Potential Nephrotoxic Effects Research Articles

Exploring the Link: DNA Methylation and Kidney Injury Markers in Farmers Exposed to Glyphosate-Surfactant Herbicides.

Glyphosate-surfactant herbicides (GSH), widely used herbicides, have raised concerns about their potential nephrotoxic effects. Despite extensive studies, the safety of GSH remains debatable. This study aimed to determine if occupational exposure to GSH causes detectable changes in renal injury biomarkers-specifically DNA methylation, KIM-1, TIMP2, and IGFBP7-in farmers regularly exposed to these chemicals. Two urine samples, pre-task (0-h) and post-task (24-h), were collected to analyze these biomarkers. No significant immediate changes were observed post-exposure, possibly due to personal protective equipment use. Moderate positive correlations were found between IGFBP7 and KIM-1, and IGFBP7 and TIMP2, suggesting early kidney injury. About 50% of subjects had a biomarker ratio greater than 1, indicating increased levels of IGFBP7, TIMP2, and KIM-1 after GSH exposure. This indicates that farmers who regularly spray GSH are at high risk of exposure, potentially leading to significant renal injury. Further long-term studies are needed to assess the chronic effects and validate these biomarkers for monitoring renal health in populations exposed to glyphosate.

Ponatinib exacerbate renal injury in systemic lupus erythematosus mouse model through PDGFR-PI3K/AKT pathway

Lupus nephritis (LN) is a common clinical complication of systemic lupus erythematosus (SLE). Proliferative lupus nephritis represents the gravest form of LN, and since effective drugs for its treatment are still lacking, tyrosine kinase inhibitors (TKIs) find extensive clinical utility due to their notable impact on suppressing cell proliferation and may serve as potential drugs for LN treatment. However, previous studies on the effects of TKI on LN have been controversial. Ponatinib, a third-generation TKI, lacks studies on its role in LN. This study aimed to investigate the impact of the ponatinib on LN. MRL/lpr mice were evaluated for renal function, autoimmune markers and histopathological changes after oral administration of ponatinib. RNA-seq analysis was performed to explore the molecular pathways involved in ponatinib-induced kidney injury. Ponatinib uniquely exacerbated renal damage in MRL/lpr mice, evidenced by a decline in renal function and acute pathological changes, without affecting lupus-related autoimmune markers. Differential expressed genes analysis and functional enrichment implicate ponatinib-induced renal damage in MRL/lpr mice associated with adiponectin. Furthermore, we verified ponatinib signaling the PI3K/AKT pathway through PDGFRα, potentially influencing high molecular weight adiponectin (HMW ADIPOQ) expression and exacerbating renal damage. In conclusion, this study demonstrates that ponatinib can up-regulate HMW ADIPOQ expression via the PI3K/AKT pathway by inhibiting PDGFRα phosphorylation, highlighting the potential nephrotoxic effects of ponatinib in lupus-prone mice, and underscoring the importance of monitoring renal function in systemic autoimmune diseases patients receiving ponatinib.

Navigating Anesthesia: Muscle Relaxants and Reversal Agents in Patients with Renal Impairment.

This comprehensive review explores the interaction between neuromuscular blocking agents, reversal agents, and renal function, focusing on various drugs commonly used in anesthesia and their effects on kidney health. Succinylcholine, commonly used for anesthesia induction, can trigger elevated potassium levels in patients with specific medical conditions, leading to serious cardiac complications. While studies suggest the use of succinylcholine in patients with renal failure is safe, cases of postoperative hyperkalemia warrant further investigation. Some agents, such as atracurium and mivacurium, are minimally affected by impaired kidney function, whereas others, such as cisatracurium and rocuronium, can have altered clearance, necessitating dose adjustments in patients with renal failure. The reversal agents neostigmine and sugammadex affect renal markers, while cystatin C levels remain relatively stable with sugammadex use, indicating its milder impact on glomerular function, compared with neostigmine. Notably, the combination of rocuronium and sugammadex in rat studies shows potential nephrotoxic effects, cautioning against the simultaneous use of these agents. In conclusion, understanding the interplay between neuromuscular blocking agents and renal function is crucial for optimizing patient care during anesthesia. While some agents can be used safely in patients with renal failure, others can require careful dosing and monitoring. Further research is needed to comprehensively assess the long-term impact of these agents on kidney health, especially in high-risk patient populations. This article aims to review the use of muscle relaxants and reversal for anesthesia in patients with impaired renal function.

BRD4 plays an antiaging role in the senescence of renal tubular epithelial cells.

Age-related kidney failure is often induced by a decrease in the bioavailability of tubular epithelial cells in elderly chronic kidney disease (CKD) patients. BRD4, an epigenetic regulator and a member of the bromodomain and extraterminal (BET) protein family, acts as a super-enhancer (SE) organizing and regulating genes expression during embryogenesis and cancer development. But the physiological function of BRD4 in normal cells has been less studied. This study aimed to research certain biological roles of BRD4 in the process of normal cell aging and discuss the potential mechanisms. In this study, we investigated the biological functions of BRD4 proteins in the aging of renal tubular cells. At first, we used a D-galactose (D-gal) and BRD4 inhibitor (Abbv-075) to replicate kidney senescence in vivo. D-gal and Abbv-075 were then used to measure the aging-related changes, such as changes in cell cycle, β-galactosidase activity, cell migration, and p16 protein expression in vitro. At last, we knocked down and over-expressed BRD4 to investigate the aging-related physiological phenomena in renal tubular cells. In vitro, D-gal treatment induced noticeable aging-related changes such as inducing cell apoptosis and cell cycle arrest, increasing β-galactosidase activity as well as up-regulating p16 protein expression in primary human tubular epithelial cells. In the aging mice model, D-gal significantly induced renal function impairment and attenuated BRD4 protein expression. At the same time, the BRD4 inhibitor (Abbv-075) was able to mimic D-gal-induced cell senescence. In vivo, Abbv-075 also decreased kidney function and up-regulated p21 protein expression. When we knocked down the expression of BRD4, the senescence-associated β-galactosidase (SA-β-gal) activity increased dramatically, cell migration was inhibited, and the proportion of cells in the G0/G1 phase increased. Additionally, the knockdown also promoted the expression of the senescence-related proteins p16. When the renal tubular cells were overexpressed with BRD4, cell aging-related indicators were reversed in the D-gal-induced cell aging model. BRD4 appears to have an active role in the aging of renal tubular cells in vivo and in vitro. The findings also suggest that BRD4 inhibitors have potential nephrotoxic effects for oncology treatment. BRD4 may be a potential therapeutic biomarker and drug target for aging-related kidney diseases, which warrants additional studies.

Cancer therapy in patients with reduced kidney function.

Chronic kidney disease (CKD) and cancer constitute two major public health burdens, and both are on the rise. Moreover, the number of patients affected simultaneously by both conditions is growing. The potential nephrotoxic effect of cancer therapies is particularly important for patients with CKD, as they are also affected by several comorbidities. Therefore, administering the right therapy at the right dose for patients with decreased kidney function can represent a daunting challenge. We review in detail the renal toxicities of anticancer therapies, i.e. conventional chemotherapy, targeted therapy, immune checkpoint inhibitors and radioligand therapies, issue recommendations for patient monitoring along with guidance on when to withdraw treatment and suggest dosage guidelines for select agents in advanced stage CKD. Various electrolytes disturbances can occur as the result of the administration of anticancer agents in the patient with decreased kidney function. These patients are prone to developing hyponatremia, hyperkalemia and other metabolic abnormalities because of a decreased glomerular filtration rate. Therefore, all electrolytes, minerals and acid base status should be checked at baseline and before each administration of chemotherapeutic agents. Moreover, studies on patients on kidney replacement therapy are very limited and only single cases or small case series have been published. Therefore, clinical therapeutical decisions in cancer patients with decreased function should be made by multidisciplinary teams constituted of medical oncologists, nephrologists and other specialists. Onconephrology is an evolving and expanding subspecialty. It is crucial to consider anticancer drug treatment in these patients and offer them a chance to be treated effectively.

A Single-Cell Transcriptome Profiling of Triptolide-Induced Nephrotoxicity in Mice.

Triptolide (TP), an active component isolated from the traditional Chinese herb Tripterygium wilfordii Hook F (TWHF), shows great promise for treating inflammation-related diseases. However, its potential nephrotoxic effects remain concerning. The mechanism underlying TP-induced nephrotoxicity is inadequately elucidated, particularly at single-cell resolution. Hence, single-cell RNA sequencing (scRNA-seq) of kidney tissues from control and TP-treated mice is performed to generate a thorough description of the renal cell atlas upon TP treatment. Heterogeneous responses of nephron epithelial cells are observed after TP exposure, attributing differential susceptibility of cell subtypes to excessive reactive oxygen species and increased inflammatory responses. Moreover, TP disrupts vascular function by activating endothelial cell immunity and damaging fibroblasts. Severe immune cell damageand the activation of pro-inflammatory Macro_C1 cells are also observed with TP treatment. Additionally, ligand-receptor crosstalk analysis reveals that the SPP1 (osteopontin) signaling pathway targeting Macro_C1 cells is triggered by TP treatment, which may promote the infiltration of Macro_C1 cells to exacerbate renal toxicity. Overall, this study provides comprehensive information on the transcriptomic profiles and cellular composition of TP-associated nephrotoxicity at single-cell resolution, which can strengthen the understanding of the pathogenesis of TP-induced nephrotoxicity and provide valuable clues for the discovery of new therapeutic targets to ameliorate TP-associated nephrotoxicity.

#284 Risk of dose-dependent methotrexate therapy on renal functions in patients with rheumatoid arthritis

Abstract Background and Aims Methotrexate is often used as first-line therapy for RA because of its proven efficacy, good safety profile, and low cost. The importance of MTX also comes from the fact that in combinatory treatments, the efficacy of bDMARDs or tsDMARDs is always higher when these drugs are combined to MTX, suggesting making MTX at the base of any conventional treatment of RA. Although renal impairment is a major concern in patients taking high-dose MTX for the treatment of malignancy, it has not been fully examined in RA patients treated with low-dose MTX, so we aimed at studying the dose- dependent effects of MTX on renal function and creatinine clearance. Method Three hundred and sixty adult RA patients, regularly attending rheumatology OPC for regular follow up participated in this retrospective cohort study. Young children, patients with any degree of renal impairment and other rhematic diseases were excluded. Serum creatinine and creatinine clearance were followed up at 1 year and 3 years of different doses of MTX therapy, and results were compared to baseline levels. Results Patients’ ages had a mean of 44.60 years, with most being females (80.6%). Range of disease duration was 2-34 years with the mean of 9.93 years. Most of the patients had significant disease activity, where 36.4% had moderate activity and 26.1% of them had high disease activity according to DAS 28 score. We noticed a significant decline of the creatinine clearance at 1 & 3 years follow up regardless the MTX dose used (P-value: ≤0.001 for both). Conclusion We may conclude that MTX therapy has a potential nephrotoxic effect regardless the dose or the duration of therapy, mandating a close monitoring of renal functions for patients maintained on the drug.

Self-induced Anuria with Diclofenac: An Interesting Case of “Quadruple Whammy” Acute Kidney Injury

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs widely prescribed and used worldwide. Patients taking NSAIDs, including diclofenac, should be aware of its potential nephrotoxic effects. However, the rapid onset of acute kidney injury (AKI) after a single dose of diclofenac is considered a very rare side effect. Case Presentation: We present a 66-year-old woman with habitual self-induced anuria with the chief complaint of shoulder pain due to falling down. The patient presented with various co-morbid conditions, including hypertension, type 2 diabetes, tricuspid valve repair, and aortic valve replacement. She rapidly developed anuria after receiving a single dose of diclofenac over the previous two days of admission. Creatinine and BUN exhibited a significant rise in laboratory tests. During hospitalization, the consumption of NSAIDs was prohibited and losartan and furosemide were discontinued. Moreover, phenacetin was used to relieve pain instead. Luckily, after two days of hospitalization, urine output returned to normal levels. Additionally, creatinine and BUN levels gradually decreased to baseline values. Conclusion: To the best of our knowledge, we described a rare case of diclofenac-induced AKI presenting with anuria, a complete cessation of urine flow, in a patient with no previous kidney complications. This case can be explained by the phenomenon known as “quadruple Whammy,” which involves the concurrent use of NSAIDs, ARBs, and diuretics in the setting of hypovolemia.

Unveiling the Impact of Nandrolone Decanoate on Kidney and Heart of Rattus Norvegicus

Background: The use of anabolic androgenic steroids (AAS) like Nandrolone Decanoate (ND) for enhancing physical performance and muscle growth is prevalent among athletes and non-athletes. However, the adverse effects of AAS on organ systems, particularly the kidney and heart, have been a growing concern within the medical and scientific community. Previous studies have highlighted the potential nephrotoxic and cardiotoxic effects of these substances, necessitating further research to elucidate the extent of organ damage. Objective: This study aims to investigate the histopathological effects of ND on the kidney and heart tissues of Rattus norvegicus and to draw comparisons with control groups to assess the severity of organ damage. Methods: A total of 15 Rattus norvegicus were divided into three groups: a control group, an olive oil group (positive control), and a steroid group (ND treated). The animals were housed under controlled conditions with a 12-hour light/dark cycle at 23±2°C. The steroid and olive oil groups received 50mg/ml intramuscular injections of ND and olive oil, respectively, twice weekly for six weeks. Following treatment, the animals were euthanized, and their kidney and heart tissues were extracted for histological examination. Tissues were fixed in 10% formalin, processed, and stained with Hematoxylin and Eosin (H&E) for microscopic evaluation. Results: Histological analysis revealed significant alterations in the ND-treated group compared to controls. Kidney tissues from the ND group exhibited tubular dilation, epithelial degeneration, and necrosis with a noticeable increase in Bowman's space and vascular congestion. Quantitatively, tubular atrophy and degeneration were observed in 80% of the ND-treated animals, compared to none in the control and olive oil groups. Heart tissues in the ND group showed evidence of myocardial fibrosis and necrosis, with myocardial fibrosis observed in 70% of the steroid-treated animals, significantly higher than the control groups. Conclusion: The administration of Nandrolone Decanoate in Rattus norvegicus significantly impacts kidney and heart histology, underscoring the potential health risks associated with AAS use. These findings contribute to the growing body of evidence on the nephrotoxic and cardiotoxic effects of steroids, emphasizing the need for caution and further research in human healthcare to develop safer therapeutic alternatives.

Acute renal failure in a patient undergoing oncological treatment

With the increasing prevalence of neoplasia and kidney disease, patients undergoing oncological treatment are at greater risk of acute renal failure. Joint oncological and nephrological management requires a thorough understanding of the patient's clinical history, as well as the potential nephrotoxic effects of chemotherapy and immunotherapy. This article proposes a comprehensive approach to the assessment of acute renal failure in patients undergoing treatment for neoplasia.

Potential Nephrotoxic Effect of UV-328 and Its Possible Salvage by Dimethoxy Curcumin in Zebrafish

The occurrence of Benzotriazole UV Stabilizer-328 (UV-328) in different environmental and natural systems is of fast regular concern these days. In this current paper, we assessed the renotoxicity of UV-328 in zebrafish kidney tissues to know the chore of oxidative devilry in kidney and to recuperate the renotoxicity utilizing Dimethoxy curcumin (DiMC) supplementation. Grown-up zebrafish were exposed 55µg/L of UV-328 and DiMC supplemented through diet at 50mg/kg BW. Close to the completion of 28 days, renal tissues were examined for the responses of oxidative pressure, antioxidant status and histopathological changes. The results demonstrated that antioxidant enzymes such as, Glutathione (GSH) levels and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) were all reduced in zebra fish kidneys treated with UV-328. Renal malondialdehyde (MDA) levels was brought prominently up in the UV-328 treated fish. All of the altered variables significantly returned to near-normal levels in the DiMC-supplemented group. Histopathological lesions, viz., hypertrophied glomerulus, cytoplasmic and nuclear degeneration, cytoplasmic vacuolization, degeneration of renal tubules were seen in UV-328 treated kidney of zebrafish which were actually reinforced in the DiMC treated fish. From our outcomes, it has been proposed that even at the low-level convergence of UV-328 exposure is malicious and to provoke oxidative insult, cell reinforcement exhaustion and kidney neurotic devilry in zebrafish and remediation with DiMC has been ended up being the better choice to conquer the harmful oppression prompted by UV-328.

Ochratoxin A-enhanced glycolysis induces inflammatory responses in human gastric epithelium cells through mTOR/HIF-1α signaling pathway

Ochratoxin A (OTA) is a mycotoxin commonly found in several food commodities worldwide with potential nephrotoxic, hepatotoxic and carcinogenic effects. We previously showed for the first time that OTA treatment enhanced glycolysis in human gastric epithelium (GES-1) cells in vitro. Here, we found that OTA exposure activated inflammatory responses, evidenced by increasing of NF-κB signaling pathway-related protein (p-p65 and p-IκBα) expressions and elevating of inflammatory cytokine (IL-1β and IL-6) mRNA expressions in GES-1 cells. To elucidate the role of glycolysis in inflammatory effects triggered by OTA, we pretreated GES-1 cells with glycolysis inhibitor (2-deoxy-D-glucose, 2-DG) before OTA exposure. The result showed that 2-DG reduced the protein expressions of p-p65 and p-IκBα and alleviated the mRNA expressions of inflammatory cytokines in OTA-treated GES-1 cells. Furthermore, OTA activated the mTOR/HIF-1α pathway by increasing the protein expressions of p-mTOR, p-eIF4E and HIF-1α, and inhibition of mTOR with rapamycin or silencing HIF-1α with siRNA significantly attenuated OTA-enhanced glycolysis by reducing glycolysis related genes and thereby decreasing inflammatory effects of GES-1 cells. These results demonstrate that OTA activates inflammatory responses in GES-1 cells and this is controlled by mTOR/HIF-1α pathway-mediated glycolysis enhancement. Our findings provide a novel mechanistic view into OTA-induced gastric cytotoxicity.

Barleria prionitis L. extracts ameliorate doxorubicin-induced acute kidney injury via modulation of oxidative stress, inflammation, and apoptosis.

Doxorubicin (DOX) is a chemotherapeutic drug with potential nephrotoxic effects on patients who are on cancer chemotherapy. An interest has been observed in using natural products to ameliorate the potential side effects of DOX. The present study is to investigate the cellular mechanisms underlying the protective effects of Barleria prionitis L. (BP) (Acanthaceae) extracts, DOX-induced acute kidney injury (AKI). Hexane (25mg/kg/day), ethyl acetate (80mg/kg/day), n-butanol (70mg/kg/day), and water (120mg/kg/day) extracts of BP, were administered to DOX-induced (5mg/kg (2500μL/kg), ip) Wistar rats for four consecutive weeks. At the end of the study, investigations were carried out for the assessment of biomarkers of nephrotoxicity, oxidative stress, inflammation, and apoptosis. Treatments with BP extracts significantly reversed DOX-induced elevations in serum and urine biochemical markers of nephrotoxicity (serum creatinine; 21-33%, blood urea nitrogen; 26-58%, β2-microglobulin; 19-22% and urine total protein; 47-67%). There was a reduction in the levels of tumor necrosis factor-α, interleukin-1β, and malondialdehyde in kidney homogenates of rats treated with the n-butanol extract (by 43, 62, and 24%) and water extract (by 57%, 85%, and 26%) (p<0.05). Immunohistochemical expression of the pro-apoptotic B-cell associated X protein was reduced while the anti-apoptotic B-cell lymphoma gene product 2 protein was increased in kidney tissues after the treatments with BP extracts. The selected BP extracts significantly ameliorated DOX-induced AKI. The findings would open new vistas for the development of a drug using the BP extracts to minimize DOX-induced AKI in cancer patients.

Antibiotic treatment of choice for urinary sepsis associated with ureteral lithiasis in Chile. Multicenter study

Inadequate antibiotic coverage in septic patients is associated with higher morbidity and mortality. This multicentric study reports antibiotic susceptibility in patients with ureterolithiasis-associated urosepsis, aiming to propose an optimal empirical therapy for this disease in the Chilean population. The prospective cohort study included patients from 7 Chilean hospitals who presented with ureterolithiasis and met sepsis criteria. We analyzed demographic data, vital signs at admission, and microbiological and radiological exams. We used descriptive statistics for the analysis of collected data. Initially, the study included 119 patients; 52 met the inclusion criteria. 77% were female, with a mean age of 52. 100% of the cohort had a urine culture taken at admission, whereas 48,7% had blood cultures. Escherichia Coli was the most common microorganism (73%), followed by Proteus Mirabilis (9.6%) and Klebsiella Pneumoniae (3.9%). Only two patients presented gram-positive pathogens. 100% of gram-negative bacteria were sensible to amikacin. The microorganisms found in our cohort were similar to those in international reports. Since the highest level of susceptibility was for amikacin, we propose its use as empirical therapy for urosepsis associated with ureterolithiasis in Chile. It is always necessary to consider the potential nephrotoxic effects of amikacin. An association of beta-lactams and glycopeptides should be considered in patients with risk factors for enterococcal infections.

Podocin, mTOR, and CHOP dysregulation contributes to nephrotoxicity induced of lipopolysaccharide/diclofenac combination in rats: Curcumin and silymarin could afford protective effect

AimSepsis is a common cause of acute kidney injury (AKI). Lipopolysaccharides (LPS) are the main gram-negative bacterial cell wall component with a well-documented inflammatory impact. Diclofenac (DIC) is a non-steroidal anti-inflammatory drug with a potential nephrotoxic effect. Curcumin (CUR) and silymarin (SY) are natural products with a wide range of pharmacological activities, including antioxidant and anti-inflammatory ones. The objective of this study was to examine the protective impact of CUR and SY against kidney damage induced by LPS/DIC co-exposure. Materials and methodsFour groups of rats were used; control; LPS/DIC, LPS/DIC + CUR, and LPS/DIC + SY group. LPS/DIC combination induced renal injury at an LPS dose much lower than a nephrotoxic one. Key findingNephrotoxicity was confirmed by histopathological examination and significant elevation of renal function markers. LPS/DIC induced oxidative stress in renal tissues, evidenced by decreasing reduced glutathione and superoxide dismutase, and increasing lipid peroxidation. Inflammatory response of LPS/DIC was associated with a significant increase of renal IL-1β and TNF-α. Treatment with either CUR or SY shifted measured parameters to the opposite side. Moreover, LPS/DIC exposure was associated with upregulation of mTOR and endoplasmic reticulum stress protein (CHOP) and downregulation of podocin These effects were accompanied by reduced gene expression of cystatin C and KIM-1. CUR and SY ameliorated LPS/DIC effect on the aforementioned genes and protein significantly. SignificanceThis study confirms the potential nephrotoxicity; mechanisms include upregulation of mTOR, CHOP, cystatin C, and KIM-1 and downregulation of podocin. Moreover, both CUR and SY are promising nephroprotective products against LPS/DIC co-exposure.

The impact of long-term exposure to tacrolimus on chronic kidney disease after lung transplantation: A retrospective analysis from a single transplantation center

BackgroundChronic kidney disease (CKD) is a progressive and irreversible complication in lung transplant patients who have received long-term treatment with tacrolimus. This study aimed to verify long-term tacrolimus exposure values in CKD progression. MethodsWe retrospectively analyzed the clinical data of adult lung transplant recipients performed at our center between 2012 and October 2015. Patients who completed the 5-year follow-up period were enrolled in this study. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. ResultsEighty patients were analyzed. Compared with baseline (109 ± 38.1 mL/min/1.73 m2), the average eGFR values of our patients gradually decreased during the fifth-year post transplantation (46.5%, 58.3 ± 28.3 mL/min/1.73 m2), and the decline in eGFR values was particularly pronounced in the first year (31.2%, 74.6 ± 28.91 mL/min/1.73 m2). Moreover, 10 (12.7%), 21 (26.9%), 24 (31.2%), 28 (41.2%), and 48 (60%) patients had eGFR <60 mL/min/1.73 m2 at 3, 6, 1, 3, and 5 years after lung transplantation (LT), respectively. A significant negative correlation was found between tacrolimus dose and eGFR 6 months after LT (P = 0.0414). We found no correlation between the serum tacrolimus concentration and CKD progression. ConclusioneGFR constantly decreased and the incidence of CKD increased during the 5-year follow-up period after LT. The tacrolimus dose had a significant negative correlation with eGFR at 6 months after LT. Meanwhile, whole-blood tacrolimus trough concentrations were not correlated with eGFR decline. When possible, lower dosing within 1 year after LT can reduce potential nephrotoxic side effects.

Risk factors for acute kidney injury at presentation among children with CNS malaria: a case control study

BackgroundRecent research has established that acute kidney injury (AKI) is a common problem in severe paediatric malaria. Limited access to kidney diagnostic studies in the low resources settings where malaria is common has constrained research on this important problem.MethodsEnrolment data from an ongoing clinical trial of antipyretics in children with central nervous system (CNS) malaria, CNS malaria being malaria with seizures or coma, was used to identify risk factors for AKI at presentation. Children 2–11 years old with CNS malaria underwent screening and enrollment assessments which included demographic and anthropomorphic data, clinical details regarding the acute illness, and laboratory studies including creatinine (Cr), quantitative parasite count (qPC), quantitative histidine rich protein 2 (HRP2), lactate, and bilirubin levels. Children with a screening Cr > 106 µmol/l were excluded from the study due to the potential nephrotoxic effects of the study drug. To identify risk factors for AKI at the time of admission, children who were enrolled in the study were categorized as having AKI using estimates of their baseline (i.e. before this acute illness) kidney function and creatinine at enrollment applying the Kidney Disease: Improving Global Outcome (KDIGO) 2012 guidelines. Logistic regressions and a multivariate model were used to identify clinical and demographic risk factors for AKI at presentation among those children enrolled in the study.Results465 children were screened, 377 were age-appropriate with CNS malaria, 22 (5.8%) were excluded due to Cr > 106 µmol/l, and 209 were enrolled. Among the 209, AKI using KDIGO criteria was observed in 134 (64.1%). One child required dialysis during recovery. Risk factors for AKI in both the logistic regression and multivariate models included: hyperpyrexia (OR 3.36; 95% CI 1.39–8.12) and age with older children being less likely to have AKI (OR 0.72; 95% CI 0.62–0.84).ConclusionAKI is extremely common among children presenting with CNS malaria. Hyperpyrexia with associated dehydration may contribute to the AKI or may simply be a marker for a more inflammatory systemic response that is also affecting the kidney. Appropriate fluid management in children with CNS malaria and AKI may be challenging since generous hydration to support kidney recovery could worsen malaria-induced cerebral oedema in this critically ill population.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03399318

Effect of waterborne exposure to perfluorooctanoic acid on nephron and renal hemopoietic tissue of common carp Cyprinus carpio

Per- and poly-fluoroalkyl substances (PFAS) are synthetic contaminants of global concern for environmental and public health. Perfluorooctanoic acid (PFOA) is an important PFAS, and considerable attention has been paid to its hepatotoxicity and reproductive and developmental impact, while potential nephrotoxic effects are largely ignored, especially in fish. This study documents the structural and ultrastructural effects on kidney of common carp Cyprinus carpio exposed to waterborne PFOA at an environmentally relevant concentration of 200 ng L−1 and at 2 mg L−1. Dilation of the glomeruli capillary bed, increased vesiculation in the proximal tubular segment, compromised mitochondria, apical blebbing, and sloughing of collecting duct cells occurred in exposed fish, primarily at 2 mg L−1. Perfluorooctanoic acid exposure resulted in higher numbers of rodlet cells (RC), putative immune cells exclusive to fish, mainly in the renal interstitium, than seen in controls, increased association with cells of myeloid lineage and modifications to ultrastructure. No differences in other cells of innate immunity were observed.Despite the absence of severe histological lesions, PFOA was shown to affect both nephron and hemopoietic interstitium at high concentration, raising concern of the impact on renal and immune function in fish. The response of RCs to PFOA concentration of 200 ng L−1 suggests a potential role as a biomarker of PFOA exposure.

Analysis of Pharmacokinetic Parameters of Acetylsalicylic Acid for Prediction of Potential Nephrotoxic Effects

Nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid, can have a dose-dependent nephrotoxic effect. The study of the pharmacokinetics of acetylsalicylic acid products will contribute to timely detection and correction of side effects caused by this medicinal product.The aim of the study was to evaluate potential nephrotoxic effects following a single oral administration of 75 mg of acetylsalicylic acid, based on the analysis of the pharmacokinetic parameters.Materials and methods: the study involved 24 healthy volunteers who received 75 mg of acetylsalicylic acid (tablets) once orally. The measurement of the active metabolite of acetylsalicylic acid—salicylic acid—in blood plasma was performed by HPLC/MS using an Agilent 1200 liquid chromatography system coupled to an Agilent 6140 tandem mass spectrometer. Agilent Eclipse XDB-C18 column (4.6 mm×150 mm; 5.0 μm) was used for chromatographic separation. The test procedure used in the study was validated. The results obtained were used to calculate the pharmacokinetic parameters: Cmax (maximum concentration), Tmax (time to maximum concentration), T1/2 (half-life of the drug), AUC0-t (area under the pharmacokinetic curve from 0 to the last time point of the curve), AUC0-∞ (total area under the pharmacokinetic curve from 0 to ∞), MRT (mean residence time of the drug in the blood), Kel (elimination rate constant), Cl/F (total clearance), Vd/F (apparent volume of distribution). The Statistics (22.0.0.0) software was used for statistical processing of the results.Results: T1/2 of salicylic acid in blood plasma was determined to be 1.6 ± 0.5 h, Cmax was 4523.0 ± 725.0 ng/mL, and Tmax was 0.98 ± 0.4 h. AUC0–t was equal to 16183.0 ± 3823.0 ng×h/m, Vd/F was 12.0 ± 3.1 L/kg, and MRT was 2.9 ± 0.6 h.Conclusions: the analysis of the pharmacokinetic parameters demonstrated a high absorption rate, intensive distribution, and moderate elimination rate of salicylic acid (the main metabolite of acetylsalicylic acid), indicating a low risk of nephrotoxic effects associated with the studied dose of the drug.

MO153RENAL FUNCTIONS OUTCOME IN METASTATIC NON SMALL LUNG CARCINOMA PATIENTS: THE RISK OF AKI IN FIRST LINE THERAPY

Abstract Background and Aims The optimal use of immune and target therapies, the optimal use of standard chemotherapy (CT) is of paramount importance, especially for patients affected by chronic kidney disease (CKD) who require dose adjustment according to the glomerular filtration rate (GFR) to avoid acute kidney injury (AKI) establishment. Immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy (CT) are options for the palliative treatment of metastatic non-small cell lung cancer (NSCLC). Recently, CT in combination with immune-checkpoint inhibitors has become the treatment of choice for this setting of patients. Therefore, it is fundamental to investigate the potential nephrotoxic effects of both treatments and their potential additive effects on renal function. Aim of our study was to compare the nephrotoxic effect of both ICIs and CT (cisplatin and carboplatin-based) in a consecutive cohort of patients affected by metastatic NSCLC. Method A consecutive cohort of 126 patients treated in first-line for NSLCL was enrolled in a single tertiary Hospital between 2018 and 2020. Inclusion criteria were: age (&amp;gt; 18 years old), eGFR (&amp;gt; 15 ml/min/1.73), histological diagnosis of metastatic NSCLC. Each patient underwent immunotherapy or CT according to clinical conditions, comorbidities and programmed death ligand 1 (PD-L1) expression status. eGFR (using CKD-EPI formula 2009) was detected at baseline and after each cycle of immunotherapy or CT (using cisplatin or carboplatin) in order to determine the correct renal status using the K-DIGO 2012 guidelines for AKI stages and CKD classes. Pts were subdivided into CKD categories G according to their eGFR values before and after the treatment. AKI onset was evaluated by rise in creatine levels according to K-DIGO criteria. Clinical stage according to cTNM (AJCC TNM system-2019) was collected at baseline before the first treatment. Comorbidities (e.g., diabetes, blood hypertension, overweight and obesity) were also included. Comparison between numerical variables was performed using linear regressions; between groups using Kruskal-Wallis rank sum test for numerical variables and Pearson’s Chi square test for categorical variables. Log rank test was used to test differences between groups in terms of AKI onset during the therapy. Results Clinical and pathological characteristics are reported in table 1. From the analysis, no significative differences were detected between Immunotherapy and CT group for age, gender, basal serum creatinine, basal eGFR, basal BMI, diagnosis of diabetes, hypertension, basal CKD G group or overall AKI onset. Treatment cycles were significantly different between the two groups (p&amp;lt;0.001) with a short median number of cycles for the CT group. No significative difference in terms of decay of eGFR calculated as final-basal values was detected (p=0.8). AKI onset over cycles was significantly different between the two groups (p=0.02), observing a higher risk of developing earlier AKI for CT group (cisplatin or carboplatin) (13,9%) with respect to immunotherapy (7,4%) (figure 1 and 2). Conclusion Our study highlights that both cisplatin and carboplatin-based CT displays an augmented incidence of AKI development after a lower number of therapy cycles in respect of immunotherapy. The nephrotoxic effects of combined therapy for NSLCL should be always evaluated by nephrologist during the treatment of NSLCL patients to avoid an augmented risk of AKI derived from the combination of immunotherapy and CT in first line.