:HUVEC co-culture exhibited efficient cell adhesion within 30 min on microchannels functionalized with plasma, 3-aminopropyltriethoxysilane, and type-I collagen. This approach significantly reduced the required incubation time for medium perfusion. In comparison, alternative methods such as plasma and plasma plus polyvinyl alcohol were only effective in promoting cell attachment to flat surfaces. The PT-on-a-chip holds great promise as a valuable tool for assessing the nephrotoxic potential of new drug candidates, enhancing our understanding of drug interactions with co-cultured renal cells, and reducing the need for animal experimentation, promoting the safe and ethical development of new pharmaceuticals.

Genomic analysis reveals genes that encode the synthesis of volatile compounds by a Bacillus velezensis-based biofungicide used in the treatment of grapes to control Aspergillus carbonarius

Fungal control strategies based on the use of Bacillus have emerged in agriculture as eco-friendly alternatives to replace/reduce the use of synthetic pesticides. Bacillus sp. P1 was reported as a new promising strain for control of Aspergillus carbonarius, a known producer of ochratoxin A, categorized as possible human carcinogen with high nephrotoxic potential. Grape quality can be influenced by vineyard management practices, including the use of fungal control agents. The aim of this study was to evaluate, for the first time, the quality parameters of Chardonnay grapes exposed to an antifungal Bacillus-based strategy for control of A. carbonarius, supporting findings by genomic investigations. Furthermore, genomic tools were used to confirm that the strain P1 belongs to the non-pathogenic species Bacillus velezensis and also to certify its biosafety. The genome of B. velezensis P1 harbors genes that are putatively involved in the production of volatiles and hydrolytic enzymes, which are responsible for releasing the free form of aroma compounds. In addition to promote biocontrol of phytopathogenic fungi and ochratoxins, the treatment with B. velezensis P1 did not change the texture (hardness and firmness), color and pH of the grapes. Heat map and hierarchical clustering analysis (HCA) of volatiles evaluated by GC/MS revealed that Bacillus-treated grapes showed higher levels of compounds with a pleasant odor descriptions such as 3-hydroxy-2-butanone, 2,3-butanediol, 3-methyl-1-butanol, 3,4-dihydro-β-ionone, β-ionone, dihydroactinidiolide, linalool oxide, and β-terpineol. The results of this study indicate that B. velezensis P1 presents desirable properties to be used as a biocontrol agent.

Chemotherapy-induced acute kidney injury: epidemiology, pathophysiology, and therapeutic approaches.

Despite significant advancements in oncology, conventional chemotherapy remains the primary treatment for diverse malignancies. Acute kidney injury (AKI) stands out as one of the most prevalent and severe adverse effects associated with these cytotoxic agents. While platinum compounds are well-known for their nephrotoxic potential, other drugs including antimetabolites, alkylating agents, and antitumor antibiotics are also associated. The onset of AKI poses substantial risks, including heightened morbidity and mortality rates, prolonged hospital stays, treatment interruptions, and the need for renal replacement therapy, all of which impede optimal patient care. Various proactive measures, such as aggressive hydration and diuresis, have been identified as potential strategies to mitigate AKI; however, preventing its occurrence during chemotherapy remains challenging. Additionally, several factors, including intravascular volume depletion, sepsis, exposure to other nephrotoxic agents, tumor lysis syndrome, and direct damage from cancer's pathophysiology, frequently contribute to or exacerbate kidney injury. This article aims to comprehensively review the epidemiology, mechanisms of injury, diagnosis, treatment options, and prevention strategies for AKI induced by conventional chemotherapy.