Renal Changes Research Articles

ShenQiWan ameliorates renal injury in type 2 diabetic mice by modulating mitochondrial fusion and endoplasmic reticulum stress.

Background: ShenQiWan is commonly used in traditional Chinese medicine for the treatment of diabetic nephropathy, which is closely related to mitochondrial fusion and endoplasmic reticulum stress. This study aimed to investigate the intervention effect and molecular mechanisms of ShenQiWan on renal injury in KKAy mice. Methods: C57BL/6J mice (11weeks old) were fed a regular diet upon arrival, while KKAy mice (11weeks old) were fed a high-fat diet upon arrival. At 12weeks of age, KKAy mice with random blood glucose ≥13.9mmol/L were identified as diabetic mice and randomly divided into the model group (n = 30) and the treatment group (n = 30), while C57BL/6J mice of 12weeks old (n = 30) served as the control group. The treatment group received daily aqueous decoction of ShenQiWan (13.5g/kg), while the control group and model group received daily equal amounts of saline from 12weeks old to 24weeks old. The general status of mice was observed regularly, and fasting blood glucose and 24-hour urine microalbumin were measured. Ten mice were euthanized in each group at the age of 16, 20, and 24weeks, serum samples were used for biochemical indexes and kidney tissues were used for morphological studies. GRP78, OPA1, MFN1, MFN2 mRNA and protein expression were detected by Real-time PCR, immunohistochemistry and Western blot. Results: The mice in the model group exhibited symptoms of lethargy, slow movement, obesity, polyuria and proteinuria. Morphological observation revealed pathological changes, including thickening of the glomerular basement membrane and interstitial fibrosis. After treatment with ShenQiWan, the fasting blood glucose level of KKAy mice was significantly reduced, urinary albuminuria was decreased, serum biochemical indexes were improved, renal tissue pathological changes were significantly alleviated. The results also showed a significant reduction in the expression of endoplasmic reticulum stress-related factor GRP78 and an increase in the expression of mitochondrial fusion-related factors OPA1, MFN1 and MFN2 after treatment with ShenQiWan. Conclusion: ShenQiWan can protect diabetic mice from renal damage by modulating mitochondrial fusion and alleviating endoplasmic reticulum stress, exerting its protective effects.

Short and long-term renal function changes with direct oral anticoagulants in elderly patients with atrial fibrillation

Abstract Background Atrial Fibrillation (AF) and chronic kidney disease (CKD) frequently coexist in elderly patient. Previous evidence showed that vitamin K antagonists (VKAs) may be associated with an accelerated decrease of estimated glomerular filtration rate (eGFR) compared to direct oral anticoagulants (DOACs). However, there is little evidence on DOACs in the elderly population and in real life settings; the evidence available to us comes from randomized clinical trials with younger populations. Purpose The main objective of this study was to investigate the medium to long term renal function changes in older AF patients treated with DOACs and VKAs. Methods Enrolled patients underwent 3 eGFR measurements during follow-up, and the between arms difference in eGFR lost over time was investigated by 1) the Linear Mixed Models (LMM) and 2) group-based trajectory model (GBTM) analyses. Analysis was done according to short-term (3.2 years) and long-term follow-up (6.7 years). During the study period 420 enrolled AF patients (77.0±6.0 years, 136 on VKAs and 284 on DOACs) underwent 1260 eGFR assessments. Results After a median follow-up of 4.9 years, in the whole sample eGFR decreased from 67.4±18.2 ml/min/1.73 m2 to 47.1±14.3 ml/min/1.73 m2, p<0.001. Patients on DOACs experienced a significantly lower eGFR decrease that those treated with VKAs (-21.3% vs -45.1%, p<0.001). The benefit of DOACs compared with VKAs was evident both in the short term (eGFR decline -6.6 (95% CI: -9.1 to -4.0) ml/min/1.73 m2 vs -19.9 (95% CI: -23.6 to -16.2) ml/min/1.73 m2 respectively) and in the long-term, (eGFR -13.5 (95% CI: -16.1 to -11.0) ml/min/1.73 m2 in DOACs group vs -34.2 (95% CI: -37.9 to -30.5) ml/min/1.73 m2), respectively). After stratifying our study population into 5 groups according to trajectories of renal function decline, from the first (lowest decline in eGFR) to the fifth (greatest decline in eGFR), the first trajectory consisted of 80% patients on DOACs therapy. Logistic regression showed that the group on DOACs therapy was 3.03- to 4.24-fold more likely to belong to the trajectory with less eGFR decline than the VKAs group. Conclusions In conclusion, DOACs were associated with less long term decline in renal function in elderly patients with AF compared with VKAs.

Impact of percutaneous coronary intervention on renal function in patients with coronary heart disease

The relationship between cardiac and renal function is complicated. The impact of percutaneous coronary intervention (PCI) on renal function in patients with coronary artery disease is still unclear. The current study sought to assess renal function change, including the time course of renal function, after elective PCI in patients with improved renal function and to identify renal function predictors of major adverse cardiovascular events. We examined data from 1572 CHD patients who had coronary angiography (CAG) or PCI in this retrospective cohort study. Patients receiving elective PCI (n=1240) and CAG (n=332) between January 2013 and December 2018 were included. Pre-PCI and procedural variables associated with post-PCI eGFR, change in renal function after post-PCI follow-up, and post-PCI eGFR association with major adverse cardiovascular events were investigated. Following the procedure, 88.7 percent of PCI group patients had unchanged or improved renal function. The treatment of PCI was found to independently correlate with IRF following coronary angiography in an analysis of patients undergoing PCI [OR 4.561 (95% CI:2 .556-8.139); p<0.001]. The area under the receiver operating characteristic (ROC) curve is 0.763 (model with the treatment of PCI). Improved renal function (IRF) and stable renal function were both associated with a lower risk of a major cardiovascular event.

MiR-497 Prevents Septic Kidney Injury and Improves Immune Function Through Inhibition of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) Pathway

Abnormal expression of miR-497 is related to the progression of septic renal injury. This study aimed to identify the protective effect of miR-497 on septic renal injury and immune function. We established a rat model of septic renal injury with sham-operated group and treated rats with culture solution of miR-497, gentianella acuta (positive control group), miR-497 plus JAK/STAT pathway agonist, and distilled water (model group). After treatment, urine output and renal histopathological changes were detected. Flow cytometry and RT-qPCR determined the levels of serum Scr, BUN, KIM-1, NGAL, IgG, IgA, and IgM, and evaluated the CD4+T, CD8+T, NK cell activity. Western blot assessed the activity of JAK/STAT signaling pathway. The model group and pathway agonist group had the highest 24-hour urine output, serum Scr, BUN, KIM-1, and NGAL levels, followed by miR-497 group and positive control group, and sham-operated group. The CD4+T, and NK cell activity was reduced with a drop in IgG, IgA, IgM levels in rats with septic renal injury, but treatment with miR-497 or gentianella acuta restored the cell activity and Ig levels and addition of JAK/STAT pathway agonist would further decrease the immune cell activity. There was no difference between the model group and pathway agonist group, miR-497 group and positive control group (p < 0.05). Following miR-497 group, and sham-operated group, the expression of miR-497 in model group, pathway agonist group, and positive control group was lowest (p < 0.05). As the expression of JAK and STAT did not vary among five groups (p > 0.05), we found highest expression of p-JAK and p-STAT levels in model group, positive control group, and pathway agonist group, and lowest expression in sham-operated group. miR-497 inhibits the activity of JAK/STAT signaling, up-regulates the activity of CD4+T, NK cells and levels of IgG, IgA, IgM, while inhibiting CD8+T cells activity to improve immune function. In conclusion, miR-497 attenuates septic kidney injury through inhibiting KIM-1 and NGAL expression, indicating that miR-497 and JAK/STAT pathways may be potential therapeutic targets for treating septic kidney injury.

Neutrophil Extracellular Traps Aggravate Contrast-Induced Acute Kidney Injury by Damaging Glomeruli and Peritubular Capillaries.

Contrast-induced acute kidney injury (CI-AKI) is considered to be the third leading cause of hospital-acquired kidney injury. Current studies mostly suggest that contrast agents mainly harm renal tubular epithelial cells, but we hypothesized that the development of CI-AKI should be the result of the interaction of renal vascular and tubular injury. First we constructed a CI-AKI mouse model and verified the success of the model by pathological injury and serum creatinine level. Immunohistochemistry, protein quantification and qRT-PCR were used to detect the location and level of expression of neutrophil extracellular traps (NETs) in the kidney. Then, we blocked the in vivo accumulation of NETs using GSK484 and DNase I and detected the expression of NETs and the damage of glomerular and peritubular capillaries. We first identified the presence of NETs in CI-AKI mice, and NETs were mainly accumulated in glomeruli and peritubular capillaries. The expression of NETs was positively correlated with the severity of CI-AKI kidney. After inhibition of NETs release or promotion of NETs degradation by drugs, renal vascular endothelial cell injury was reduced and renal pathological changes and creatinine levels were reversed in CI-AKI mice. In addition, inhibition of NETs reduced apoptosis and pyroptosis of renal cells and attenuated inflammation in vivo. These findings suggest that NETs are involved in the development of CI-AKI by damaging glomerular and peritubular capillary endothelial cells. This study will provide a new strategy for clinical prevention and treatment of CI-AKI.

Safe and Effective Blood Preservation Through Acute Normovolemic Hemodilution and Low-Dose Tranexamic Acid in Open Partial Hepatectomy.

In this study, we evaluated the efficacy of tranexamic acid (TXA) and acute normovolemic hemodilution (ANH) with 6% hydroxyethyl starch (130/0.4) in minimizing blood loss during open partial liver resection. Coagulation function was assessed using thromboelastography (TEG) and hemostasis tests, while renal function changes were tracked through serum creatinine values post-surgery. Thirty patients undergoing open partial liver resection were allocated to two groups: Group T received TXA + ANH, and Group A received ANH alone. Blood was drawn from the radial artery under general anesthesia. Both groups received peripheral vein injections of 6% hydroxyethyl starch 130/0.4. Group T additionally received intravenous TXA. Primary outcomes included blood loss and allogeneic blood transfusions. TEG assessed coagulation status and renal function was monitored. Group T demonstrated superior outcomes compared to Group A. Group T had significantly lower intraoperative blood loss (700 mL vs 1200 mL) and a lower bleeding rate per kilogram of body weight (13.3 mL/kg vs 20.4 mL/kg). Coagulation parameters favored Group T, with higher TEG maximum amplitude (55.91 mm vs 45.88 mm) and lower activated partial thromboplastin time (38.04 seconds vs 41.49 seconds). Neither group experienced acute renal injury or kidney function deficiency during hospitalization. TXA and ANH in a small dose during liver resection stabilize clotting, reduce blood loss by 6% compared to hydroxyethyl starch 130/0.4, and do not affect renal function.

Acute toxicity study of the isomeric mixture of alpha and beta amyrin from Protium heptaphyllum (Aubl.) Marchand

The isomeric mixture of alpha and beta amyrin (AMY), present in the resin of Protium heptaphyllum, is popularly used as anti-inflammatory and anti-ulcer. The literature has been demonstrating pharmacological activities of these triterpenes in the central and peripheral nervous systems, and in the gastrointestinal and immunological systems. This study traces a toxicological profile of amyrin, aiming to provide information that may clarify its safety. Nine female Wistar rats (170 to 200 g) were divided into three groups of three animals each (control, amyrin 300 and amyrin 2000 mg kg-1, p.o.), which were evaluated by protocols preconized by the Organization for Economic Co-operation and Development (OECD). Open field Test and Malone Hippocratic Screening Scale were performed. AMY, mostly at 2000 mg kg-1, reduced the number of crossings by 57% vs. saline (22.67 ± 2.40) and the number of rearing by 53% vs. saline (42.67 ± 2.96), but increased the number of grooming by 26% vs. saline (1.66 ± 0.33). AMY (2000 mg kg-1) increased the serum glucose by 77% vs. saline (126.70 ± 4.33 mg dL-1), triglycerides by 50% vs. saline (78.67 ± 2.18 mg dL-1) and uric acid by 65% vs. saline (0.73 ± 0.03 mg dL-1). AMY induced vascular congestion and hemorrhage in the liver, spleen and cerebral cortex. Renal changes (cellular damage, inflammatory infiltrate, tubular protein deposition and glomeruli atrophy) were also seen. In conclusion, AMY decreased rat locomotor activity, caused minor biochemical changes, and altered the morphology of the kidney. The present study may contribute to deepen the knowledge about the safety of AMY, aiming the development of a novel pharmacological product.

Investigation of the effects of oral dapoxetine on kidney function and histopathologic changes in male rats; an animal study and future perspectives

Introduction: Dapoxetine is a novel therapeutic agent employed in treating specific diseases. However, its potential impact on renal excretion processes has yet to be thoroughly investigated, necessitating further exploration in this study. Objectives: This research aimed to assess the effects of dapoxetine on renal function and explore any potential disturbances in kidney excretion processes. Materials and Methods: In this study, 32 male Albino rats weighing between 200-250 g were utilized. The rats were randomly divided into four groups. Group one served as the control and received a normal diet, while groups two to four were administered dapoxetine through gavage at doses of 1 mg/kg, 2 mg/kg, and 4 mg/kg, respectively. The study evaluated blood urea nitrogen (BUN), and serum creatinine levels and examined renal pathological changes in the rats. Results: The results demonstrated a significant increase in average BUN levels in group four compared to other groups (P<0.001). For creatinine, group three displayed higher levels compared to other groups. However, the difference was not statistically significant (P>0.05). Importantly, no indications of apoptosis, necrosis, edema, hydropic degeneration, or glomerular changes were observed in any of the renal cells from the rat groups. Conclusion: Dapoxetine administration led to changes in BUN and creatinine levels; however, it did not adversely affect the renal cells’ pathological outcomes. These results suggest that dapoxetine could be considered for use in the future treatment of certain diseases, considering its minimal impact on renal function. Further investigations and clinical trials are warranted to corroborate these findings and inform medical decision-making.

Rutin ameliorate PFOA induced renal damage by reducing oxidative stress and improving lipid metabolism

Perfluorooctanoic acid (PFOA) is a persistent environmental pollutant that can accumulate in the kidneys and eventually cause kidney damage. Rutin (RUTIN) is a natural flavonoid with multiple biological activities, and its use in against kidney damage has been widely studied in recent years. It is not yet known whether rutin protects against kidney damage caused by PFOA. In this study, 30 ICR mice were randomly divided into three groups: CTRL group, PFOA group and PFOA+RUTIN group. The mice were fed continuously by gavage for 28 days. Renal pathological changes were assessed by HE and PASM staining, and serum renal function and lipid indicators were measured. RNA-seq and enrichment analysis using GO, KEGG and PPI to detect differential expression of genes in treatment groups. Kidney tissue protein expression was determined by Western blot. Research has shown that rutin can improve glomerular and tubular structural damage, and increase serum CREA, HDL-C levels and decrease LDH, LDL-C levels. The expression of AQP1 and ACOT1 was up-regulated after rutin treatment. Transcriptomic analysis indicated that PFOA and rutin affect the transcriptional expression of genes related to lipid metabolism and oxidative stress, and may affected by PI3K-Akt, PPAR, NRF2/KEAP1 signaling pathways. In conclusion, rutin ameliorated renal damage caused by PFOA exposure, and this protective effect may be exerted by ameliorating oxidative stress and regulating lipid metabolism.

Targeted inhibition of CX3CL1 limits podocytes ferroptosis to ameliorate cisplatin-induced acute kidney injury

BackgroundIt is widely acknowledged that cisplatin-induced nephrotoxicity hinders its efficacy during clinical therapy. Effective pharmaceutical interventions for cisplatin-induced acute kidney injury (Cis-AKI) are currently lacking. Prior studies have implicated the chemokine CX3CL1 in the development of lipopolysaccharide-induced AKI; however, its specific role in Cis-AKI remains uncertain. This research aimed to comprehensively characterize the therapeutic impact and mechanism of CX3CL1 inhibition on Cis-AKI.MethodsThis study employed an in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes. Kidney pathological changes were assessed using hematoxylin–eosin (HE) and Periodic-Schiff (PAS) staining. Transcriptome changes in mouse kidney tissue post-cisplatin treatment were analyzed through RNA sequencing (RNA-seq) datasets. Evaluation parameters included the expression of inflammatory markers, intracellular free iron levels, ferroptosis-related proteins—solute carrier family 7 member 11 (SLC7A11/XCT) and glutathione peroxidase 4 (GPX4)—as well as lipid peroxidation markers and mitochondrial function proteins. Mitochondrial morphological changes were visualized through transmission electron microscopy. The impact of CX3CL1 on the glucose-regulated protein 78/eukaryotic translation initiation factor 2A/CCAAT enhancer binding protein-homologous protein (GRP78/eIF2α/CHOP) and hypoxia-inducible factor 1-alpha/heme oxygenase-1 (HIF1A/HO-1) pathways in Cis-AKI was assessed via Western Blot and Immunofluorescence experiments, both in vivo and in vitro.ResultsKidney CX3CL1 levels were elevated following cisplatin injection in wild-type (WT) mice. Cisplatin-treated CX3CL1-Knockout mice exhibited reduced renal histological changes, lowered blood creatinine (Cre) and blood urea nitrogen (BUN) levels, and decreased expression of inflammatory mediators compared to cisplatin-treated WT mice. RNA-seq analysis revealed the modulation of markers associated with oxidative stress and lipid metabolism related to ferroptosis in the kidneys of mice with Cis-AKI. Both the in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes demonstrated that CX3CL1 inhibition could mitigate ferroptosis. This effect was characterized by alleviated intracellular iron overload, malondialdehyde (MDA) content, and reactive oxygen species (ROS) production, alongside increased glutathione/glutathione disulfide ratio, superoxide dismutase (SOD), XCT, and GPX4 activity. CX3CL1 inhibition also ameliorated mitochondrial dysfunction and upregulated expression of mitochondrial biogenesis proteins-uncoupling protein (UCP), mitofusin 2 (Mfn2), and peroxisome proliferators-activated receptor γ coactivator l-alpha (PGC1α)-both in vivo and in vitro. Furthermore, CX3CL1 inhibition attenuated cisplatin-induced endoplasmic reticulum (ER) stress in podocytes. Notably, CX3CL1 inhibition reduced cisplatin-induced expression of HIF-1α and HO-1 in vivo and in vitro.ConclusionOur findings suggest that CX3CL1 inhibition exerts therapeutic effects against Cis-AKI by suppressing podocyte ferroptosis.

Acteoside protects podocyte against apoptosis through regulating AKT/GSK-3β signaling pathway in db/db mice

BackgroundPodocyte apoptosis is one of the important pathological mechanisms of diabetic kidney disease (DKD). Acteoside (Act), a major active component of Rehmannia glutinosa leaves total glycoside, has a strong renoprotective action. Our study aims to demonstrate Act’s renoprotective actions in db/db mice.MethodsWe adopted C57BLKS/J db/db mice as DKD animal models. After 8 weeks of Act administration, the 24-hour urine albumin, renal function index, and blood lipid levels were quantified using matching kits. Renal pathology was evaluated by HE and PAS staining. The podocyte damage and apoptosis-related signaling pathway were observed by using immunohistochemistry, western blot, and TUNEL staining.ResultsThe albuminuria of db/db mice was reduced from 391 ug/24 h to 152 ug/24 h, and renal pathology changes were alleviated after Act administration. The western blot and immunohistochemistry showed that Act treatment upregulated the synaptopodin and podocin expression compared with db/db mice, while the TUNEL staining indicated podocyte apoptosis was inhibited. The B-cell lymphoma-2 (Bcl-2) level was upregulated in the Act group, but cleaved caspase-3 and Bcl-2 associated X protein (Bax) expression declined, while the protein kinase B/glycogen synthase kinase-3β (AKT/GSK-3β) signaling pathway was repressed.ConclusionsBy inhibiting the AKT/GSK-3β signaling pathway, Act protected podocytes from apoptosis, decreasing the urine albumin of db/db mice and delaying the course of DKD.

TRF-003634 alleviates adriamycin-induced podocyte injury by reducing the stability of TLR4 mRNA.

Podocyte injury plays a key role in the production of proteinuria and is closely related to the progression of chronic kidney disease (CKD). Alleviating podocyte injury is beneficial to prevent the occurrence and development of CKD. tRNA-derived RNA fragments (tRFs) are associated with podocytes injury processes such as protein binding, cell adhesion, synapses, the actin cytoskeleton. Our previous data showed that tRF-003634 tightly correlated with podocyte injury, while its effect remains unclear. This study aimed to investigate the role of tRF-003634 in podocyte injury and the potential mechanisms. The expression level of tRF-003634, nephrin, podocin and tRF-003634 targeted toll-like receptor 4 (TLR4) in podocytes and kidney tissues were examined by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The biochemical indices were monitored and renal pathological changes were assessed by hematoxylin and eosin PAS staining. Furthermore, potential target genes of tRF-003634 were screened using high-throughput mRNA sequencing, and then confirmed by RNA pulse-chase analysis. The results showed that tRF-003634 was downregulated in adriamycin (Adr)-induced podocyte injury. Overexpression of tRF-003634 increased the expression of nephrin and podocin in vivo and in vitro and alleviated podocyte injury. Meanwhile, overexpression of tRF-003634 alleviated proteinuria and renal pathological damage. In addition, high-throughput sequencing after overexpression of tRF-003634 showed that TLR4 might be a downstream target gene. tRF-003634 can alleviate podocyte injury by reducing the stability of TLR4 mRNA, possibly by competing with TLR4 mRNA to bind to YTH domain-containing protein 1 (YTHDC1). In conclusion, tRF-003634 was underexpressed in Adr-induced podocyte injury, and its overexpression alleviated podocyte injury in vitro and in vivo by reducing the stability of TLR4 mRNA.

Vancomycin removal and pharmacokinetics during accelerated venovenous hemofiltration.

Vancomycin pharmacokinetics are affected by renal replacement therapy and physiologic changes in critically ill patients. Literature regarding vancomycin removal and pharmacokinetics during accelerated venovenous hemofiltration (AVVH), a form of prolonged intermittent renal replacement therapy, is limited. To describe the removal and pharmacokinetics of vancomycin during AVVH. Eighteen critically ill adults receiving vancomycin and AVVH were included. Vancomycin serum concentrations were obtained within 4 h before and 2-6 h after the AVVH session. Patients' serum concentrations were plotted against time, and individual pharmacokinetic parameters were determined by a one-compartmental analysis. Continuous data are reported as a median (interquartile range [IQR]) and categorical data as a percentage. The median AVVH effluent rate was 39.3 mL/kg/h (IQR 35.5-48 mL/kg/h) for a duration of 9 h (IQR 8-9.75 h). AVVH decreased vancomycin concentrations by 29.8% (IQR 24.9%-35.9%), at a rate of 3.4% per hour (IQR 3.1%-4.3% per hour) of AVVH. The vancomycin elimination rate constant and half-life were 0.039 h-1 (IQR 0.036-0.053 h-1 ) and 17.6 h (IQR 13.1-18.8 h), respectively. The area under the curve during AVVH was 171.7 mg*h/L (IQR 149.1-190 mg*h/L). The volume of distribution in 10 patients was 1 L/kg (IQR 0.73-1.1 L/kg). After AVVH, vancomycin 1000 mg (IQR 750-1000 mg) was needed to maintain a serum trough concentration ≥15 mg/L. Vancomycin is significantly removed by AVVH, which requires supplemental dosing after completion of the AVVH session to maintain desired serum concentrations. Therapeutic drug monitoring of vancomycin serum concentrations is recommended for patients undergoing AVVH.

Dioscin Mediated IgA Nephropathy Alleviation by Inhibiting B Cell Activation In Vivo and Decreasing Galactose-Deficient IgA1 Production In Vitro.

The increase of circulating galactose-deficient IgA1 (Gd-IgA1) is caused by excessive activation of IgA-positive secretory cells in the process of mucosal immune responses, which is a critical link in the pathogenesis of IgA nephropathy (IgAN). Peyer's patch, the prominent place where B lymphocytes are transformed into IgA-secreting plasma cells, is the primary source of IgA. In addition, the lower expression of core 1β-1,3-galactosyltransferase (C1GalT1) and its molecular chaperone, C1GalT1-specific molecular chaperone (Cosmc), is related to abnormal glycosylation of IgA1 in IgAN patients. Our clinical experience shows that Dioscoreae Nipponicae Rhizoma's (DNR) herbal medicine can relieve proteinuria and hematuria and improve renal function in IgAN patients. Dioscin (DIO) is one of the main active ingredients of DNR, which has various pharmacological activities. This study explores DIO's possible mechanism in treating IgAN.The IgAN model mouse was established by mucosal immune induction. The mice were divided into the control, model, and DIO gavage groups. The glomerular IgA deposition in mice, renal pathological changes, and B cell markers CD20 and CXCR5 expression in Peyer's patch were detected by immunofluorescence and immunohistochemistry. After lipopolysaccharide (LPS) stimulation, DIO's effects on DAKIKI cells proliferation, IgA and Gd-IgA1 secretion, C1GalT1, and Cosmc expression were studied by cell counting kit-8 (CCK-8) assay, enzyme-linked immunosorbent assay (ELISA) test, quantitative real-time polymerase chain reaction (QRT-PCR), and western blotting (WB). In in vivo studies, IgA deposition accompanied by glomerular mesangial hyperplasia and increased expression of CD20 and CXCR5 in Peyer's patch in the IgAN model mouse was alleviated by DIO. In vitro studies showed 0.25 µg/mL to 1.0 µg/mL DIO inhibited LPS-induced DAKIKI cell proliferation, IgA and Gd-IgA1 secretion, and up-regulated the mRNA and protein expression of C1GalT1 and Cosmc. This study demonstrates that DIO may reduce Gd-IgA1 production by inhibiting excessive activation of IgA-secreting cells and up-regulating C1GALT1/Cosmc expression.

Single and combined effect of fluoride and hardness of drinking water on nephrotoxicity: <em>in-vivo</em> study using Wistar rats as an animal model

Drinking water in areas with a high prevalence of chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka is known to have high concentrations of fluoride and hardness. The present study evaluated the individual and combined effects of water hardness and fluoride on potential nephrotoxicity, using Wistar rats as an animal model. Thirty-five Wistar rats were randomly assigned into five groups (n=7). Test groups F, H, RL, and RH were given de-ionized water containing 1.5 mg/L fluoride, 200 mg/L hardness, 1.5:200 mg/L fluoride: hardness, and 5:800 mg/L fluoride: hardness respectively, while control group C was given de-ionized water. Body weight and daily water consumption were measured. Serum creatinine, urine creatinine, and urinary biomarker KIM-1 were analyzed. Histopathological changes in the kidneys were observed. There were no significant differences in body weights (p>0.05) while daily water consumption was reduced significantly in the test groups RL and RH (p<0.05). A significant increment in serum creatinine in the RL and RH groups (p<0.05), and a significant reduction in urine creatinine in the F, H, RL and RH groups (p<0.05), were recorded compared to the control. However, the highest magnitude of the effect on serum creatinine and urine creatinine was recorded in the RL group. Significant increment in KIM-1 levels were recorded in the RH group (p<0.05) while the RH group indicated a more rapid increment from the 28th day. When considering histopathology, renal tubular changes were observed in the test groups. The individual and combined effects of water hardness and fluoride may contribute to the aetiology of CKDu in Sri Lanka.

DPP-4i versus SGLT2i as modulators of PHD3/HIF-2α pathway in the diabetic kidney

RationaleRenal hypoxia is one of the currently highlighted pathophysiologic mechanisms of diabetic nephropathy (DN). Both hypoxia-inducible factor-1α (HIF-1α) and HIF-2α are major regulators of renal adaptive responses to hypoxia. ObjectivesThis study aims to compare the effects of vildagliptin (a dipeptidyl peptidase-IV inhibitor, DPP-4i) and empagliflozin (a sodium-glucose cotransporter 2 inhibitor, SGLT2i) on the differential expression of renal HIF-1α/2α. Tissue expression of prolylhydroxylase 3 (PHD3), a key regulator of HIF-2α stability, was also highlighted in a diabetic nephropathy rat model. Type 1 diabetes mellitus was induced and diabetic rats were treated with either Vildagliptin or Empagliflozin (10 mg/kg/d each) for 12 weeks. Improvements in the kidney functional and histopathological parameters were addressed and correlated to changes in the renal expression of HIF-1α/2α, and PHD3. Urinary KIM-1 concentration was tested as a correlate to HIF pathway changes. FindingsBoth vildagliptin- and empagliflozin-treated groups exhibited significant improvement in the functional, pathological, and ultra-structural renal changes induced by chronic diabetes. Compared to the untreated group, renal gene expression of HIF-1α was decreased while that of HIF-2α was increased in both treated groups, with significantly greater effects observed with SGLT2i. Renal PHD3 immune-reactivity was also decreased by both drugs, again with better efficacy for the SGLT2i. Importantly, improvements in the diabetic kidney biochemical and structural biomarkers were significantly correlated to PHD3 reductions and HIF-2α increments. ConclusionsBoth DPP-4i and SGLT2i could delay the progression of DN through their differential modulating effects on the PHD3/ HIF-2α pathway with significantly better efficacy for SGLT2i.

An integrated machine learning predictive scheme for longitudinal laboratory data to evaluate the factors determining renal function changes in patients with different chronic kidney disease stages.

Chronic kidney disease (CKD) is a global health concern. This study aims to identify key factors associated with renal function changes using the proposed machine learning and important variable selection (ML&IVS) scheme on longitudinal laboratory data. The goal is to predict changes in the estimated glomerular filtration rate (eGFR) in a cohort of patients with CKD stages 3-5. A retrospective cohort study. A total of 710 outpatients who presented with stable nondialysis-dependent CKD stages 3-5 at the Shin-Kong Wu Ho-Su Memorial Hospital Medical Center from 2016 to 2021. This study analyzed trimonthly laboratory data including 47 indicators. The proposed scheme used stochastic gradient boosting, multivariate adaptive regression splines, random forest, eXtreme gradient boosting, and light gradient boosting machine algorithms to evaluate the important factors for predicting the results of the fourth eGFR examination, especially in patients with CKD stage 3 and those with CKD stages 4-5, with or without diabetes mellitus (DM). Subsequent eGFR level after three consecutive laboratory data assessments. Our ML&IVS scheme demonstrated superior predictive capabilities and identified significant factors contributing to renal function changes in various CKD groups. The latest levels of eGFR, blood urea nitrogen (BUN), proteinuria, sodium, and systolic blood pressure as well as mean levels of eGFR, BUN, proteinuria, and triglyceride were the top 10 significantly important factors for predicting the subsequent eGFR level in patients with CKD stages 3-5. In individuals with DM, the latest levels of BUN and proteinuria, mean levels of phosphate and proteinuria, and variations in diastolic blood pressure levels emerged as important factors for predicting the decline of renal function. In individuals without DM, all phosphate patterns and latest albumin levels were found to be key factors in the advanced CKD group. Moreover, proteinuria was identified as an important factor in the CKD stage 3 group without DM and CKD stages 4-5 group with DM. The proposed scheme highlighted factors associated with renal function changes in different CKD conditions, offering valuable insights to physicians for raising awareness about renal function changes.

Association of metabolic syndrome and chronic kidney disease.

The prevalence of kidney disease is increasing rapidly worldwide, reflecting rising rates of obesity, diabetes, and associated metabolic syndrome (MetS). Chronic kidney disease and related comorbidities such as obesity, diabetes, and hypertension place a significant financial burden on healthcare systems. Despite the widespread use of RAAS inhibitors, intensive blood pressure and glycemic control, and newer therapeutic options consisting of sodium/glucose cotransporter-2 (SGLT-2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists, a significant risk of progression to end-stage renal disease remains in the high-risk obese and diabetic population. The MetS is a cluster of cardiovascular risk factors that adversely affect the development and progression of chronic kidney failure. According to the criteria of the World Health Organization, it is defined by visceral adiposity, impaired glucose tolerance or insulin resistance, atherogenic dyslipidemia, raised blood pressure, and microalbuminuria with a albumin-to-creatinine ratio ≥30 mg/g. At molecular level MetS is marked by a proinflammatory state and increased oxidative stress leading to various pathophysiological changes causing endothelial dysfunction and a hypercoagulable state. Because the kidney is a highly vascularized organ, it is especially susceptible for those microvascular changes. Therefore, the MetS and its individual components are associated with the premature development, acceleration, and progression of chronic kidney disease. Therefore, it is becoming increasingly important to elucidate the underlying mechanisms of MetS-associated chronic kidney disease in order to develop new strategies for preventing and slowing the progression of renal disease. In this review, we will elucidate (i) the renal structural, hemodynamic, and metabolic changes that occur in obesity and obesity-related kidney injury; (ii) the clinicopathological characteristics of obesity-related kidney injury, primarily focusing on obesity-associated glomerulopathy; (iii) the potential additional factors or predisposing factors that may turn patients more susceptible to renal structural or functional compensatory failure and subsequent injury.

Dynamic Changes in the Renal Function of Acute Myocardial Infarction Patients with Reduced eGFR After Emergency Percutaneous Coronary Intervention.

Renal dysfunction greatly influences decision-making for emergency percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI). This observational study investigated renal function changes and risk factors for renal injury in patients with AMI with reduced estimated glomerular filtration rate (eGFR) who underwent emergency PCI. The study included 85 patients with AMI with decreased eGFR who underwent emergency PCI, categorized into stage 2, 3, and 4 chronic kidney disease groups. Baseline data, laboratory indicators, coronary characteristics, and serum creatinine concentration were monitored at multiple time points. Renal injury was defined using two criteria: an increase in serum creatinine level by 0.3 mg/dL or a 50% increase from baseline. During the 1-year follow-up, renal injury incidence varied from 1.18% to 15.29%. The pattern showed an increasing trend in the 1st week after PCI, peaking at 1 week, followed by a decrease at 3 months, and another increase at one year. Low basal eGFR, high contrast agent dosage, and diabetes were associated with renal injury according to logistic regression analysis. The eGFR cutoff value of 35.475 mL/minute·1.73 m2 had a sensitivity of 83.05% and specificity of 57.69% for predicting renal injury based on receiver operating characteristic curve analysis. In summary, patients with AMI with basal eGFR lower than 35.475 mL/minute·1.73 m2 have a higher risk of renal injury after PCI. These findings emphasize the importance of assessing renal function and considering associated risk factors when deciding on emergency PCI for AMI with reduced eGFR.

Preventive Action of Beta-Carotene against the Indoxyl Sulfate-Induced Renal Dysfunction in Male Adult Zebrafish via Regulations of Mitochondrial Inflammatory and β-Carotene Oxygenase-2 Actions.

Indoxyl sulfate (IS) is a metabolic byproduct of indole metabolism. IS readily interacts with the mitochondrial redox metabolism, leading to altered renal function. The β-carotene oxygenase-2 (BCO2) enzyme converts carotenoids to intermediate products. However, the role of β-carotene (BC) in IS-induced renal dysfunction in zebrafish and their modulatory action on BCO2 and mitochondrial inflammations have not been explored yet. Hence, the present study is designed to investigate the role of BC in the attenuation of IS-induced renal dysfunction via regulations of mitochondrial redox balance by BCO2 actions. Renal dysfunction was induced by exposure to IS (10 mg/L/hour/day) for 4 weeks. BC (50 and 100 mg/L/hour/day) and coenzyme Q10 (CoQ10; 20 mg/L/hour/day) were added before IS exposure. BC attenuated the IS-induced increase in blood urea nitrogen (BUN) and creatinine concentrations, adenosine triphosphate (ATP), and complex I activity levels, and the reduction of renal mitochondrial biomarkers, i.e., BCO2, superoxide dismutase-2 (SOD2), glutathione peroxidase-1 (GPX1), reduced and oxidized glutathione (GSH/GSSG) ratio, and carbonylated proteins. Moreover, renal histopathological changes were analyzed by the eosin and hematoxylin staining method. As a result, the administration of BC attenuated the IS-induced renal damage via the regulation of mitochondrial function.