First analytical confirmation of drug-induced crystal nephropathy in felines caused by GS-441524, the active metabolite of Remdesivir.

GS-441524 is an adenosine nucleoside antiviral demonstrating significant efficacy in the treatment of feline infectious peritonitis (FIP), an otherwise fatal illness, resulting from infection with feline coronavirus. However, following the emergence of COVID-19, veterinary development was halted, and Gilead pursued clinical development of a GS-441524 pro-drug, resulting in the approval of Remdesivir under an FDA emergency use authorization. Despite lack of regulatory approval, GS-441524 is available without a prescription through various unlicensed online distributors and is commonly purchased by pet owners for the treatment of FIP. Herein, we report data obtained from the analytical characterization of two feline renal calculi, demonstrating the propensity for GS-441524 to cause renal toxicity through drug-induced crystal nephropathy in vivo. As definitive diagnosis of drug-induced crystal nephropathy requires confirmation of the lithogenic material to accurately attribute a mechanism of toxicity, renal stone composition and crystalline matrix were characterized using ultra-performance liquid chromatography photodiode array detection (UPLC-PDA), ultra-performance liquid chromatography mass spectrometry (LCMS), nuclear magnetic resonance (NMR) spectroscopy, X-ray powder diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). This work serves to provide the first analytical confirmation of GS-441524-induced crystal nephropathy in an effort to support toxicologic identification of adverse renal effects caused by administration of GS-441524 or any pro-drug thereof.

Case report: Is severe toxicity the price to pay for high sensitivity to checkpoint inhibitors immunotherapy in desmoplastic melanoma?

Background: Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors (ICIs) treatment. Case presentation: We report the case of a 53-year-old man with metastatic DM successfully treated with the combination of anti-CTLA-4 and anti-PD-1 antibodies, who developed serious immune-related adverse events (irAEs). The primary tumor was characterized by absent PD-L1 expression and no-brisk lymphocytes infiltration. NGS showed absence of BRAF mutation, a high tumor mutational burden, and an UV-induced DNA damage signature. Metastatic lesions regressed rapidly after few cycles of ICIs until complete response, however the patient developed serious irAEs including hypothyroidism, adrenal deficiency, and acute interstitial nephritis which led to the definitive suspension of treatment. Currently, the patient has normal renal functionality and no disease relapse after 26 months from starting immunotherapy, and after 9 months from its definitive suspension. Conclusion: Efficacy and toxicity are two sides of the same coin of high sensitivity to ICIs in DM. For this reason, these patients should be closely monitored during ICIs therapy to promptly identify serious side effects and to correctly manage them.

Kefir mitigates renal damage caused by zearalenone in female wistar rats by reducing oxidative stress.

The estrogen-like mycotoxin zearalenone (ZEA) was popularly occurred in several food and feeds, posing threats to human and animal health. ZEA induced renal toxicity and caused oxidative stress. In the current study, the protecting effect of kefir administration against ZEA-induced renal damage in rats was explored. Rats were divided into 4 groups, each consisting of 5 animals. For the initial 7 days, they were orally administered sterile milk (200 µL/day). Subsequently, during the second week, the groups were exposed to kefir (200 µL/day), ZEA (40 mg/kg b.w./day) and a combination of kefir and ZEA. The biochemical parameters, kidney histological changes and ZEA residue were assessed. Kefir supplementation enhanced the antioxidant enzymes in the kidney, such as superoxide dismutase, catalase and glutathione peroxidase activities, which increased by 1.2, 4 and 20 folds, respectively, relative to the ZEA group. Remarkably, the concomitant administration kefir + ZEA suppressed ZEA residues in both serum and kidney. Additionally, serum levels of blood urea nitrogen, uric acid and renal malondialdehyde decreased by 22, 65 and 54%, respectively, in the kefir + ZEA group; while, the creatinine content increased by around 60%. Rats co-treated with kefir showed a normal kidney histological architecture contrary to tissues alterations mediated in the ZEA group. These results suggest that kefir may showed a protective effect on the kidneys, mitigating ZEA-induced acute toxicity in rats.

The Role of Phthalocyanine-Gold Nanoconjugates (Pc-Au NCs) in Ameliorating the Hepatic and Renal Toxicity-Induced by Silver Nanoparticles (Ag NPs) in Male Rats.

Recently, gold nanoparticles (Au Nps) have gained tremendous attention for its unique properties as a safe nanocarrier for delivering drugs that are used in different disease diagnoses. Although silver nanoparticles (Ag NPs) have been generally applied due to their strong antibacterial, antiviral, antifungal, and antimicrobial properties, their toxicity is a subject of sustained debate, thus requiring further studies. The present study aims to evaluate the potential protective effect of gold nanoparticles and phthalocyanine-gold nanoconjugates (Pc-Au NCs) against the hepatorenal toxicity of silver nanoparticles in male rats. Herein, 60 adult male Rattus norvegicus rats were divided into six equal groups (n = 10/group); the first group was kept as control, the second received gold nanoparticles (Au NPs) intraperitoneally (10 µg/kg) daily for 3 weeks, the third group is gold-phthalocyanine (Pc-Au) group where rats were injected intraperitoneally with gold-phthalocyanine for 3 weeks (10 µg/kg), the fourth group received silver nanoparticles (Ag NPs) (4 mg/kg) daily intraperitoneally for 3 weeks, the fifth group is silver + gold nanoparticles group (Ag + Au), and the sixth is silver + gold-phthalocyanine nanoconjugates (Ag + Pc-Au) group in which rats were intraperitoneally injected firstly with Ag NPs (4 mg/kg) for 3 weeks then with gold or gold-phthalocyanine for another 3 weeks (10 µg/kg). Our results revealed that Ag NPs could increase the serum AST, ALT, ALP, urea, creatinine, and lipid profile and significantly decreased the total protein and albumin. Moreover, histopathological alterations detected in the kidney and the liver of the Ag NPs group included vascular congestion, inflammatory cell infiltration, and tissue distortion. Alongside, exposure to Ag NPs induces hepatic and renal oxidative stress by suppressing the antioxidant-related genes including glutathione peroxidase 1 (gpx1), superoxide dismutase (sod), and catalase (cat). Ag NPs also upregulated the hepatic and renal genes involved in inflammation such as the interleukin-6 (il-6) and tumor necrosis factor-α (tnf-α), nuclear factor kappa B (nf-κß), apoptosis such as the BCL2 associated X (bax), casp3, and other related to metabolism including asparagine synthetase (asns), suppressor of cytokine signaling 3 (socs3), MYC proto-oncogene (myc), and C-C motif chemokine ligand 2 (ccl2). On the other hand, treatment with Au NPs and Pc-Au NCs could effectively ameliorate the hepatorenal damages induced by Ag NPs and improve liver and kidney architecture and function, especially in the Pc-Au NCs group. Briefly, our study revealed the underlined mechanism of Ag NPs hepatotoxic and nephrotoxic effects and that Pc-Au NCs could alleviate these adverse impacts via their anti-oxidative, anti-apoptotic, and anti-inflammatory activities.

A comparative study on the protective effects of cuminaldehyde, thymoquinone, and gallic acid against carbon tetrachloride-induced pulmonary and renal toxicity in rats by affecting ROS and NF-κB signaling.

CCl4 toxicity is a fatal condition that can cause numerous organ dysfunctions. We evaluated and compared the protective effects of cuminaldehyde (CuA), thymoquinone (TQ), and gallic acid (GA) on CCl4-induced pulmonary and renal toxicity in rats. The impacts of these compounds on CCl4-induced oxidative stress, inflammation, and morphological alterations were examined. The results showed that the compounds under investigation prevented CCl4 from significantly increasing pulmonary and renal lipid peroxidation and NO levels, as well as massively depleting GSH levels and GPX and SOD activities. Moreover, they suppressed the CCl4-induced increase in mucus secretion in the lung and upregulated the gene expression of pulmonary and renal NF-Ò¡B, iNOS, TNF-α, and COX-2. The heatmap cluster plots showed that GA and TQ had better protective potencies than CuA. The external organ morphology, histopathological results, and chest X-ray analysis confirmed the toxicity of CCl4 and the protective influences of the tested compounds in both the lungs and kidneys of rats. These compounds displayed predicted competitive inhibitory effects on iNOS activity and may block the IL-13α2 receptor, as revealed by molecular docking analysis. Thus, CuA, TQ, and GA, particularly the latter two, are prospective protective compounds against the pulmonary and renal toxicity caused by CCl4.

Oleuropein attenuates the nephrotoxic effect of sunitinib in rats: Unraveling the potential role of SIRT6/Notch-1/NLRP-3/IL-1ß axis.

Sunitinib (SUN) is a chemotherapeutic agent clinically approved for treatment of metastatic renal carcinoma. Despite its remarkable benefits, various renal toxicities have been reported that limit its clinical uses. Oleuropein (OLE) is the main polyphenolic constituent of olive tree and mediates the majority of its valuable pharmacological activities. The current study examined the probable renoprotective effects of OLE against SUN-induced nephrotoxicity. Adult male albino rats were co-treated by SUN (25 mg/kg, 3 times/week, PO) with either a drug vehicle or OLE (60 mg/kg/day, daily, PO) for four weeks. A control group comprising of age-matched rats was used. Four weeks later, blood specimens were collected to assess kidney functions. Kidneys were harvested for biochemical and histopathological analyses. Administration of SUN induced kidney dysfunction, along with marked rises in endothelin-1 (ET-1) and monocyte chemotactic protein-1 (MCP-1) levels in renal tissues. Histological abnormalities were also detected in kidneys of SUN-treated rats including glomerular and tubular interstitial congestion along with interstitial fibrosis. On molecular levels, there was a decline in renal SIRT6 expression along with significant up-regulation of Notch-1, NLRP-3, interleukin -1ß (IL-1ß) and cleaved caspsase-3. All these changes were almost alleviated by OLE co-treatment. These findings suggest the implication of SIRT6/Notch-1/NLRP3/IL-1ß axis in the pathogenesis of SUN-induced nephrotoxicity and highlight OLE as a prospective renoprotective agent during SUN chemotherapy to halt its renal toxicity likely through promotion of SIRT6 and suppression of Notch-1/NLRP3/IL-1ß signaling pathway.

Immunohistochemical Evaluation of Renal Biopsy with Anti-PD1 and p53 to Solve the Dilemma between Platinum- and Pembrolizumab-Induced AKI: Case Report and Review.

Introduction: The combination therapy of platinum and pembrolizumab looks like a promising treatment in advanced non-small-cell lung cancer. However, both platinum-based chemotherapy and pembrolizumab can lead to AKI. AKI can occur due to acute tubular necrosis or interstitial nephritis. It is essential to identify the drug responsible for renal damage. For this purpose, we used new immunohistochemistry markers (p53 and anti-PD1 analysis). Case Description: A 77-year-old female patient with advanced non-small-cell lung cancer received the PD-1 inhibitor pembrolizumab and platinum-based chemotherapy carboplatin. The patient, after 60 days, experienced AKI. A kidney biopsy was performed, and two new immunohistochemical techniques for p53 (experimental markers of ATN from platinum) and anti-PDL1 (experimental markers of PD-1 inhibitors nephritis) were employed. Renal biopsies revealed severe tubular damage. No infiltration was detected, and the immunohistochemical assessment of PDL-1 was negative. The expression of p53 was positive. The renal biopsy suggested platinum-induced acute tubular necrosis. After discontinuing steroids and reducing carboplatin, the patient continued with pembrolizumab, and their renal function returned to normal within two months. Discussion: Combining checkpoint inhibitors and platinum-based therapies may result in AKI. The standard method of examining kidney tissue may not provide sufficient information about the effects of these drugs on the kidneys. To address this issue, we recommend incorporating an assessment of the analysis of the expression of PDL1 and p53. This personalized approach will help identify the best treatment option for the patient while ensuring the best possible cancer treatment plan.

Valsartan Mitigates the Progression of Methotrexate-Induced Acute Kidney Injury in Rats via the Attenuation of Renal Inflammation and Oxidative Stress.

Background: Methotrexate (MTX) is a folic acid antagonist, commonly administered for the treatment of a variety of cancers. However, methotrexate toxicity including bone marrow suppression and hepatic and renal toxicity limits its use. Angiotensin AT1 receptor blockers including Valsartan (Val) possess the ability to ameliorate MTX-induced toxicity through various mechanisms. In this study, we explored the potential reno-protective effects of Val against MTX-induced acute kidney injury in rats. Methods: Twenty-four Wistar rats were randomly segregated into 3 groups. Group 1 served as the control group and received an oral dose of 1mL/kg of normal saline. Group 2 received a single dose of 20 mg/kg of MTX intraperitoneally (IP) for 5 days. Group 3 received a single IP dose of 20 mg/kg of MTX followed by an oral dose of 10 mg/kg of Valsartan for 5 days. At the end of the experiment, the levels of serum kidney biomarkers, inflammatory and oxidative stress markers were accessed. Furthermore, the effect of MTX on kidney tissue histology was examined. Results and discussion: Our results showed that MTX treatment increased the level of serum kidney and inflammatory biomarkers and decreased the level of antioxidants SOD and GSH while increasing the lipid peroxidation contents. Furthermore, MTX treatment caused structural changes to kidney histology. However, the administration of Val significantly prevented these changes. Conclusion: Valsartan possesses nephroprotective potential and might serve as a potential therapeutic strategy against MTX-induced kidney injury.

Butylparaben induced zebrafish (Danio rerio) kidney injury by down-regulating the PI3K-AKT pathway.

Butylparaben, a common endocrine disruptor in the environment, is known to be toxic to the reproductive system, heart, and intestines, but its nephrotoxicity has rarely been reported. In order to study the nephrotoxicity and mechanism of butylparaben, we examined the acute and chronic effects on human embryonic kidney cells (HEK293T) and zebrafish. Additionally, we assessed the potential remedial effects of salidroside against butylparaben-induced nephrotoxicity. Our in vitro findings demonstrated oxidative stress and cytotoxicity to HEK293T cells caused by butylparaben. In the zebrafish model, the concentration of butylparaben exposure ranged from 0.5 to 15 µM. An assortment of experimental techniques was employed, including the assessment of kidney tissue morphology using Hematoxylin-Eosin staining, kidney function analysis via fluorescent dextran injection, and gene expression studies related to kidney injury, development, and function. Additionally, butylparaben caused lipid peroxidation in the kidney, thereby damaging glomeruli and renal tubules, which resulted from the downregulation of the PI3K-AKT signaling pathway. Furthermore, salidroside ameliorated butylparaben-induced nephrotoxicity through the PI3K-AKT signaling pathway. This study reveals the seldom-reported kidney toxicity of butylparaben and the protective effect of salidroside against toxicological reactions related to nephrotoxicity. It offers valuable insights into the risks to kidney health posed by environmental toxins.

Subchronic toxicity study of indium-tin oxide nanoparticles following intratracheal administration into the lungs of rats.

OBJECTIVES: We aimed to analyze the subchronic toxicity and tissue distribution of indium after the intratracheal administration of indium-tin oxide nanoparticles (ITO NPs) to the lungs of rats. METHODS: Male Wistar rats were administered a single intratracheal dose of 10 or 20 mg In/kg body weight (BW) of ITO NPs. The control rats received only an intratracheal dose of distilled water. A subset of rats was periodically euthanized throughout the study from 1 to 20 weeks after administration. Indium concentrations in the serum, lungs, mediastinal lymph nodes, kidneys, liver, and spleen as well as pathological changes in the lungs and kidneys were determined. Additionally, the distribution of ionic indium and indium NPs in the kidneys was analyzed using laser ablation-inductively coupled plasma mass spectrometry. RESULTS: Indium concentrations in the lungs of the 2 ITO NP groups gradually decreased over the 20-week observation period. Conversely, the indium concentrations in the mediastinal lymph nodes of the 2 ITO groups increased and were several hundred times higher than those in the kidneys, spleen, and liver. Pulmonary and renal toxicities were observed histopathologically in both the ITO groups. Both indium NPs and ionic indium were detected in the kidneys, and their distributions were similar to the strong indium signals detected at the sites of inflammatory cell infiltration and tubular epithelial cells. CONCLUSIONS: Our results demonstrate that intratracheal administration of 10 or 20 mg In/kg BW of ITO NPs in male rats produces pulmonary and renal toxicities.

Nephroprotective effects of silymarin and its fabricated nanoparticles against aluminum-induced oxidative stress, hyperlipidemia, and genotoxicity.

BACKGROUND: Aluminum (Al) is a ubiquitous element with proven nephrotoxicity. Silymarin (SM) is a mixture of polyphenolic components extracted from Silybum marianum and exhibited protective influences. However, SM bioactivity can be enhanced by its incorporation in chitosan (CS) through the use of nanotechnology. This work proposed to assess the protective influence of SM and its loaded chitosan nanoparticles (SM-CS-NPs) on aluminum chloride (AlCl3)-induced nephrotoxicity. METHODS: Six groups were created randomly from 42 male Wistar rats and each one contains 7 rats (n = 7). Group I, acted as a control and received water. Group II received SM (15 mg/kg/day) and group III administered with SM-CS-NPs (15 mg/kg/day). Group IV received AlCl3 (34 mg/kg) and groups V and VI were treated with SM and SM-CS-NPs with AlCl3 respectively for 30 days. RESULTS: AlCl3 administration significantly elevated TBARS, H2O2, and kidney function levels besides LDH activity. Whereas GSH, CAT, SOD, GPx, GST, and GR values were all substantially reduced along with protein content, and ALP activity. Additionally, significant alterations in lipid profile, hematological parameters, and renal architecture were observed. Moreover, TNF-α, TGF-ß, and MMP9 gene expression were upregulated in kidney tissues. The administration of SM or its nanoparticles followed by AlCl3 intoxication attenuated renal dysfunction replenished the antioxidant system, and downregulated TNF-α, TGF-ß, and MMP9 gene expression in renal tissues compared to the AlCl3 group. CONCLUSION: SM-CS-NPs have more pronounced appreciated protective effects than SM and have the proficiency to balance oxidant/antioxidant systems in addition to their anti-inflammatory effect against AlCl3 toxicity.

In Vivo Assessment of Hepatic and Kidney Toxicity Induced by Silicon Quantum Dots in Mice.

In the last decade, silicon-based quantum dots (SiQDs) have attracted the attention of researchers due to their unique properties for which they are used in medical applications and in vivo imaging. Detection of cytotoxic effects in vivo is essential for understanding the mechanisms of toxicity, a mandatory step before their administration to human subjects. In this context, we aimed to evaluate the in vivo hepatic and renal acute toxicity of SiQDs obtained by laser ablation. The nanoparticles were administrated at different doses (0, 1, 10, and 100 mg of QDs/kg of body weight) by intravenous injection into the caudal vein of Swiss mice. After 1, 6, 24, and 72 h, the animals were euthanatized, and liver and kidney tissues were used in further toxicity tests. The time- and dose-dependent effects of SiQDs on the antioxidant defense system of mice liver and kidney were investigated by quantifying the activity of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase) in correlation with the morphological changes and inflammatory status in the liver and kidneys. The results showed a decrease in the activities of antioxidant enzymes and histopathological changes, except for superoxide dismutase, in which no significant changes were registered compared with the control. Furthermore, the immunohistochemical expression of TNF-α was significant at doses over 10 mg of QDs/kg of body weight and were still evident at 72 h after administration. Our results showed that doses under 10 mg of SiQDs/kg of b.w. did not induce hepatic and renal toxicity, providing useful information for further clinical trials.

Efficacy and safety of streptozocin-based chemotherapy for gastroenteropancreatic neuroendocrine tumors in Japanese clinical practice.

BACKGROUND: Streptozocin has been used to treat neuroendocrine tumors in Europe and the USA; however, its actual status in Japan has not been fully clarified owing to the rarity of this disease and the relatively recent approval of streptozocin in Japan. METHODS: We retrospectively analyzed 53 patients with gastroenteropancreatic neuroendocrine tumors who were treated with streptozocin-based chemotherapy at two Japanese hospitals between January 2004 and June 2023. RESULTS: The overall response and disease control rates were 27.7 and 74.5%, respectively, and the median progression-free survival and overall survival were 7.1 and 20.3 months, respectively. Performance status ≥1 showed a significant negative correlation with progression-free survival, and performance status ≥1 and liver tumor burden ≥25% showed a significant negative correlation with overall survival. No significant differences were observed in the treatment response between pancreatic and gastrointestinal neuroendocrine tumors. No treatment-related serious adverse events were observed; however, 87.7% of patients expressed a decrease in the estimated glomerular filtration rate, which negatively correlated with the duration of streptozocin treatment (r = 0.43, P = 0.0020). In the streptozocin re-administration group (n = 5), no differences were found in efficacy between the initial and second streptozocin treatments. CONCLUSIONS: Although streptozocin is a safe, streptozocin-induced renal dysfunction is a dilemma in streptozocin responders. Streptozocin may benefit patients with gastroenteropancreatic neuroendocrine tumors, especially those with a good performance status; however, in some cases, planned streptozocin withdrawal or switching to other drugs should be considered.

Modulation of the Sirtuin-1 signaling pathway in doxorubicin-induced nephrotoxicity (synergistic amelioration by resveratrol and pirfenidone).

The current study was conducted to determine the precise mechanisms of Sirtuin-1 (Sirt-1), TGF- ß (Transforming Growth Factor-ß), and long non-coding RNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (LncRNA MALAT-1) in signaling pathways in doxorubicin (DOX)-induced nephrotoxicity. The potential therapeutic effect of Resveratrol and Pirfenidone in DOX toxicity was also assessed. Thirty-six male adult rats were evenly distributed into four groups: Group 1: control rats. Group 2: DOX exposed rats' group, each animal received 7.5 mg/kg DOX as a single intravenous dose, Group 3: DOX exposed group subjected to oral resveratrol (20 mg/kg/daily for two weeks), Group 4: DOX exposed group subjected to oral Pirfenidone (200 mg/kg once daily for 10 days). At the planned time, animals were sacrificed. Renal tissue was collected to assess matrix metalloproteinase-9 (MMP9), inflammatory and apoptotic markers: tumor necrosis factor-alpha (TNF- ß, caspase-3, cyclo-oxygenase-2 (COX-2), and oxidative stress markers: nitric oxide (NO), Glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD). Sirtuin-1 (Sirt-1), TGF-ß, and LncRNA MALAT-1 were quantitatively assessed by real-time RT-PCR in the whole blood. Results showed that the DOX group exhibited a significant increase in oxidative stress markers, and inflammatory, and apoptotic markers in the renal tissue. Histologically, the renal tubule lining cells exhibited vacuolar alterations in the cytoplasm, glomerular atrophy, and vascular congestion. Furthermore, renal degeneration was evident, as confirmed by the heightened immuno-expression of MMP9. Exposure to DOX resulted in a significant decrease in Sirtuin-1 (Sirt-1) with a significant increase in the TGFß, and LncRNA MALAT-1 gene expression. However, pre-treatment with either resveratrol/or Pirefenidone ameliorated the histological renal alterations, regulated the pathways of Sirt-1, TGFß, and LncRNA MALAT-1, and decreased all oxidative stress, inflammatory and apoptotic markers. In conclusion, DOX exposure leads to renal toxicity by inducing renal degeneration, oxidative stress, and apoptosis. Administration of either resveratrol or Pirfenidone counteracted these changes and protected the kidney against DOX-induced renal damage.

Cyclooxygenase-2 inhibition prevents renal toxicity but not hypertension during sunitinib treatment.

BACKGROUND: Anticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI2). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI2 during angiogenesis inhibition. METHODS: Male WKY rats received vehicle, sunitinib ((SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day) or a PGI2 analogue (iloprost, 100 µg/kg/day) for 8 days (n = 8-9 per group). Mean arterial pressure (MAP) was measured via radiotelemetry, biochemical measurements were performed via ELISA and vascular function was assessed via wire myography. RESULTS: SU increased MAP (17±1mmHg versus 3±1mmHg after vehicle on day 4, P < 0.002), which could not be significantly blunted by celecoxib (+12±3mmHg on day 4, P = 0.247), but was temporarily attenuated by iloprost (treatment days 1 + 2 only). Urinary PGI2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P < 0.001), but not circulating PGI2 increased during SU, which remained unaffected by celecoxib and iloprost. Celecoxib reduced sunitinib-induced albuminuria (0.36 ± 0.05 versus 0.58 ± 0.05mg/24h after SU, P = 0.005). Wire myography demonstrated increased vasoconstriction to endothelin-1 after SU (Emax P = 0.005 versus vehicle), which remained unaffected by celecoxib or iloprost. CONCLUSION: Selective COX-2 inhibition ameliorates albuminuria during angiogenesis inhibition with sunitinib, which most likely acts independently of PGI2. To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential.

Brief Report: Tyrosine Kinase Inhibitors for Lung Cancers That Inhibit MATE-1 Can Lead to "False" Decreases in Renal Function.

INTRODUCTION: Select tyrosine kinase inhibitors (TKIs) used to treat oncogene-driven lung cancers also inhibit MATE-1. When MATE-1 is blocked, creatinine is retained in the serum. Elevated creatinine levels raise the specter of drug-induced intrarenal insufficiency despite the lack of true renal injury. We conducted a systematic analysis of MATE-1 inhibitor (MATEi)-treated patients to comprehensively characterize this phenomenon. METHODS: Patients with oncogene-driven lung cancer treated with a wide variety of MATEi TKIs (brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib, and tepotinib) were eligible for an analysis of renal dysfunction. Acute kidney injury was classified on the basis of creatinine levels (Kidney Disease: Improving Global Outcomes criteria) as stage 1 (≥1.5× but <2× baseline), stage 2 (≥2× but <3× baseline), or stage 3 (>3× baseline). When available, cystatin C, a marker of kidney function unaffected by MATE-1, was used to evaluate the glomerular filtration rate (GFR). RESULTS: We identified 863 patients receiving MATEi TKIs including crizotinib (39%, n = 333), lorlatinib (17%, n = 144), cabozantinib (10%, n = 87), selpercatinib (10%, n = 82), capmatinib (9%, n = 77), brigatinib (6%, n = 53), entrectinib (5%, n = 45), tepotinib (5%, n = 41), and pralsetinib (0.1%, n = 1). Of the 90 patients (10%) with acute kidney injury, Kidney Disease: Improving Global Outcomes stages 1, 2, and 3 were observed in 72% (n = 65), 21% (n = 19), and 7% (n = 6) of patients, respectively. Concurrently drawn creatinine and cystatin C levels on TKI therapy were available for 17 patients. In most cases (n = 15 of 17), the calculated GFR was higher using cystatin C versus creatinine. The percentage of patients whose GFR was higher using cystatin C versus creatinine by less than 10 mL/min, 10 to 19 mL/min, 20 to 29 mL/min, and more than or equal to 30 mL/min was 27% (n = four of 15), 20% (n = three of 15), 20% (n = three of 15), and 33% (n = five of 15), respectively. Long-term data in three patients that spanned 3 years revealed that GFR was higher using cystatin C versus creatinine in 96% (n = 49 of 51) of all time points. Using a virtual clinical trial GFR cutoff of 40 mL/min, the percentage of eligible patients rose from 41% (n = seven of 17) using creatinine calculations to 71% (n = 12 of 17) using cystatin C calculations. CONCLUSIONS: The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine level seems elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.

[Exploring Tyrosine Kinase Inhibitor (TKI)-Induced Nephrotoxicity: An Emerging Issue from Bench to Bedside].

Tyrosine Kinase Inhibitors (TKIs) have significantly contributed to revolutionizing cancer treatment, as they are orally administered small molecules able to target key pathways involved in tumor growth and angiogenesis. However, the clinical utility of TKIs may be compromised by adverse effects, which can affect tissues and organs, including kidneys. This comprehensive review offers a general overview of studies reporting the incidence and clinical characteristics of TKI-related nephrotoxicity and it explores the mechanisms underlying the intricate relationship between TKIs and renal toxicity. The biological rationale for the kidney manifestations of toxicity associated with TKI agents is here discussed, underlying potential off-target effects and emphasizing the importance of accurate risk assessment and tailored patient management strategies. Deep insight into the molecular mechanisms of TKI nephrotoxicity will help to improve the global understanding of the pathophysiology of this peculiar toxicity and to develop more effective and safer therapies.

The Nephroprotective Potential of Brassica nigra Sprout Hydroalcoholic Extract against Carbon Tetrachloride-Induced Renal Toxicity in Rats.

The nephroprotective potential of the Brassica nigra sprout (BNS) hydroalcoholic extract against carbon tetrachloride (CCl4)-induced renal toxicity in rats was the object of this study. B. nigra sprouts were prepared in the lab to monitor the bio-changes in bioactive compounds during the sprouting for up to 7 days at 17 ± 1 °C and 90% relative humidity. Subsequently, 6-day sprouts of B. nigra were selected according to their phenolics and antioxidant activity, extracted, and examined for their nephroprotective and antioxidative stress potential at 250 and 500 mg sprout extracts kg-1 bw, in vivo. Weight gain, organ weight, lipid profile, atherogenic index, kidney functions, and oxidative stress biomarkers were assessed. The results indicated that the most proficient treatment for weight gain improvement was BNS extract at 500 mg kg-1. BNS at 250 mg kg-1 was remarked as the lowest weight gain enhancer compared to the NR group. A significant increase in TG, TC, LDL-c, and VLDL-c levels in the rats with CCl4-induced renal toxicity, and a significant decrease in HDL level, was noted. The administration of the BNS extract at 250 and 500 mg kg-1 considerably attenuated TG, TC, LDL-c, and VLDL-c levels, compared to the NR group. The most efficient treatment for improving the lipid profile was the BNS extract at 500 mg kg-1, even better than 250 mg kg-1. Administrating the BNS extract substantially attenuated the alterations in the creatinine, urea, and BUN caused by the CCl4 injection. The most efficient improvement was markedly recorded with the BNS extract at 500 mg kg-1, compared to the NR group. The rats treated with the BNS extract showed significant enhancement in GSH, CAT, and SOD activities and a considerable reduction in MDA levels. Administering the BNS extract at 250 and 500 mg kg-1 can efficiently reverse CCl4 inhibition of antioxidant enzyme activities, significantly increase GSH, CAT, and SOD, and decrease the MDA levels dose-dependently. The BNS extract at 250 and 500 mg kg-1 exhibits nephroprotection and antioxidative stress in a dose-dependent matter. The total nephroprotection % was recorded at 65.18% and 99.21% for rats treated with 250 and 500 mg kg-1, respectively. These findings could prove and potentiate the nephroprotective activities of the BNS extract in the range of the given doses. Further clinical studies are highly recommended for confirming the nephroprotection efficiency of the B. nigra sprout.

L-methionine protects against nephrotoxicity induced by methotrexate through modulation of redox status and inflammation.

Objective: Methotrexate (MTX) is a drug used in the treatment of cancer and autoimmune disorders; however, its clinical use is limited because of serious side effects including renal toxicity. This study aimed to investigate the protective effect of Lmethionine (L-Met) on MTX toxicity in the kidneys of rats.Methods: Thirty male rats were divided equally into five groups: control (saline), Met400 (400 mg/kg L-Met), MTX (20 mg/kg MTX), MTX-Met300 (300 mg/kg L-Met and 20 mg/kg MTX), and MTX-Met400 (400 mg/kg L-Met and 20 mg/kg MTX). Rats were euthanized one day after the last dose administration (day 16) and serum and renal tissue samples were collected. Renal function and injury indices, oxidative stress/antioxidant indices and proinflammatory cytokines were evaluated.Results: The results showed that L-Met could effectively counteract the nephrotoxic effects of MTX, in a dose-related manner, by improving most of the tested parameters. Furthermore, the higher dose of L-Met was able to restore several parameters to normal levels. In addition, investigation of MTX-induced hematological changes revealed a corrective potential of L-Met.Conclusion: L-Met can be an effective adjuvant therapy to modulate renal toxicity associated with MTX because of its antioxidant and antiinflammatory effects.

A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes.

BACKGROUND: People of Sub-Saharan African ancestry are at higher risk of developing chronic kidney disease (CKD), attributed to the Apolipoprotein L1 (APOL1) gene risk alleles (RA) G1 and G2. The underlying mechanisms by which the APOL1-RA precipitate CKD remain elusive, hindering the development of potential treatments. RESULTS: Using a Drosophila genetic modifier screen, we found that SNARE proteins (Syx7, Ykt6, and Syb) play an important role in preventing APOL1 cytotoxicity. Reducing the expression of these SNARE proteins significantly increased APOL1 cytotoxicity in fly nephrocytes, the equivalent of mammalian podocytes, whereas overexpression of Syx7, Ykt6, or Syb attenuated their toxicity in nephrocytes. These SNARE proteins bound to APOL1-G0 with higher affinity than APOL1-G1/G2, and attenuated APOL1-G0 cytotoxicity to a greater extent than either APOL1-RA. CONCLUSIONS: Using a Drosophila screen, we identified SNARE proteins (Syx7, Ykt6, and Syb) as antagonists of APOL1-induced cytotoxicity by directly binding APOL1. These data uncovered a new potential protective role for certain SNARE proteins in the pathogenesis of APOL1-CKD and provide novel therapeutic targets for APOL1-associated nephropathies.