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Immunotactoid glomerulopathy (ITG), a condition characterised by highly organised microtubules on electron microscopy, and cryoglobulin glomerulopathy (CG) are rare forms of kidney injury that may be encountered in patients with cryoglobulinaemia. It has been proposed these two entities are part of the same disease process following observed clinical and histological similarities. [ABSTRACT FROM AUTHOR]

Background: Recent reports have revealed that nephropathy leading to kidney injury (KI) is a prevalent complication of COVID-19 and is linked to high mortality and morbidity in diabetes mellitus type II (DM-T-II) patients. This systematic literature review and meta-analysis aimed to critically analyze existing studies and evidence on the impact of COVID-19 on nephropathy and kidney injury in diabetes mellitus type II (DM-T-II) patients. Method: A systematic search was conducted in the Web of Science (WoS), PubMed and Cochrane databases for relevant studies published between March 2020 and July 2023. To ensure the integrity of the systematic literature review and meta-analysis, observational studies that specifically reported post-COVID-19 kidney injury in DM-T2 patients were included, whereas we did not include articles in the press, meta-analyses, case reports, case series, Diabetes Type-I articles or non-English papers. The primary outcome was kidney injury in patients with type II diabetes after contracting COVID-19. The protocol for this study was published on PROSPERO (registration number CRD42023413887). Results: Initially, 6,339 articles were included in the search, from which only 6 observational studies were selected by following the 2020 PRISMA statement. The quality of the evidence was assessed by a tool provided by the National Institutes of Health (observational studies). The total number of participants included in the studies was 14,723. Our systematic literature review and meta-analysis provide compelling evidence that kidney injury is a prevalent complication of COVID-19 infection in the type II diabetes population, with a pooled odds ratio of 2.27 (95% CI: 2.05–2.51; p < 0.00001), often necessitating hospitalization and hemodialysis in severe cases. Conclusion: Covid-19 is associated with a two-fold increase in nephropathy and acute kidney injury in diabetes mellitus type 2 patients compared to non-diabetic patients. This implies that kidney injury is more likely to occur in diabetes mellitus type 2 patients post Covid infection. [ABSTRACT FROM AUTHOR]

Introduction: To investigate the protective effects of anisodamine (654-1/654-2) against acute kidney injury (AKI) in LPS-induced septic shock rats and explore its molecular mechanisms. Methods: 56 rats were randomly divided into 8 groups: control, LPS, LPS + 654-1, and LPS + 654-2 (1.25, 2.5 and 5 mg/kg). The model was evaluated by monitoring MAP, HR, and plasma LD levels. ELISA and biochemical assay kits were used to measure the levels of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and kidney injury markers (BUN and CRE). Additionally, RNA-seq and bioinformatic analysis were performed to explore the mechanism of action of 654-1/654-2, and verification was conducted by western blotting and RT-PCR. Results: 654-1/654-2 significantly restored the levels of MAP, HR, and plasma LD in septic shock rats. Furthermore, 654-1/654-2 (5 mg/kg) effectively ameliorated LPS-induced kidney structural damage and exhibited a dose-dependent reduction in levels of inflammatory cytokines and kidney injury markers. In addition, RNA-seq, WB, and RT-PCR analyses revealed that 654-1/654-2 exerted its effects by inhibiting the expressions of the NF-κB and MAPK pathways and activating the Pi3K/Akt/Bcl-2 signaling pathway, thereby mitigating AKI. Discussion: This study suggested that 654-1/654-2 could alleviate AKI in septic shock rats by improving inflammation invasion and cell apoptosis. Notably, 654-1/654-2 collectively suppressed inflammation response through the p38/JNK/AP-1/NF-κB pathway. Additionally, 654-1 promotes survival signaling via the Pi3K/Akt/Bcl-2 pathway, whereas 654-2 reduces apoptosis through the P53/Bax pathway. These findings provided a theoretical basis for the clinical application of 654-1/654-2 in treating organ damage caused by septic shock. [ABSTRACT FROM AUTHOR]

• Renal proximal tubular epithelial cells (RPTECs) are the main targets of drug-induced kidney injury; however, no useful evaluation system is currently available. • We evaluated kidney injuries induced by 32 nephrotoxic drugs for up to 28 days using three-dimensional cultured RPTECs (3D-RPTECs) with enhanced expression of drug transporters. • The predictive performance of 3D-RPTECs for drug-induced kidney injury was better than conventional 2D-cultured RPTECs and HK-2 cells. • 3D-RPTECs are useful for in vitro evaluation of RPTEC injury by measuring intracellular ATP levels. Drug-induced kidney injury (DIKI) is the major cause of acute kidney injury (AKI). Renal proximal tubular epithelial cells (RPTECs) are the primary target sites of DIKI and express transporters involved in renal drug disposition. In the present study, we focused on three-dimensionally cultured human RPTECs (3D-RPTECs) with elevated expression of drug transporters to investigate their utility in DIKI evaluation. Intracellular ATP levels in 3D-RPTECs are reduced by tenofovir and cisplatin that are substrates of an organic anion transporter 1 and an organic cation transporter 2, respectively. In addition, 3D-RPTECs were exposed to 17 and 15 drugs that are positive and negative to RPTEC toxicity, respectively, for up to 28 d. The 20 % decreasing concentration of drugs for ATP amount (EC 20) was obtained, and the ratio of EC 20 values and clinical maximum concentration (C max) ≤100 were used as cut-off value to evaluate potential of DIKI. The sensitivities of 3D-RPTECs were 82.4 % and 88.2 % after 7 d and 28 d of drug exposure, respectively, and the specificities were 100 % and 93.3 %, respectively. The predictive performance of 3D-RPTECs was higher than that of two-dimensional cultured RPTECs and the kidney cell line HK-2. In conclusion, 3D-RPTECs are useful for in vitro evaluation of RPTEC injury by measuring intracellular ATP levels. [ABSTRACT FROM AUTHOR]

Background: In recent years, the African spiny mouse Acomys cahirinus has been shown to regenerate a remarkable array of severe internal and external injuries in the absence of a fibrotic response, including the ability to regenerate full-thickness skin excisions, ear punches, severe kidney injuries, and complete transection of the spinal cord. While skeletal muscle is highly regenerative in adult mammals, Acomys displays superior muscle regeneration properties compared with standard laboratory mice following several injuries, including serial cardiotoxin injections of skeletal muscle and volumetric muscle loss (VML) of the panniculus carnosus muscle following full-thickness excision injuries. VML is an extreme muscle injury defined as the irrecoverable ablation of muscle mass, most commonly resulting from combat injuries or surgical debridement. Barriers to the treatment of VML injury include early and prolonged inflammatory responses that promote fibrotic repair and the loss of structural and mechanical cues that promote muscle regeneration. While the regeneration of the panniculus carnosus in Acomys is impressive, its direct relevance to the study of VML in patients is less clear as this muscle has largely been lost in humans, and, while striated, is not a true skeletal muscle. We therefore sought to test the ability of Acomys to regenerate a skeletal muscle more commonly used in VML injury models. Methods: We performed two different VML injuries of the Acomys tibialis anterior muscle and compared the regenerative response to a standard laboratory mouse strain, Mus C57BL6/J. Results: Neither Acomys nor Mus recovered lost muscle mass or myofiber number within three months following VML injury, and Acomys also failed to recover force production better than Mus. In contrast, Acomys continued to express eMHC within the injured area even three months following injury, whereas Mus ceased expressing eMHC less than one-month post-injury, suggesting that Acomys muscle was primed, but failed, to regenerate. Conclusions: While the panniculus carnosus muscle in Acomys regenerates following VML injury in the context of full-thickness skin excision, this regenerative ability does not translate to regenerative repair of a skeletal muscle. [ABSTRACT FROM AUTHOR]

Ferroptosis is known to mediate the pathogenesis of chemotherapeutic drug‐induced acute kidney injury (AKI); however, leveraging the benefits of ferroptosis‐based treatments for nephroprotection remains challenging. Here, ultrasmall nanodots, denoted as FerroD, comprising the amphiphilic conjugate (tetraphenylethylene‐L‐serine‐deferoxamine, TPE‐lys‐Ser‐DFO (TSD)) and entrapped ferrostatin‐1 are designed. After being internalized through kidney injury molecule‐1‐mediated endocytosis, FerroD can simultaneously remove the overloaded iron ions and eliminate the overproduction of lipid peroxides by the coordination‐disassembly mechanisms, which collectively confer prominent inhibition efficiency of ferroptosis. In cisplatin (CDDP)‐induced AKI mice, FerroD equipped with dual anti‐ferroptotic ability can provide long‐term nephroprotective effects. This study may shed new light on the design and clinical translation of therapeutics targeting ferroptosis for various ferroptosis‐related kidney diseases. [ABSTRACT FROM AUTHOR]

The kidney, an essential excretory organ of the body, performs a series of crucial physiological functions such as waste removal, maintenance of electrolyte and acid–base balance, and endocrine regulation. Due to its rich blood flow and high metabolic activity, the kidney is susceptible to damage. Currently, kidney injury is classified into acute kidney injury (AKI) and chronic kidney disease (CKD), both of which are associated with high rates of morbidity and mortality on a global scale. The current clinical diagnosis of renal injury relies on the assessment of renal filtration function using creatinine and urea nitrogen as "gold-standard" markers. However, the delayed response time, limited specificity, and reduced accuracy of creatinine and urea nitrogen in evaluating kidney injury have significantly hindered advancements in diagnostic methods for kidney injury. Urinary protein is widely utilized as a biomarker for the early diagnosis of kidney injury due to the selectivity of the glomerular filtration system determining whether proteins can pass through the filtration barrier based on their size and charge. Therefore, as a complex biological sample with varying charges and particle sizes, urinary protein is considered an ideal indicator for monitoring the progression of kidney disease. Exploring the relationship between urinary protein and the advancement of kidney injury based on differences in particle size and charge offers a new perspective for assessing and treating such injuries. Hence, we conducted a comprehensive review of 74 relevant studies to gain a thorough understanding of the physiological mechanism and significance of proteinuria production. The aim was to explore the challenges and opportunities in clinical urine protein detection, as well as to discuss strategies targeting glomerular filtration barriers in order to effectively reduce urine protein levels and treat kidney injury, which could provide a new perspective for identifying the progression of kidney injury. [ABSTRACT FROM AUTHOR]

This study investigated the effects of heat shock protein 22 (HSP22) against doxorubicin (DOX)-induced kidney injury. Mice were randomly assigned to four groups: CON, ad-HSP22, DOX, and ad-HSP22 + DOX. Adeno-associated virus carrying the HSP22 gene (ad-HSP22) was administered via tail vein injection for four weeks, followed by intraperitoneal simulation with DOX (20 mg/kg) for another five days. Upon euthanasia, ELISA, histological staining (H&E, IHC, DHE, and TUNEL), and western blot analyses were employed to assess relevant markers. Serum biomarkers of kidney injury, SCr, and BUN, were upregulated after DOX administration but normalized with HSP22 overexpression. Pathological changes induced by DOX were also reversed by HSP22 overexpression in H&E, IHC, DHE, and TUNEL stains. DOX-induced upregulation of NOX-2 and NOX-4 and downregulation of SOD-1 and SOD-2 were reversed by HSP22 overexpression. Similarly, DOX-induced increases in Bax and decrease in Bcl-2 were attenuated by HSP22 overexpression. The study further demonstrated that the Nrf2/HO-1 signaling pathway was activated by HSP22 overexpression. In vitro experiments corroborated the findings from in vivo experiments. In conclusion, HSP22 alleviates DOX-induced kidney injury by suppressing oxidative stress and apoptosis, primarily through the activation of the Nrf2/HO-1 signaling pathway. These results suggest HSP22 as a potential therapeutic target for DOX-induced kidney injury. [ABSTRACT FROM AUTHOR]

Introduction: To investigate the protective effects of anisodamine (654-1/654-2) against acute kidney injury (AKI) in LPS-induced septic shock rats and explore its molecular mechanisms. Methods: 56 rats were randomly divided into 8 groups: control, LPS, LPS + 654-1, and LPS + 654-2 (1.25, 2.5 and 5 mg/kg). The model was evaluated by monitoring MAP, HR, and plasma LD levels. ELISA and biochemical assay kits were used to measure the levels of inflammatory cytokines (IL-1ß, IL-6, and TNF-a) and kidney injury markers (BUN and CRE). Additionally, RNA-seq and bioinformatic analysis were performed to explore the mechanism of action of 654-1/654-2, and verification was conducted by western blotting and RT-PCR. Results: 654-1/654-2 significantly restored the levels of MAP, HR, and plasma LD in septic shock rats. Furthermore, 654-1/654-2 (5 mg/kg) effectively ameliorated LPS-induced kidney structural damage and exhibited a dose-dependent reduction in levels of inflammatory cytokines and kidney injury markers. In addition, RNA-seq, WB, and RT-PCR analyses revealed that 654-1/654-2 exerted its effects by inhibiting the expressions of the NF-κB and MAPK pathways and activating the Pi3K/Akt/Bcl-2 signaling pathway, thereby mitigating AKI. Discussion: This study suggested that 654-1/654-2 could alleviate AKI in septic shock rats by improving inflammation invasion and cell apoptosis. Notably, 654-1/654-2 collectively suppressed inflammation response through the p38/JNK/AP-1/NF-κB pathway. Additionally, 654-1 promotes survival signaling via the Pi3K/Akt/Bcl-2 pathway, whereas 654-2 reduces apoptosis through the P53/Bax pathway. These findings provided a theoretical basis for the clinical application of 654-1/654-2 in treating organ damage caused by septic shock. [ABSTRACT FROM AUTHOR]

G protein‐coupled receptor (GPCR) kinase 2 (GRK2) is an integrative node in many signalling network cascades. An emerging study indicates that GRK2 can interact with GPCRs and non‐GPCR substrates in both kinase‐dependent and ‐independent modes. Alterations in the functional levels of GRK2 have been found in a variety of renal diseases, such as hypertension‐related kidney injury, sepsis‐associated acute kidney injury (S‐AKI), cardiorenal syndrome (CRS), acute kidney injury (AKI), age‐related kidney injury or hyperglycemia‐related kidney injury. Abnormal GRK2 expression contribute to the development of renal diseases, making them promising molecular targets for treating renal diseases. Blocking the prostaglandin E2 (PGE2)‐EP1‐Gaq‐Ca2+ signal pathway in glomerular mesangial cells (GMCs) by internalizing prostaglandin E2 receptor 1 (EP1) with GRK2 may be a potential treatment for diabetic nephropathy (DN). In addition, GRK2 inhibition may have therapeutic effects in a variety of renal diseases, such as SLE‐related kidney injury, DN, age‐related kidney injury, hypertension‐related kidney injury, and CRS. However, there is still a long way to go for the large‐scale application of GRK2 inhibition in the field of renal diseases. In this review, we discuss recent updates in understanding the role of GRK2 in kidney dysfunction. Furthermore, we explore the potential of GRK2 as a possible therapeutic target for renal pathologies. We believe it will shed light on the future development of small‐molecule inhibitors of GRK, as well as the clinical applications in renal diseases. [ABSTRACT FROM AUTHOR]

The chemotherapeutic agent cisplatin accumulates in the kidneys, leading to acute kidney injury (AKI). Preclinical and clinical studies have demonstrated sex-dependent outcomes of cisplatin-AKI. Deranged histone deacetylase (HDAC) activity is hypothesized to promote the pathogenesis of male murine cisplatin-AKI; however, it is unknown whether there are sex differences in the kidney HDACs. We hypothesized that there would be sex-specific Hdac expression, localization, or enzymatic activity, which may explain sexual dimorphic responses to cisplatin-AKI. In normal human kidney RNA samples, HDAC10 was significantly greater in the kidneys of women compared with men, whereas HDAC1, HDAC6, HDAC10, and HDAC11 were differentially expressed between the kidney cortex and medulla, regardless of sex. In a murine model of cisplatin-AKI (3 days after a 15 mg/kg injection), we found few sex- or cisplatin-related differences in Hdac kidney transcripts among the mice. Although Hdac9 was significantly greater in female mice compared with male mice, HDAC9 protein localization did not differ. Hdac7 transcripts were greater in the inner medulla of cisplatin-AKI mice, regardless of sex, and this agreed with a greater HDAC7 abundance. HDAC activity within the cortex, outer medulla, and inner medulla was significantly lower in cisplatin-AKI mice but did not differ between the sexes. In agreement with these findings, a class I HDAC inhibitor did not improve kidney injury or function. In conclusion, even though cisplatin-AKI was evident and there were transcript level differences among the different kidney regions in this model, there were few sex- or cisplatin-dependent effects on kidney HDAC localization or activity. NEW & NOTEWORTHY: Kidney histone deacetylases (HDACs) are abundant in male and female mice, and the inner medulla has the greatest HDAC activity. A low dose of cisplatin caused acute kidney injury (AKI) in these mice, but there were few changes in kidney HDACs at the RNA/protein/activity level. A class I HDAC inhibitor failed to improve AKI outcomes. Defining the HDAC isoform, cellular source, and interventional timing is necessary to determine whether HDAC inhibition is a therapeutic strategy to prevent cisplatin-AKI in both sexes. [ABSTRACT FROM AUTHOR]

The disease familial hyperkalemic hypertension (FHHt; also known as Gordon syndrome) is caused by aberrant accumulation of with-no-lysine kinase (WNK4) activating the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) of the kidney. Mutations in cullin 3 (CUL3) cause FHHt by disrupting interaction with the deneddylase COP9 signalosome (CSN). Deletion of Cul3 or Jab1 (the catalytically active CSN subunit) along the entire nephron causes a partial FHHt phenotype with activation of the WNK4-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NCC pathway. However, progressive kidney injury likely prevents hypertension, hyperkalemia, and hyperchloremic metabolic acidosis associated with FHHt. We hypothesized that DCT-specific deletion would more closely model the disease. We used Slc12a3-Cre-ERT2 mice to delete Cul3 (DCT-Cul3−/−) or Jab1 (DCT-Jab1−/−) only in the DCT and examined the mice after short- and long-term deletion. Short-term DCT-specific knockout of both Cul3 and Jab1 mice caused elevated WNK4, pSPAKS373, and pNCCT53 abundance. However, neither model demonstrated changes in plasma K+, Cl−, or total CO2, even though no injury was present. Long-term DCT-Jab1−/− mice showed significantly lower NCC and parvalbumin abundance and a higher abundance of kidney injury molecule-1, a marker of proximal tubule injury. No injury or reduction in NCC or parvalbumin was observed in long-term DCT-Cul3−/− mice. In summary, the prevention of injury outside the DCT did not lead to a complete FHHt phenotype despite activation of the WNK4-SPAK-NCC pathway, possibly due to insufficient NCC activation. Chronically, only DCT-Jab1−/− mice developed tubule injury and atrophy of the DCT, suggesting a direct JAB1 effect or dysregulation of other cullins as mechanisms for injury. NEW & NOTEWORTHY: CUL3 degrades WNK4, which prevents activation of NCC in the DCT. CSN regulation of CUL3 is impaired in the disease FHHt, causing accumulation of WNK4. Short-term DCT-specific disruption of CUL3 or the CSN in mice resulted in activation of the WNK4-SPAK-NCC pathway but not hyperkalemic metabolic acidosis found in FHHt. Tubule injury was observed only after long-term CSN disruption. The data suggest that disruption of other cullins may be the cause for the injury. [ABSTRACT FROM AUTHOR]

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N -acetyl-beta- d -glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n  = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n  = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n  = 121), and (iv) healthy volunteers (n  = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations. [ABSTRACT FROM AUTHOR]

Purpose: Blunt abdominopelvic trauma frequently results in injuries to the urinary organs, especially in polytrauma. The urotrauma is rarely an acute life-threatening event; however, it may lead to severe complications. Methods: This review addresses the under-representation of urological trauma management in interdisciplinary medical training and its impact on patient outcomes. It compiles evidence-based recommendations and guidelines from multiple specialties, focusing on common challenges in managing these injuries. The resource is tailored for primary care physicians in radiology, trauma surgery, internal medicine, urology, and nephrology. Results: Urinary tract injuries can occur even if the patient's condition initially appears normal. An exclusion diagnosis is obligatory by contrast medium tomography of the entire urinary tract and, if suspected, an additional uroendoscopic examination. Interventional therapy by catheterisation of the urinary tract is often required. Urosurgical treatment is not commonly needed, but when there is a demand, it must be administered via an interdisciplinary approach with visceral and trauma surgery. Over 90% of life-threatening kidney injuries (usually up to grade 4–5 AAST) are presently treated by interventional radiologists. Acute kidney injury (AKI) as a complication in trauma patients may complicate clinical management and often worsens the outcome. The incidence of trauma-associated AKI in patients admitted to an intensive care unit is high. Conclusions: Patients suffering from blunt abdominopelvic trauma should ideally be referred to certified trauma centres with subspecialised or fully specialised care provided by visceral/vascular surgery, trauma surgery, interventional radiology, urology, and nephrology. This recommendation is based on the complex nature of most damage patterns. [ABSTRACT FROM AUTHOR]

Ischaemia‐reperfusion (IR)‐associated acute kidney injury (AKI) is a severe clinical condition that lacks effective pharmacological treatments. Our recent research revealed that pretreatment with the angiotensin II type 2 receptor (AT2R) agonist C21 alleviates kidney damage during IR. Primary cilia are organelles crucial for regulation of epithelial cell homeostasis, which are significantly affected by IR injury. This study aimed to evaluate the impact of AT2R activation on cilia integrity during IR and to identify pathways involved in the nephroprotective effect of C21. Rats were subjected to 40 min of unilateral ischaemia followed by 24 h of reperfusion. Immunofluorescence analysis of the kidneys showed that the nephroprotective effect of C21 was associated with preservation of cilia integrity in tubular cells. AT2R agonists increased α‐tubulin acetylation in primary cilia in tubular cells in vivo and in a cell model. Analysis of ERK phosphorylation indicated that AT2R activation led to diminished activation of ERK1/2 in tubular cells. Similar to AT2R agonists, inhibitors of α‐tubulin deacetylase HDAC6 or inhibitors of ERK activation ameliorated IR‐induced cell death and preserved cilia integrity. Immunofluorescence analysis of tubular cells revealed significant ERK localization at primary cilia and demonstrated that ERK inhibition increased cilia levels of acetylated α‐tubulin. Overall, our findings demonstrate that C21 elicits a preconditioning effect that enhances cilia stability in renal tubular cells, thereby preserving their integrity when exposed to IR injury. Furthermore, our results indicate that this effect might be mediated by AT2R‐induced inhibition of ERK activation. These findings offer potential insights for the development of pharmacological interventions to mitigate IR‐associated AKI. Key points: The AT2R agonist C21 prevents primary cilia shortening and tubular cell deciliation during renal ischaemia‐reperfusion.AT2R activation inhibits ERK1/2 in renal tubular cells.Both AT2R agonists and ERK1/2 inhibitors increase alpha‐tubulin acetylation at the primary cilium in tubular cells.AT2R activation, ERK1/2 inhibition or inhibition of alpha‐tubulin deacetylation elicit protective effects in tubular cells subjected to ischaemia‐reperfusion injury. [ABSTRACT FROM AUTHOR]

During the hibernation season, the thirteen-lined ground squirrel undergoes cyclical torpor and arousal periods. The decrease and restoration of metabolic rate and oxygen delivery during torpor and arousal, respectively, may cause reperfusion-ischemia injury in the kidneys. In order to maintain the structural integrity of the kidneys necessary for renal function resumption during arousal, the thirteen-lined ground squirrel has developed adaptive methods to prevent and repair kidney injury. In this present study, computational methods were used to clean and analyze sequenced kidney RNA samples. Significantly differentially expressed microRNAs and enriched gene sets were also determined. From the gene set analysis, the results showed an increase in ubiquitin-related processes and p53 signaling pathways which suggested the occurrence of kidney damage during torpor. There was also an observed increase in cell cycle processes and the anchoring junction cellular compartment which may lend to the prevention of kidney injury. From the differentially expressed microRNAs, miR-27a (log 2 FC = 1.639; p-value = 0.023), miR-129 (log 2 FC = 2.516; p-value = 0.023), miR-let-7b (log 2 FC = 2.360; p-value = 0.025), miR-let-7c (log 2 FC = 2.291; p-value = 0.037) and miR-let-7i (log 2 FC = 1.564; p-value = 0.039) were found to be significantly upregulated. These biochemical adaptations may allow the thirteen-lined ground squirrel to maintain kidney structure and function during hibernation. • Increased ubiquitin-related action and p53 signaling suggest torpid kidney damage. • Increased cell cycle processes and anchoring junction may prevent kidney injury. • Changes in microRNA expression contribute to the prevention of kidney lesions. • Conflicting results show increase in pathways that encourage renal fibrosis. [ABSTRACT FROM AUTHOR]

Oliguria is a clinical symptom characterized by decreased urine output, which can occur at any stage of acute kidney injury and also during renal replacement therapy. In some cases, oliguria may resolve with adjustment of blood purification dose or fluid management, while in others, it may suggest a need for further evaluation and intervention. It is important to determine the underlying cause of oliguria during renal replacement therapy and to develop an appropriate treatment plan. This review looks into the mechanisms of urine production to investigate the mechanism of oliguria during renal replacement therapy from two aspects: diminished glomerular filtration rate and tubular abnormalities. The above conditions all implying a renal oxygen supply–demand imbalance, which is the signal of worsening kidney injury. It also proposes a viable clinical pathway for the treatment and management of patients with acute kidney injury receiving renal replacement therapy. [ABSTRACT FROM AUTHOR]

Advanced glycation endproducts (AGEs) contribute to cellular damage of various pathologies, including kidney diseases. Acute kidney injury (AKI) represents a syndrome seldom characterized by a single, distinct pathophysiological cause. Rhabdomyolysis-induced acute kidney injury (RIAKI) constitutes roughly 15% of AKI cases, yet its underlying pathophysiology remains poorly understood. Using a murine model of RIAKI induced by muscular glycerol injection, we observed elevated levels of AGEs and the AGE receptor galectin-3 (LGALS3) in the kidney. Immunofluorescence localized LGALS3 to distal nephron segments. According to transcriptomic profiling via next-generation sequencing, RIAKI led to profound changes in kidney metabolism, oxidative stress, and inflammation. Cellular stress was evident in both proximal and distal tubules, as shown by kidney injury markers KIM-1 and NGAL. However, only proximal tubules exhibited overt damage and apoptosis, as detected by routine morphology, active Caspase-3, and TUNEL assay, respectively. In vitro, distal convoluted tubule (DCT) cells challenged with AGEs underwent apoptosis, which was markedly enhanced by Lgals3 siRNA treatment. Thus, in RIAKI, the upregulation of LGALS3 may protect the distal nephron from AGE-mediated damage, while proximal tubules lacking LGALS3 stay at risk. Thus, stimulating LGALS3 in the proximal nephron, if achievable, may attenuate RIAKI. [ABSTRACT FROM AUTHOR]

Objective(s): Prior research has indicated that hydroxycitric acid (HCA) can impede the formation of calcium oxalate (CaOx) crystals, yet the specific mechanisms underlying its therapeutic effects remain unclear. In this study, we delved into the protective effects of HCA against glyoxylate-induced renal stones in rats and sought to elucidate the underlying metabolic pathways. Materials and Methods: Forty rats were randomly assigned to five groups: control group, model group, L-HCA-treated group, M-HCA-treated group, and H-HCA-treated group. Von Kossa staining was conducted on renal sections, and blood urea nitrogen and serum creatinine were determined by biochemical analysis. Meanwhile, body weight and urine volume were also measured. We subjected urine samples from the rats to analysis using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Next, we employed a metabolomic approach to scrutinize the metabolic profiles of each group. Results: HCA significantly reduced blood urea nitrogen and serum creatinine, and increased body weight and urine volume. It also reduced CaOx crystal deposition. A total of 24 metabolites, exhibiting a significant reversal pattern following HCA administration, were identified as urine biomarkers indicative of HCA’s preventive effects against CaOx crystal-induced renal injury. These metabolites are primarily associated with glycine, serine, and threonine metabolism; phenylalanine metabolism; tricarboxylic acid cycle; taurine and hypotaurine metabolism; and tryptophan metabolism. Conclusion: It was demonstrated that HCA has a protective effect against CaOx crystal-induced kidney injury in rats by modulating various metabolic pathways. Additionally, results suggest that HCA holds promise as a potential clinical therapeutic drug for both the prevention and treatment of renal stones. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a serious public health problem worldwide, and ferroptosis is deeply involved in the pathogenesis of DN. Prediabetes is a critical period in the prevention and control of diabetes and its complications, in which kidney injury occurs. This study aimed to explore whether ferroptosis would induce kidney injury in prediabetic mice, and whether vitamin D (VD) supplementation is capable of preventing kidney injury by inhibiting ferroptosis, while discussing the potential mechanisms. High-fat diet (HFD) fed KKAy mice and high glucose (HG) treated HK-2 cells were used as experimental subjects in the current study. Our results revealed that serious injury and ferroptosis take place in the kidney tissue of prediabetic mice; furthermore, VD intervention significantly improved the kidney structure and function in prediabetic mice and inhibited ferroptosis, showing ameliorated iron deposition, enhanced antioxidant capability, reduced reactive oxygen species (ROS) and lipid peroxidation accumulation. Meanwhile, VD up-regulated Klotho, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, and down-regulated p53, transferrin receptor 1 (TFR1) and Acyl-Coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Moreover, we demonstrated that HG-induced ferroptosis is antagonized by treatment of VD and knockdown of Klotho attenuates the protective effect of VD on ferroptosis in vitro. In conclusion, ferroptosis occurs in the kidney of prediabetic mice and VD owns a protective effect on prediabetic kidney injury, possibly by via the Klotho/p53 pathway, thus inhibiting hyperglycemia-induced ferroptosis. [ABSTRACT FROM AUTHOR]

Kidney is an essential organ that is highly susceptible to cellular injury caused by various toxic substances in the blood. Several studies have shown that untreated injuries to this organ can cause glomerulosclerosis, tubulointerstitial fibrosis, and tubular cell apoptosis, leading to kidney failure. Despite significant advancements in modern treatment, there is no fully effective drug for repairing its function, providing complete protection, and assisting in cell regeneration. Furthermore, some available medications have been reported to exacerbate injuries, showing the need to explore alternative treatments. Natural drugs are currently being explored as a new therapeutic strategy for managing kidney diseases. Kaempferol, a polyphenol found in plants, including vegetables, legumes, and fruits, has been extensively studied in various nephrotoxicity protocols. The compound has been reported to have potential as a nephroprotective agent with beneficial effects on various physiological pathways, such as CPL‐induced kidney injury, DOX, LPO, ROS, RCC, and diabetic nephropathy. Therefore, this study aims to provide a brief overview of the current nephroprotective effects of kaempferol, as well as its molecular mechanisms of action, biosynthesis pathways, and clinical prospects. [ABSTRACT FROM AUTHOR]

Epilepsy is a common disorder caused by a myriad of drugs, of that levetiracetam is being commonly used late because of its strong safety profile and efficacy. With the increasing usage of drugs, some rare side effects may sometimes appear that can escape the most stringent checks, possibly due to the rarity of their occurrence. Rhabdomyolysis is known to occur in some patients owing to a variety of causes, even leading to kidney injury. When a drug has a side effect that is not well recognized in the literature, especially when the side effect can mimic an adverse effect of an uncommon primary illness, identifying the causal factor can be doubly difficult. To date, only limited studies have been published suggesting rhabdomyolysis linked to levetiracetam use. We report the first case of levetiracetam‐induced​ rhabdomyolysis in Kuwait. [ABSTRACT FROM AUTHOR]

The challenges of long-term graft survival and the side effects of current immunosuppressive therapies in kidney transplantation highlight the need for improved drugs with fewer adverse effects. Biomarkers play a crucial role in quickly detecting post-transplant complications, with new biomarkers showing promise for ongoing monitoring of disease and potentially reducing the need for unnecessary invasive biopsies. The chemokines such as C-X-C motif chemokine ligand 10 (CXCL10), are particularly promising protein biomarkers for acute renal rejection, with urine samples being a desirable source for biomarkers. The aim of this review is to analyze the literature on the potential role of urinary CXCL10 protein in predicting kidney graft injuries. The results of this study demonstrate that evaluating urinary CXCL10 levels is more successful in identifying post-transplant injuries compared to assessing the CXCL10/Cr ratio. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to establish baseline morphological and functional data for normal mouse kidneys via a clinical 33 MHz ultra-high-frequency (UHF) transducer, compare the data with the findings from fibrotic mice, and assess correlations between ultrasonography (US) parameters and fibrosis-related markers. Methods: This retrospective study aggregated data from three separate experiments (obstructive nephropathy, diabetic nephropathy, and acute-to-chronic kidney injury models). Morphological parameters (kidney size, parenchymal thickness [PT]) and functional (shear-wave speed [SWS], stiffness, resistive index [RI], and microvascular imaging-derived vascular index [VI]) were assessed and compared between normal and fibrotic mouse kidneys. Semi-quantitative histopathologic scores were calculated and molecular markers (epithelial cadherin), Collagen 1A1 [Col1A1], transforming growth factor-β, and α-smooth muscle actin [α-SMA]) were evaluated using western blots. Correlations with US parameters were explored. Results: Clinical UHF US successfully imaged the kidneys of the experimental mice. A three-layer configuration was prevalent in the normal mouse kidney parenchyma (34/35) but was blurred in most fibrotic mouse kidneys (33/40). US parameters, including size (11.14 vs. 10.70 mm), PT (2.07 vs. 1.24 mm), RI (0.64 vs. 0.77), VI (22.55% vs. 11.47%, only for non-obstructive kidneys), SWS (1.67 vs. 2.06 m/s), and stiffness (8.23 vs. 12.92 kPa), showed significant differences between normal and fibrotic kidneys (P<0.001). These parameters also demonstrated strong discriminative ability in receiver operating characteristic curve analysis (area under the curve, 0.76 to 0.95; P<0.001). PT, VI, and RI were significantly correlated with histological fibrosis markers (ρ=-0.64 to -0.68 for PT and VI, ρ=0.71-0.76 for RI, P<0.001). VI exhibited strong negative correlations with Col1A1 (ρ=-0.76, P=0.006) and α-SMA (ρ=-0.75, P=0.009). Conclusion: Clinical UHF US effectively distinguished normal and fibrotic mouse kidneys, indicating the potential of US parameters, notably VI, as noninvasive markers for tracking fibrosis initiation and progression in mouse kidney fibrosis models. [ABSTRACT FROM AUTHOR]

Background • Intestinal obstruction frequently leads to acute kidney injury (AKI), yet understanding the specific clinical features and influencing factors in these patients remains limited. Objective • This study aims to comprehensively evaluate the clinical features and affecting factors of AKI in patients with intestinal obstruction. Methods • We conducted a systematic search of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service platform, VIP, and China Biology Medicine Literature Database from 2010 to the present. Relevant literature addressing the clinical features or affecting factors of AKI in patients with intestinal obstruction was retrieved. The study group (SG) comprised patients with intestinal obstruction complicated by AKI, while the control group (CG) included patients without AKI after intestinal obstruction. Meta-analysis was performed to investigate the clinical features of both patient groups and funnel plots were employed to assess publication bias. Results • This study included 5 articles with a total of 7583 patients (1472 in the SG and 6111 in the CG). Meta-analysis results indicated a higher prevalence of hypertension (OR=1.80, 95% CI: 1.59-2.04, P < .00001), cardiovascular disease (OR=1.60, 95% CI: 1.06-2.41, P = .03), and diabetes (OR=1.61, 95% CI: 1.35-1.91, P < .00001) in both groups. Additionally, factors such as infection rate (OR=4.03, 95% CI: 2.10-7.73, P < .0001), age (OR=2.90, 95% CI: 1.07-7.90, P = .04), and BMI (OR=1.31, 95% CI: 1.15-1.48, P < .0001) significantly influenced AKI occurrence. No significant difference was observed in the history of pelvic surgery between both groups (OR=0.91, 95% CI: 0.53-1.55, P = .73). Funnel plot analysis suggested minimal publication bias. Conclusions • Age, BMI, hypertension, cardiovascular disease, diabetes mellitus, and infection emerge as primary influencing factors for AKI in patients with intestinal obstruction. Our findings advocate for early interventions to mitigate the global incidence of AKI in this patient population. [ABSTRACT FROM AUTHOR]

Deranged gut microbiota can release increased levels of uremic toxins leading to exacerbated kidney injury. In diabetic kidney disease (DKD), phenyl sulfate (PS) derived from tyrosine catabolism by gut microbiota has been demonstrated to be both an early diagnostic marker and a therapeutic target. In this perspective article, we summarize PS generation pathways and recent findings on PS and kidney injury in DKD. Increasing evidence has shown that the underlying mechanisms of PS-induced kidney injury mainly involve oxidative stress, redox imbalance, and mitochondrial dysfunction, which all may be targeted to attenuate PS-induced kidney injury. For future research directions, we think that a deeper understanding of the pathogenic role of PS in kidney injury using a variety of diabetic animal models should be investigated. Moreover, we also suggest beneficial approaches that could be used to mitigate the deleterious effect of PS on the kidney. These approaches include caloric restriction, tyrosine restriction, and administration of ketogenic drugs, ketogenic diets or natural products; all of which should be conducted under obese and diabetic conditions. [ABSTRACT FROM AUTHOR]

We have previously observed that prolonged administration of rapamycin, an inhibitor targeting the mammalian target of rapamycin complex (mTORC)1, partially reduced hypertension and alleviated kidney inflammation in Dahl salt-sensitive (SS) rats. In contrast, treatment with PP242, an inhibitor affecting both mTORC1/mTORC2, not only completely prevented hypertension but also provided substantial protection against kidney injury. Notably, PP242 exhibited potent natriuretic effects that were not evident with rapamycin. The primary objective of this study was to pinpoint the specific tubular sites responsible for the natriuretic effect of PP242 in SS rats subjected to either 0.4% NaCl (normal salt) or 4.0% NaCl (high salt) diet. Acute effects of PP242 on natriuretic, diuretic, and kaliuretic responses were determined in unanesthetized SS rats utilizing benzamil, furosemide, or hydrochlorothiazide [inhibitors of epithelial Na+ channel (ENaC), Na-K-2Cl cotransporter (NKCC2), or Na-Cl cotransporter (NCC), respectively] either administered alone or in combination. The findings indicate that the natriuretic effects of PP242 in SS rats stem predominantly from the inhibition of NCC and a reduction of ENaC open probability. Molecular analysis revealed that mTORC2 regulates NCC activity through protein phosphorylation and ENaC activity through proteolytic cleavage in vivo. Evidence also indicated that PP242 also prevents the loss of K+ associated with the inhibition of NCC. These findings suggest that PP242 may represent an improved therapeutic approach for antihypertensive intervention, potentially controlling blood pressure and mitigating kidney injury in salt-sensitive human subjects. NEW & NOTEWORTHY: This study explored mechanisms underlying the natriuretic effects of mammalian target of rapamycin protein complex 2 inhibition using PP242 and revealed both epithelial Na+ channel and Na-Cl cotransporter in the distal tubular segments were potentially inhibited. These observations, with prior lab evidence, indicate that PP242 prevents hypertension via its potent inhibitory effects on these specific sodium transporters and by reducing renal immune responses. This dual action, coupled with potassium sparing effects, suggests an improved approach for managing hypertension and associated kidney damage. [ABSTRACT FROM AUTHOR]

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-LRt-reated 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 MCLR- contaminated water may lead to kidney injury in Wistar rats. [ABSTRACT FROM AUTHOR]

Systemic chronic inflammation may cause kidney injury as a result of an impaired immune response and pro-inflammatory cytokine overload due to various factors that prevent the resolution of inflammation. Therefore, it is important to determine pro-inflammatory cytokine levels by renal biopsy and to investigate treatment modalities in systemic chronic inflammation-related kidney injury. We aimed to investigate the therapeutic effect of methylprednisolone on extra-renal systemic chronic inflammation-induced renal tissue damage in terms of histopathological alterations and immunohistochemically on tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels. The mice used in this study were divided into three equally sized groups (n: 10). Group I (control) received 0.3 mL 0.9% NaCl, and group II received 0.3 mL complete Freund's adjuvant-casein emulsion intraperitoneally for systemic chronic inflammation induction. Group III received methylprednisolone 10 mg/kg intramuscularly after intraperitoneal injection of 0.3 mL complete Freund's adjuvant-casein emulsion. Injections were administered on days 1 and 14 of the study, and the experiment was ended 5 week after the second injections following the development of systemic chronic inflammation. Finally, kidney tissues were examined histopathologically and immunohistochemically for tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels. While normal renal histology was observed in group I, glomerulonephritis and tubulointerstitial nephritis findings were detected in group II and group III. Methylprednisolone treatment decreased the histopathologic lesions observed in group III. Immunostaining with anti-tumor necrosis factor-α, interleukin-1β and interleukin-6 showed severe immunopositivity in group II and mild immunopositivity in group III, whereas they were immunonegative in group I. Our study provides histopathological and immunohistochemical evidence supporting the decreasing effect of methylprednisolone on tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels in kidney tissue against SCI-induced renal damage due to excessive pro-inflammatory cytokine overload. [ABSTRACT FROM AUTHOR]

Multidrug and toxin extrusion protein 1 (MATE1), an efflux transporter mainly expressed in renal proximal tubules, mediates the renal secretion of organic cationic drugs. The inhibition of MATE1 will impair the excretion of drugs into the tubular lumen, leading to the accumulation of nephrotoxic drugs in the kidney and consequently potentiating nephrotoxicity. Screening and identifying potent MATE1 inhibitors can predict or minimize the risk of drug‐induced kidney injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter‐mediated food/herb–drug interactions. Our objective was to investigate the inhibitory effects of flavonoids on MATE1 in vitro and in vivo and to assess the effects of flavonoids on cisplatin‐induced kidney injury. Thirteen flavonoids exhibited significant transport activity inhibition (>50%) on MATE1 in MATE1‐MDCK cells. Among them, the six strongest flavonoid inhibitors, including irisflorentin, silymarin, isosilybin, sinensetin, tangeretin, and nobiletin, markedly increased cisplatin cytotoxicity in these cells. In cisplatin‐induced in vivo renal injury models, irisflorentin, isosilybin, and sinensetin also increased serum creatinine and blood urea nitrogen levels to different degrees, especially irisflorentin, which exhibited the most potent nephrotoxicity with cisplatin. The pharmacophore model indicated that the hydrogen bond acceptors at the 3, 5, and 7 positions may play a critical role in the inhibitory effect of flavonoids on MATE1. Our findings provide helpful information for predicting the potential risks of flavonoid‐containing food/herb–drug interactions and avoiding the exacerbation of drug‐induced kidney injury via MATE1 mediation. Our research indicates flavonoids exhibited significant inhibition of MATE1, blocking the renal secretion of cationic drugs and heightening nephrotoxicity risks, especially when combined with cisplatin. Six potent flavonoid MATE1 inhibitors, especially irisflorentin, exacerbated cisplatin cytotoxicity and renal injury to different degrees. The pharmacophore model clarified that hydrogen bond acceptors in the 3, 5, and 7 positions play a critical role for flavonoids in inhibiting MATE1. Our findings help predict the potential risk of FDI and avoid MATE1‐mediated DIKI in clinical practice. [ABSTRACT FROM AUTHOR]

To explain the effect and mechanism of cordycepin (COR) in resisting acute kidney injury (AKI). Network pharmacology was employed to analyze the correlations between COR, AKI, and pyroptosis, as well as the action target of COR. A mouse model of AKI was established by ischemia reperfusion injury (IRI), and after treatment with COR, the renal function, tissue inflammatory cytokine levels, and pyroptosis‐related signals were detected in mice. In in‐vitro experiments, damage of renal macrophages was caused by the oxygen‐glucose deprivation model, and pyroptosis indicators and inflammatory cytokine levels were assayed after COR treatment. Network pharmacological analysis revealed that nuclear factor kappa‐B (NF‐κB) was the primary action target of COR and that COR could inhibit kidney injury and tissue inflammation during IRI by inhibiting NF‐κB‐mediated gasdermin D cleavage. When NF‐κB was inhibited, the effect of COR was weakened. COR in renal macrophages could inhibit pyroptosis and lower the levels of inflammatory cytokines, whose effect was associated with NF‐κB. Our study finds that COR can play an anti‐inflammatory role and inhibit the progression of AKI through the NF‐κB‐mediated pyroptosis, which represents its nephroprotective mechanism. [ABSTRACT FROM AUTHOR]

Liraglutide, a glucagon-like peptide-1 receptor agonist, has been shown to regulate blood sugar and control body weight, but its ability to treat obesity-related nephropathy has been poorly studied. Therefore, this study was designed to observe the characteristics and potential mechanism of liraglutide against obesity-related kidney disease. Thirty-six C57BL/6J male mice were randomly divided into six groups (n = 6 per group). Obesity-related nephropathy was induced in mice by continuous feeding of high-fat diet (HFD) for 12 weeks. After 12 weeks, liraglutide (0.6 mg/kg) and AMP-activated protein kinase (AMPK) agonists bortezomib (200 μg/kg) were injected for 12 weeks, respectively. Enzyme-linked immunosorbent assay was employed to detect the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, blood urea nitrogen, creatinine in serum, as well as urinary protein in urine. Besides, hematoxylin–eosin staining and periodic acid-Schiff staining were used to observe the pathological changes of kidney tissue; immunohistochemistry, western blot, and real-time quantitative PCR to assess the calmodulin-dependent protein kinase kinase beta (CaMKKβ)/AMPK signaling pathway activation. Liraglutide significantly reduced serum lipid loading, improved kidney function, and relieved kidney histopathological damage and glycogen deposition in the mouse model of obesity-related kidney disease induced by HFD. In addition, liraglutide also significantly inhibited the CaMKKβ/AMPK signaling pathway in kidney tissue of HFD-induced mice. However, bortezomib partially reversed the therapeutic effect of liraglutide on HDF-induced nephropathy in mice. Liraglutide has a therapeutic effect on obesity-related kidney disease, and such an effect may be achieved by inhibiting the CaMKKβ/AMPK signaling pathway in kidney tissue. [ABSTRACT FROM AUTHOR]

Chronic liver disease is a common and important clinical problem.Hepatorenal syndrome (HRS) is a life threatening complication. Serum creatinine (Cr) remains the only conventional indicator of renal function. However, the interpretation of serum Cr level can be confounded by malnutrition and reduced muscle mass often observed in patients with severe liver disease. Here, we present a cross-sectional study to explore the sensitivity and specificity of other markers as urinary KIM-1 and NGAL for cases of HRS. Cross-sectional study was conducted on 88 patients who were admitted to Alexandria main university hospital. Enrolled patients were divided in two groups; group 1: patients with advanced liver cirrhosis (child B and C) who have normal kidney functions while group 2: patients who developed HRS. Stata© version 14.2 software package was used for analysis. Group 1 included 18 males and 26 females compared to 25 males and 19 females in group 2 (p = 0.135). Only the urinary KIM-1 showed a statistically significant difference between both groups in the multivariate logistic regression analysis adjusted for gender, serum bilirubin, serum albumin, INR, serum K, AST and ALT levels. In conclusion, our study aligns with prior research, as seen in the consistent findings regarding Urinary NGAL elevation in cirrhotic patients with AKI. Urinary KIM-1, independent of Urinary NGAL, may have a role in precisely distinguishing between advanced liver cirrhosis and HRS and merits further exploration. [ABSTRACT FROM AUTHOR]

Nickel (Ni) is a common metal with a nephrotoxic effect, damaging the kidneys. This study investigated the mechanism by which gallic acid (GA) protects mice kidneys against renal damage induced by Nickel oxide nanoparticles (NiO-NPs). Forty male Swiss albino mice were randomly assigned into four groups, each consisting of ten mice (n = 10/group): Group I the control group, received no treatment; Group II, the GA group, was administrated GA at a dosage of 110 mg/kg/day body weight; Group III, the NiO-NPs group, received injection of NiO-NPs at a concentration of 20 mg/kg body weight for 10 consecutive days; Group IV, the GA + NiO-NPs group, underwent treatment with both GA and NiO-NPs. The results showed a significant increase in serum biochemical markers and a reduction in antioxidant activities. Moreover, levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), phosphorylated nuclear factor kappa B (p65), and protein carbonyl (PC) were significantly elevated in group III compared with group I. Furthermore, the western blot analysis revealed significant high NF-κB p65 expression, immunohistochemistry of the NF-κB and caspase-1 expression levels were significantly increased in group III compared to group I. Additionally, the histopathological inspection of the kidney in group III exhibited a substantial increase in extensive necrosis features compared with group I. In contrast, the concomitant coadministration of GA and NiO-NPs in group IV showed significant biochemical, antioxidant activities, immunohistochemical and histopathological improvements compared with group III. Gallic acid has a protective role against kidney dysfunction and renal damage in Ni-nanoparticle toxicity. [ABSTRACT FROM AUTHOR]

To investigate the effects of canagliflozin (20 mg/kg) on Dahl salt-sensitive (DSS) rat gut microbiota and salt-sensitive hypertension-induced kidney injury and further explore its possible mechanism. Rats were fed a high-salt diet to induce hypertension and kidney injury, and physical and physiological indicators were measured afterwards. This study employed 16S rRNA sequencing technology and liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based metabolic profiling combined with advanced differential and association analyses to investigate the correlation between the microbiome and the metabolome in male DSS rats. A high-salt diet disrupted the balance of the intestinal flora and increased toxic metabolites (methyhistidines, creatinine, homocitrulline, and indoxyl sulfate), resulting in severe kidney damage. Canagliflozin contributed to reconstructing the intestinal flora of DSS rats by significantly increasing the abundance of Corynebacterium spp., Bifidobacterium spp., Facklamia spp., Lactobacillus spp., Ruminococcus spp., Blautia spp., Coprococcus spp., and Allobaculum spp. Moreover, the reconstruction of the intestinal microbiota led to significant changes in host amino acid metabolite concentrations. The concentration of uremic toxins, such as methyhistidines, creatinine, and homocitrulline, in the serum of rats was decreased by canagliflozin, which resulted in oxidative stress and renal injury alleviation. Canagliflozin may change the production of metabolites and reduce the level of uremic toxins in the blood circulation by reconstructing the intestinal flora of DSS rats fed a high-salt diet, ultimately alleviating oxidative stress and renal injury. [ABSTRACT FROM AUTHOR]

To investigate the preventive effect of aerobic exercise on renal damage caused by obesity. The mice in the Control (Con) and Control + Exercise (Con + Ex) groups received a standard chow diet for the 21-week duration of the study, while the High-fat diet (HFD) group and High-fat diet + Exercise (HFD + Ex) group were fed an HFD. Mice were acclimated to the laboratory for 1 week, given 12 weeks of being on their respective diets, and then the Con + Ex and HFD + Ex groups were subjected to moderate intensity aerobic treadmill running 45 min/day, 5 days/week for 8 weeks. We found that HFD-induced obesity mainly impacts kidney glycerin phospholipids, glycerides, and fatty acyls, and aerobic exercise mainly impacts kidney glycerides, amino acids and organic acids as well as their derivatives. We identified 18 metabolites with significantly altered levels that appear to be involved in aerobic exercise mediated prevention of HFD-induced obesity and renal damage, half of which were amino acids and organic acids and their derivatives. Aerobic exercise rewires kidney metabolites to reduce high-fat diet-induced obesity and renal injury. [ABSTRACT FROM AUTHOR]

Background: This study aims to analyse changes in urinary kidney injury markers in children with Mycoplasma pneumoniae pneumonia (MPP), investigate the risk factors for MPP-related acute kidney injury (AKI) and establish a model to predict MPP-related AKI. Methods: Ninety-five children were enrolled based on the study's inclusion and exclusion criteria. They were divided into a severe MPP (SMPP) group and a non-SMPP group and then into an AKI group and a non-AKI group according to the presence of AKI. A univariate logistic regression analysis was performed to explore the early risk factors for AKI. Based on a multivariate logistic regression analysis and a least absolute shrinkage and selection operator regression analysis, appropriate variables were selected to establish a prediction model, and R 4.2.2 software was used to draw nomograms and generate a dynamic nomogram website. Results: Seven urinary kidney injury markers were abnormally elevated in the SMPP group and the non-SMPP group: urinary N-acetyl-β-D-glucosaminidase (NAG), β2-microglobulin, α1-microglobulin, retinol-binding protein, urinary immunoglobulin G, urinary transferrin and urinary microalbumin. Sixteen children were identified with AKI during hospitalisation. The AKI group had higher levels of urinary NAG, α1-microglobulin, β2-microglobulin, urinary microalbumin, urinary transferrin and retinol-binding protein than the non-AKI group (P < 0.05). The MPP-related AKI prediction model consists of four indicators (serum immunoglobulin M [IgM], C-reactive protein [CRP], urine NAG and sputum plug presence) and a dynamic nomogram. Conclusion: Urinary kidney injury markers are often elevated in children with MPP; urinary NAG is the marker most likely to be elevated, and it is especially evident in severe cases. The nomogram of the prediction model, comprising serum IgM, CRP, urinary NAG and sputum plug presence, can predict the probability of AKI in children with MPP. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) vasculitis, or Henoch‐Schonlein purpura, is the most common systemic vasculitis in children, clinically presenting as palpable purpura in combination with arthritis, gastrointestinal involvement, or kidney injury. Subcutaneous edema is reported in patients with IgA vasculitis, and it commonly affects the lower extremities, especially around joints. Here, we report a case of IgA vasculitis with a rare presentation of edema isolated to the periorbital area in a 7‐year‐old boy, who subsequently developed crescentic glomerulonephritis with nephrotic range proteinuria. Isolated periorbital edema is an uncommon cutaneous feature of IgA vasculitis. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase (MMP)‐12 has been reported to have diverse functions, including regulation of immune reactions and anti‐inflammatory effects, but the potential roles of MMP‐12 in kidney injury have not been fully elucidated. This study aimed to determine whether MMP‐12 contributes to tubulointerstitial injury in a unilateral ureteric obstruction (UUO) model. MMP‐12‐deficient (MMP‐12−/−) mice and C57BL/6J mice as controls (MMP‐12+/+) were subjected to UUO and analysed 7 days after UUO. To analyse the functions of MMP‐12 on monocytes/macrophages, we generated MMP‐12‐deficient, irradiated, chimeric mice (BM‐MMP‐12−/−) and performed UUO. Bone marrow‐derived macrophages (BMDMs) were isolated from both groups of mice and used for investigations. MMP‐12−/− mice showed exacerbation of macrophage accumulation and interstitial fibrosis in the UUO‐kidney compared with control mice. BM‐MMP‐12−/− mice also showed exacerbation of kidney injury. UUO induced accumulation of Ly6C+ macrophages in MMP‐12−/− mice compared with control mice. Increases in inflammatory cytokine (tumour necrosis factor α, interleukin [IL]‐1β, IL‐6) levels from BMDMs after lipopolysaccharide stimulation were higher in MMP‐12−/− mice than in MMP‐12+/+ mice. MMP‐12 may play protective roles against kidney injury by UUO in mice, decreasing inflammatory cytokines from BMDMs and macrophage accumulation. [ABSTRACT FROM AUTHOR]

The most common mechanism for renal injury is blunt trauma, while penetrating trauma comprise the rest. The mainstay of renal trauma diagnosis is based on contrast-enhanced computed tomography (CT), which is indicated in all stable patients with gross haematuria and in patients presenting with microscopic haematuria and hypotension. Based on the classification of the organic injuries survey committee, which is from the American Association of the Surgery in Trauma (AAST), renal injuries are classified based on severity. There are five gradings. The aim is to study the pattern and management of renal injury with its outcome analysis of the patients admitted for blunt trauma abdomen. The study was conducted in the department of General Surgery, Assam Medical College and Hospital for a period of one year. It was a crosssectional study. Sample size was 114. Patients are managed according to the stages of kidney injury and the associated injuries. For isolated Grades I, II and III, conservative management is done. For Grade IV and Grade V, renorraphy or partial nephrectomy was done. Our results show that the most common age group is between 20-30 years, with male preponderance. Road traffic accidents were the most common mode of injury. USG plays a major role in finding renal injuries and the side of injury. Most study participants had Grade II and Grade I injuries. The majority of the study participants were stable. Majority of the injuries are minor and managed conservatively. If any patient has associated injury and hemodynamic instability status, he requires surgical intervention. Though CT is effective in grading renal injuries, USG is available in all secondary and tertiary centres, which helps healthcare professionals in decision-making. It is also the time interval taken from the site of the accident and admission and also from admission to surgery that decides the fatality of the patients. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is considered to be an autoimmune disease characterized by the formation of IgA1-containing immune complexes in the circulation and glomerular immunodeposits. Extensive research has identified multiple genetic, immunological, and environmental factors contributing to disease development and progression. The pathogenesis of IgAN is considered a multifactorial process involving the formation of immune complexes wherein aberrantly O-glycosylated IgA1 is recognized as an autoantigen. Consequently, the clinical presentation of IgAN is highly variable, with a wide spectrum of manifestations ranging from isolated microscopic hematuria or episodic macroscopic hematuria to nephrotic-range proteinuria. Whereas some patients may exhibit a slowly progressive form of IgAN, others may present with a rapidly progressive glomerulonephritis leading to kidney failure. Development of the treatment for IgAN requires an understanding of the characteristics of the pathogenic IgA1-containing immune complexes that enter the glomerular mesangium and induce kidney injury. However, not all details of the mechanisms involved in the production of galactose-deficient IgA1 and immune-complex formation are fully understood. Here, we review what we have learned about the characteristics of nephritogenic IgA1 in the half-century since the first description of IgAN in 1968. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a devastating kidney disease and lacks effective therapeutic interventions. The present study was aimed to determine whether reconstituted high‐density lipoprotein (rHDL) ameliorated renal injury in eNOS−/−dbdb mice, a mouse model of DKD. Three groups of mice, wild type C57BLKS/J (non‐diabetes), eNOS−/−dbdb (diabetes), and eNOS−/−dbdb treated with rHDL (diabetes+rHDL) with both males and females were used. The rHDL nanoparticles were administered to eNOS−/−dbdb mice at Week 16 at 5 μg/g body weight in ~100 μL of saline solution twice per week for 4 weeks via retroorbital injection. We found that rHDL treatment significantly blunted progression of albuminuria and GFR decline observed in DKD mice. Histological examinations showed that the rHDLs significantly alleviated glomerular injury and renal fibrosis, and inhibited podocyte loss. Western blots and immunohistochemical examinations showed that increased protein abundances of fibronectin and collagen IV in the renal cortex of eNOS−/−dbdb mice were significantly reduced by the rHDLs. Taken together, the present study suggests a renoprotective effect of rHDLs on DKD. [ABSTRACT FROM AUTHOR]

Background: Apoptosis and oxidative stress in kidneys are critical players in acute kidney injury (AKI). Rehmapicrogenin, a monomeric compound extracted from Rehmanniae radix, has been found to possess nitric oxide inhibitory and anti‐inflammatory activities. Thus, this study aimed to investigate the roles and mechanisms of rehmapicrogenin in AKI. Methods: Lipopolysaccharide (LPS) was used to induce AKI‐like conditions. Cell survival conditions were detected by cell counting kit‐8 assays and flow cytometry. Several renal function markers including blood urea nitrogen, proteinuria, creatinine, and albumin were measured. Apoptosis and reactive oxygen species (ROS) production were examined by TUNEL and dihydroethidium staining, respectively. Haematoxylin–eosin staining and periodic acid‐Schiff staining were conducted to assess histopathological changes. Gene expression was evaluated by western blotting, commercially available kits and immunofluorescence staining. Results: For in vitro analysis, rehmapicrogenin inhibited the LPS‐induced podocyte apoptosis by activating the Nrf2/ARE pathway. For in vivo analysis, rehmapicrogenin improved renal functions in LPS‐induced mice. Additionally, rehmapicrogenin suppressed LPS‐induced podocyte apoptosis and oxidative stress in kidney tissues. Mechanistically, rehmapicrogenin activated the Nrf2/ARE pathway in LPS‐induced mice. Conclusion: Rehmapicrogenin relieves the podocyte injury and renal dysfunctions through activating the Nrf2/ARE pathway to inhibit apoptosis and oxidative stress. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a common complication after on-pump cardiac surgery, and previous studies have suggested that blood glucose is associated with postoperative AKI. However, limited evidence is available regarding intraoperative glycemic thresholds in cardiac surgery. The aim of this study was to explore the association between peak intraoperative blood glucose and postoperative AKI, and determine the cut-off values for intraoperative glucose concentration associated with an increased risk of AKI. The study was retrospective and single-centered. Adult patients in West China Hospital of Sichuan University who underwent on-pump cardiac surgery (n = 3375) were included. The primary outcome was the incidence of AKI. Multivariable logistic analysis using restricted cubic spline was performed to explore the association between intraoperative blood glucose and postoperative AKI. The incidence of AKI in the study population was 18.0% (607 of 3375). Patients who developed AKI had a significantly higher peak intraoperative glucose during the surgery compared to those without AKI. After adjustment for confounders, the incidence of AKI increased with peak intraoperative blood glucose (adjusted odds ratio, 1.08, 95% confidence interval 1.03, 1.12). Furthermore, it was demonstrated that the possibility of AKI was relatively flat till 127.8 mg/dL (7.1 mmol/L) glucose levels which started to rapidly increase afterward. Increased intraoperative blood glucose was associated with an increased risk of AKI. Among patients undergoing on-pump cardiac surgery, avoiding a high glucose peak (i.e., below 127.8 mg/dL [7.1 mmol/L]) may reduce the risk of postoperative AKI. [ABSTRACT FROM AUTHOR]

Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model. Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1β, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated. VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen. Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients. [ABSTRACT FROM AUTHOR]

Through improved insights into the increasing incidence and detrimental effects of acute kidney injury (AKI), its clinical relevance has become more and more apparent. Although treatment strategies for AKI have also somewhat improved, an adequate remedy still does not exist. Finding one is complicated by a multifactorial pathophysiology and by heterogeneity in the patient population. Alkaline phosphatase (ALP) has been suggested as a therapy for sepsis-associated AKI because of its protective effects against lipopolysaccharide (LPS)-induced inflammation and kidney injury in animals. However, its effectiveness as an AKI treatment has not been demonstrated definitively. Because the anti-inflammatory properties of ALP are likely not reliant on a direct effect on LPS itself, we postulate that other pathways are much more important in explaining the renoprotective properties ascribed to ALP. The re-evaluation of which properties of the ALP enzyme are responsible for the benefit seen in the lab is an important step in determining where the true potential of ALP as a treatment strategy for AKI in the clinic lies. In this review we will discuss how ALP can prevent activation of harmful pro-inflammatory receptors, redirect cell–cell signalling and protect barrier tissues, which together form the basis for current knowledge of the role of ALP in the kidney. With this knowledge in mind and by analysing currently available clinical evidence, we propose directions for new research that can determine whether ALP as a treatment strategy for AKI has a future in the clinical field. [ABSTRACT FROM AUTHOR]

Background and hypothesis Acute kidney injury (AKI) could progress to chronic kidney disease (CKD) and the AKI-CKD transition has major clinical significance. A growing body of evidence has unveiled the role of pyroptosis in kidney injury. We postulate that GSDMD and GSDME exert cumulative effects on the AKI-CKD transition by modulating different cellular responses. Methods We established an AKI-CKD transition model induced by folic acid in wildtype (WT), Gsdmd −/−, Gsdme −/−, and Gsdmd −/− Gsdme −/− mice. Tubular injury, renal fibrosis and inflammatory responses were evaluated. In vitro studies were conducted to investigate the interplay among tubular cells, neutrophils, and macrophages. Results Double deletion of Gsdmd and Gsdme conferred heightened protection against AKI, mitigating inflammatory responses, including the formation of neutrophil extracellular traps (NETs), macrophage polarization and differentiation, and ultimately renal fibrosis, compared with wildtype mice and mice with single deletion of either Gsdmd or Gsdme. Gsdme , but not Gsdmd deficiency, shielded tubular cells from pyroptosis. GSDME-dependent tubular cell death stimulated NETs formation and prompted macrophage polarization towards a pro-inflammatory phenotype. Gsdmd deficiency suppressed NETs formation and subsequently hindered NETs-induced macrophage-to-myofibroblast transition (MMT). Conclusion GSDMD and GSDME collaborate to contribute to AKI and subsequent renal fibrosis induced by folic acid. Synchronous inhibition of GSDMD and GSDME could be an innovative therapeutic strategy for mitigating the AKI-CKD transition. [ABSTRACT FROM AUTHOR]

The podocyte cytoskeleton determines the stability of podocyte structure and function, and their imbalance plays a pathogenic role in podocyte diseases. However, the underlying mechanism of podocyte cytoskeleton damage is not fully understood. Here, we investigate the specific role of cuproptosis in inducing podocyte cytoskeleton injury. In in vitro and in vivo studies, exposure to high levels of copper and adriamycin (ADR) caused significant increases in copper concentration in intracellular and renal tissue. Moreover, excessive accumulation of copper induced cuproptosis, resulting in the destruction of the podocyte cytoskeleton. However, inhibition of copper accumulation to reduce cuproptosis also significantly alleviated the damage of podocyte cytoskeleton. In addition, inhibition of cuproptosis mitigated ADR-induced mitochondrial damage as well as the production of reactive oxygen species and depolarization of mitochondrial membrane potential, and restored adenosine triphosphate (ATP) synthesis. Among the transcriptome sequencing data, the difference of CXCL5 (C-X-C motif chemokine ligand 5) was the most significant. Both high copper and ADR exposure can cause upregulation of CXCL5, and CXCL5 deletion inhibits the occurrence of cuproptosis, thereby alleviating the podocyte cytoskeleton damage. This suggests that CXCL5 may act upstream of cuproptosis that mediates podocyte cytoskeleton damage. In conclusion, cuproptosis induced by excessive copper accumulation may induce podocyte cytoskeleton damage by promoting mitochondrial dysfunction, thereby causing podocyte injury. This indicates that cuproptosis plays an important role in the pathogenesis of podocyte injury and provides a basis for seeking potential targets for the treatment of chronic kidney disease. NEW & NOTEWORTHY: Cuproptosis induced by excessive copper accumulation leads to podocyte cytoskeleton damage by promoting mitochondrial dysfunction, and CXCL5 acts as an upstream signal mediating the occurrence of cuproptosis. [ABSTRACT FROM AUTHOR]

Drug-induced kidney injury (DIKI) is a frequently reported adverse event, associated with acute kidney injury, chronic kidney disease, and end-stage renal failure. Prospective cohort studies on acute injuries suggest a frequency of around 14%–26% in adult populations and a significant concern in pediatrics with a frequency of 16% being attributed to a drug. In drug discovery and development, renal injury accounts for 8 and 9% of preclinical and clinical failures, respectively, impacting multiple therapeutic areas. Currently, the standard biomarkers for identifying DIKI are serum creatinine and blood urea nitrogen. However, both markers lack the sensitivity and specificity to detect nephrotoxicity prior to a significant loss of renal function. Consequently, there is a pressing need for the development of alternative methods to reliably predict drug-induced kidney injury (DIKI) in early drug discovery. In this article, we discuss various aspects of DIKI and how it is assessed in preclinical models and in the clinical setting, including the challenges posed by translating animal data to humans. We then examine the urinary biomarkers accepted by both the US Food and Drug Administration (FDA) and the European Medicines Agency for monitoring DIKI in preclinical studies and on a case-by-case basis in clinical trials. We also review new approach methodologies (NAMs) and how they may assist in developing novel biomarkers for DIKI that can be used earlier in drug discovery and development. [ABSTRACT FROM AUTHOR]

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