Kidney Injury Molecule-1 Research Articles

Distal convoluted tubule-specific disruption of the COP9 signalosome but not its regulatory target cullin 3 causes tubular injury.

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.

Understanding Cisplatin Pharmacokinetics and Toxicodynamics to Predict and Prevent Kidney Injury.

Cisplatin is a common platinum-based chemotherapeutic that induces acute kidney injury (AKI) in about 30% of patients. Pharmacokinetic/toxicodynamic (PKTD) models of cisplatin-induced AKI have been used to understand risk factors and evaluate potential mitigation strategies. While both traditional clinical biomarkers of kidney function [e.g. serum creatinine (SCr), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl)] and newer subclinical biomarkers of kidney injury [e.g. urinary kidney injury molecule 1 (KIM-1), beta-2 microglobulin (B2M), neutrophil gelatinase-associated lipocalin (NGAL), calbindin, etc.] can be used to detect cisplatin-induced AKI, published PKTD models are limited to using only traditional clinical biomarkers. Previously identified risk factors for cisplatin nephrotoxicity have included dose, age, sex, race, body surface area, genetics, concomitant medications, and comorbid conditions. However, the relationships between concentrations and PK of platinum and biomarkers of kidney injury have not been well elucidated. This review discusses the evaluation of cisplatin-induced nephrotoxicity in clinical studies, mouse models, and in vitro models, and examines the available human PK and TD data. Improved understanding of the relationships between platinum PK and TD, in the presence of identified risk factors, will enable the prediction and prevention of cisplatin kidney injury. Significance Statement As cisplatin treatment continues to cause AKI in a third of patients, it is critical to improve the understanding of the relationships between platinum PK and nephrotoxicity as assessed by traditional clinical and contemporary subclinical TD markers of kidney injury. Prediction and prevention of cisplatin-induced nephrotoxicity will be advanced by the evolving development of PKTD models that incorporate kidney injury biomarkers with enhanced sensitivity and include covariates that can impact risk of developing cisplatin-induced AKI.

Amelioration Potency of a Nano-Therapeutic Drug in Rats with Uninephrectomy and Cisplatin-induced Toxicity

While physicians describe drugs to treat diseases, these medications may have cytotoxic effects on certain organs, necessitating the use of some drugs to ameliorate such adverse effects. The study was conducted to investigate the protective behavior of nanoemulsified sodium salicylate on uninephrectomized rats injected with cisplatin to induce nephrotoxicity. Fifty adult male albino rats, aged five weeks and weighing approximately 100-120 g, were divided into five groups. The first group received 200 mg/kg/day i.p normal saline for 30 days. The second group was administrated 200 mg/kg/day of nanoemulsified salt of salicylic acid for 30 days. The third group, comprising uninephrectomized rats, was injected with two doses of cisplatin (20 mg/kg body weight) on alternate days from the start of the experiment to induce nephrotoxicity. The fourth group, also uninephrectomized, received 200 mg/kg/day i.p of nanoemulsified sodium salicylate for 30 days. The fifth group, uninephrectomized and treated with 200 mg/kg/day sodium salicylate nanoemlusion for 21 days, was subsequently injected with two doses of cisplatin, followed by continued nanoemulsified sodium salicylate treatment until day 30 from the start of the study. The results showed a significant increase in tissue inhibitor metalloproteinase 1 (TIMP-1), Hyaluronic acid (HA), malondialdehyde, kidney injury molecule -1(KIM-1), and nitric oxide in the nephrotoxic group injected with cisplatin compared to the control group. Additionally, there was an elevation in the mRNA expression of nephrotoxic group with uninephrectomy. However, nephrotoxic rats treated with nanoemulsified sodium salicylate exhibited only a modest increase in TIMP-1, HA, and KIM-1 levels, along with elevated expressions of podocin and nephrin compared to the healthy control group. These findings suggest that nanoemulsified sodium salicylate exerts a protective effect against cisplatin-induced nephrotoxicity in uninephrectomized.

Antidiabetic and Antihyperlipidemic Activities and Molecular Mechanisms of Phyllanthus emblica L. Extract in Mice on a High-Fat Diet.

We planned to explore the protective activities of extract of Phyllanthus emblica L. (EPE) on insulin resistance and metabolic disorders including hyperlipidemia, visceral obesity, and renal dysfunction in high-fat diet (HFD)-progressed T2DM mice. Mice treatments included 7 weeks of HFD induction followed by EPE, fenofibrate (Feno), or metformin (Metf) treatment daily for another 4-week HFD in HFD-fed mice. Finally, we harvested blood to analyze some tests on circulating glycemia and blood lipid levels. Western blotting analysis was performed on target gene expressions in peripheral tissues. The present findings indicated that EPE treatment reversed the HFD-induced increases in blood glucose, glycosylated HbA1C, and insulin levels. Our findings proved that treatment with EPE in HFD mice effectively controls hyperglycemia and hyperinsulinemia. Our results showed that EPE reduced blood lipid levels, including a reduction in blood triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA); moreover, EPE reduced blood leptin levels and enhanced adiponectin concentrations. EPE treatment in HFD mice reduced BUN and creatinine in both blood and urine and lowered albumin levels in urine; moreover, EPE decreased circulating concentrations of inflammatory NLR family pyrin domain containing 3 (NLRP3) and kidney injury molecule-1 (KIM-1). These results indicated that EPE displayed antihyperglycemic and antihyperlipidemic activities but alleviated renal dysfunction in HFD mice. The histology examinations indicated that EPE treatment decreased adipose hypertrophy and hepatic ballooning, thus contributing to amelioration of lipid accumulation. EPE treatment decreased visceral fat amounts and led to improved systemic insulin resistance. For target gene expression levels, EPE enhanced AMP-activated protein kinase (AMPK) phosphorylation expressions both in livers and skeletal muscles and elevated the muscular membrane glucose transporter 4 (GLUT4) expressions. Treatment with EPE reduced hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) expressions to suppress glucose production in the livers and decreased phosphorylation of glycogen synthase kinase 3β (GSK3β) expressions to affect hepatic glycogen synthesis, thus convergently contributing to an antidiabetic effect and improving insulin resistance. The mechanism of the antihyperlipidemic activity of EPE involved a decrease in the hepatic phosphorylation of mammalian target of rapamycin complex C1 (mTORC1) and p70 S6 kinase 1 (S6K1) expressions to improve insulin resistance but also a reduction in hepatic sterol regulatory element binding protein (SREBP)-1c expressions, and suppression of ACC activity, thus resulting in the decreased fatty acid synthesis but elevated hepatic peroxisome proliferator-activated receptor (PPAR) α and SREBP-2 expressions, resulting in lowering TG and TC concentrations. Our results demonstrated that EPE improves insulin resistance and ameliorates hyperlipidemia in HFD mice.

Transition from acute kidney injury to chronic kidney disease: mechanisms, models, and biomarkers.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are increasingly recognized as interconnected conditions with overlapping pathophysiological mechanisms. This review examines the transition from AKI to CKD, focusing on the molecular mechanisms, animal models, and biomarkers essential for understanding and managing this progression. AKI often progresses to CKD due to maladaptive repair processes, persistent inflammation, and fibrosis, with both conditions sharing common pathways involving cell death, inflammation, and extracellular matrix (ECM) deposition. Current animal models, including ischemia-reperfusion injury (IRI) and nephrotoxic damage, help elucidate these mechanisms but have limitations in replicating the complexity of human disease. Emerging biomarkers such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and soluble tumor necrosis factor receptors (TNFRs) show promise in early detection and monitoring of disease progression. This review highlights the need for improved animal models and biomarker validation to better mimic human disease and enhance clinical translation. Advancing our understanding of the AKI-to-CKD transition through targeted therapies and refined research approaches holds the potential to significantly improve patient outcomes.

Comprehensive biomarker assessment for predicting severe acute kidney injury and need of kidney replacement therapy in liver transplantation patients

Background Renal dysfunction is a common complication following liver transplantation (LT). This study aimed to determine whether a comprehensive assessment of kidney function using nineteen serum and urinary biomarkers (BMs) within the first 48 h post-LT could enhance the prediction of severe acute kidney injury (AKI) and the need of kidney replacement therapy (KRT) during the first postoperative week. Methods Blood and urine (U) samples were collected during the pre- and postoperative periods. Nineteen BMs were evaluated to assess kidney health in the first 48 h after LT. Classification and regression tree (CART) cross-validation identified key predictors to determine the best BM combination for predicting outcomes. Results Among 100 LT patients, 36 developed severe AKI, and 34 required KRT within the first postoperative week. Preoperative assessment of U neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP) predicted the need for KRT with 75% accuracy. The combined assessment of U osmolality (OSM), U kidney injury molecule 1 (KIM-1), and tissue inhibitor of metalloproteinase (TIMP-1) within 48 h post-LT predicted severe AKI with 80% accuracy. U-OSM alone, measured within 48 h post-LT, had an accuracy of 83% for predicting KRT need, outperforming any BM combination. Conclusions Combined BM analysis can accurately predict severe AKI and KRT needs in the perioperative period of LT. U-OSM alone proved to be an effective tool for monitoring the risk of severe AKI, available in most centers. Further studies are needed to assess its impact on AKI progression postoperatively. Registered at Clinical Trials (clinicaltrials.gov) in March 24th, 2014 by title ‘Acute Kidney Injury Biomarkers: Diagnosis and Application in Pre-operative Period of Liver Transplantation (AKIB)’ and identifier NCT02095431.

Association of Angiotensin Converting Enzyme (insertion\deletion) and Angiotensin II Type 1 Receptor (A1166C) gene polymorphisms with diabetic nephropathy in Iraqi type 2 diabetic patients

Renin-angiotensin-aldosterone system abnormalities are the most prevalent cause of renal hemodynamic abnormalities, and candidate genes in this system are involved in the etiology of diabetic nephropathy (DN). A polymorphism in the angiotensin converting enzyme (ACE) gene I(insertion)\D(deletion) has been correlated to plasma ACE levels. Furthermore, the Angiotensin II Type 1 Receptor AGT1R (A1166C) expression pattern is highly related to nephropathy. The objectives of this study involved evaluating the frequency of the ACE (I/D) and AGT1R (A1166C) gene polymorphisms and investigating the association of these polymorphism with the development of DN in Iraqi patients with Type 2 diabetes mellitus (T2DM) and evaluating the levels of several urinary and serum markers in relation to studied polymorphisms. This is a cross-sectional study that included 161 T2DM patients whom were divided into two groups: T2DM with DN(included 98 patients) and normalbuminuric T2DM (included 63 patients). ACE gene polymorphism analysis revealed that the D allele was far more prevalent in DN patients compared to normalbuminuric patients (60.2% vs. 50.8%), while the I allele frequency was 39.8% in DN and 49.2% in normoalbuminuric patients. In addition, DN patients carrying the DD genotype had higher serum kidney injury molecule 1 (KIM1), serum cystatin C (CysC), and HbA1C and lower glomerular filtration rate (GFR) compared to ID+II genotypes. For AGT1R (A1166C), both DN and normalbuminuric patients had a comparable high prevalence of the AA genotype, followed by the AC genotype, while the CC genotype had been seen only in 3 patients. In conclusion, among the studied T2DM patients, individuals with DD genotype had higher frequency of DN and had 2-fold risk for DN compared to II genotype which had the lowest risk for DN. Also the current study shows that the A1166C polymorphisms of AGT1R distribution frequency were similar for both study groups with higher frequency for A allele compared to C allele and not associated with risk of DN in Iraqi T2DM Keywords: Angiotensin Converting Enzyme (I\D) gene polymorphism, Angiotensin II Type 1 Receptor (A166C) gene polymorphisms, Cystatin C, Diabetic nephropathy, Kidney injury molecule1.

Novel Biomarkers for Kidney Disease: New Frontiers in Early Diagnosis and Monitoring

Kidney diseases pose a significant threat to global public health, with early diagnosis and accurate monitoring being crucial for improving patient outcomes. However, traditional kidney disease markers such as serum creatinine and blood urea nitrogen have limitations in sensitivity and specificity. In recent years, rapid advancements in molecular biology and proteomics have led to the discovery of a series of novel biomarkers that are gradually being applied in clinical practice. This review examines novel kidney disease biomarkers, including cystatin C (Cys-C), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). These markers not only reflect kidney injury earlier and more accurately but may also provide important bases for kidney disease classification, severity assessment, and prognosis prediction. Additionally, this paper explores the potential of multi-marker combined detection strategies in improving diagnostic accuracy. Although these novel markers show immense potential, they still face challenges such as standardization and cost-effectiveness before widespread clinical application. Future research should focus on optimizing detection methods, establishing clinical decision thresholds, and evaluating the value of these markers in personalized medicine, thereby paving new paths for precise diagnosis and treatment of kidney diseases.

The Use of Kidney Biomarkers, Nephrin and KIM-1, for the Detection of Early Glomerular and Tubular Damage in Patients with Acromegaly: A Case-Control Pilot Study.

Acromegaly is a rare disorder caused by excessive growth hormone (GH) secreted from a pituitary tumor. High levels of GH and insulin growth factor-1 can lead to renal hypertrophy, as well as to diabetes mellitus and hypertension, which negatively impact kidney function. It is believed that high GH may also be involved in the onset of diabetic nephropathy, the main cause of end-stage kidney disease in developed countries. This case-control study was conducted on 23 acromegalic patients and on a control group represented by 21 healthy subjects. The following parameters were determined for all the subjects: serum creatinine, serum urea, estimated glomerular filtration rate (eGFR), urinary albumin/creatinine ratio (UACR), nephrin and kidney injury molecule 1 (KIM-1). Patients with acromegaly showed higher levels of UACR and lower levels of eGFR as compared to healthy subjects. No significant correlations were found between clinical or biochemical parameters associated with acromegaly and nephrin or KIM-1. There was no glomerular or proximal tubular damage at the time of the study, as proven by the normal levels of the biomarkers nephrin and KIM-1. Studies including more patients with uncontrolled disease are needed to clarify the utility of nephrin and KIM-1 for the detection of early kidney involvement in acromegalic patients.

Hollow mesoporous Prussian blue nanoenzymes as Rapamycin carrier for targeted treatment of ischemia/reperfusion-induced acute kidney injury through pro-mitophagy and oxidative stress alleviation

The kidney’s abundant mitochondrial content and substantial oxygen requirements make it particularly vulnerable to a series of detrimental events following ischemia/reperfusion (I/R). These events encompass oxidative stress, mitochondrial impairment, depletion of adenosine triphosphate (ATP), and inflammation, cumulatively leading to acute kidney injury (AKI). Currently, no approved therapy beyond supportive care is available for AKI. While numerous studies have focused on neutralizing pre-existing reactive oxygen species (ROS) to mitigate AKI, insufficient attention has been paid to addressing the root causes of ROS. Here, we prepared Rapamycin (Rapa)-loaded hollow mesoporous Prussian blue nanoparticles (HMPB-Rapa) and grafted injured renal-targeted hyaluronic acid (HA) onto HMPB-Rapa (HA-HMPB-Rapa), which effectively scavenge pre-existing ROS and the source (massive damaged mitochondria) through the dual function of HMPB carrier and Rapa, thus preventing the further burst of ROS. In the I/R-induced AKI rat model, a single-dose of HA-HMPB-Rapa 6 h after I/R injury effectively inhibited oxidative stress and inflammation, protected renal cells from apoptotic damage, as well as ultimately restored renal function, and attenuated pathological changes. Mechanistically, HA-HMPB-Rapa cleared damaged mitochondria by activating the pro-mitophagy signaling pathway (PINK-1/Parkin-P62-LC3), cutting off the conduction in the intrinsic apoptotic pathway mediated by the Bax-Cyt-c-Cleaved Casp-3 signaling axis, and reduced the expression of renal tubular marker kidney injury molecule-1. HA-HMPB-Rapa represents an exciting new avenue for the treatment of diseases related to I/R-induced injury.

Transcriptional activation of PINK1 by MyoD1 mediates mitochondrial homeostasis to induce renal calcification in pediatric nephrolithiasis

This study aims to uncover the molecular mechanisms underlying pediatric kidney stone formation induced by renal calcium deposition by utilizing high-throughput sequencing data to reveal the regulation of PINK1 by MyoD1. We performed transcriptome sequencing on peripheral blood samples from healthy children and children with kidney stones to obtain differentially expressed genes (DEGs). Genes related to mitochondrial oxidative stress were obtained from the Genecards website and intersected with DEGs to obtain candidate target genes. Additionally, we conducted protein-protein interaction (PPI) analysis using the STRING database to identify core genes involved in pediatric kidney stone disease (KSD) and predicted their transcription factors using the hTFtarget database. We assessed the impact of MyoD1 on the activity of the PINK1 promoter using dual-luciferase reporter assays and investigated the enrichment of MyoD1 on the PINK1 promoter through chromatin immunoprecipitation (ChIP) experiments. To validate our hypothesis, we selected HK-2 cells and established an in vitro kidney stone model induced by calcium oxalate monohydrate (COM). We evaluated the expression levels of various genes, cell viability, volume of adherent crystals in each group, as well as mitochondrial oxidative stress in cells by measuring mitochondrial membrane potential (Δψm), superoxide dismutase (SOD) activity, reactive oxygen species (ROS), and malondialdehyde (MDA) content. Mitochondrial autophagy was assessed using mtDNA fluorescence staining and Western blot analysis of PINK1-related proteins. Apoptosis-related proteins were evaluated using Western blot analysis, and cell apoptosis was measured using flow cytometry. Furthermore, we developed a rat model of KSD and assessed the expression levels of various genes, as well as the pathologic changes in rat renal tissues using H&E and von Kossa staining, transmission electron microscopy (TEM), and the expression of creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) to evaluate the mitochondrial oxidative stress in vivo (through measurement of Δψm, SOD activity, ROS, and MDA content). Mitochondrial autophagy was evaluated by Western blot analysis of PINK1-associated proteins. Apoptosis-related proteins were detected using Western blot analysis, and cellular apoptosis was examined using cell flow cytometry and TUNEL staining. Bioinformatics analysis revealed that the PINK1 gene is upregulated and vital in pediatric kidney stone patients. Our in vitro and in vivo experiments demonstrated that silencing PINK1 could inhibit kidney stone formation by suppressing mitochondrial oxidative stress both in vitro and in vivo. We identified MyoD1 as an upstream transcription factor of PINK1 that contributes to the occurrence of pediatric kidney stones through the activation of PINK1. Our in vivo and in vitro experiments collectively confirmed that silencing MyoD1 could inhibit mitochondrial oxidative stress, mitochondrial autophagy, and cellular apoptosis in a rat model of kidney stones by downregulating PINK1 expression, consequently suppressing the formation of kidney stones. In this study, we discovered that MyoD1 may promote kidney stone formation and development in pediatric patients by transcriptionally activating PINK1 to induce mitochondrial oxidative stress.

Association of biomarkers of endothelial function, coagulation activation and kidney injury with persistent albuminuria in sickle cell anaemia.

Persistent albuminuria (PA) is common in sickle cell anaemia (SCA). With the association of chronic kidney disease (CKD) with increased mortality, biomarkers that predict its development or progression are needed. We evaluated the association of select biomarkers with PA in adults with SCA using Kruskal-Wallis rank-sum test and logistic regression models, with adjustment for multiple testing. Of 280 subjects, 100 (35.7%) had PA. Median plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) (1176.3 vs. 953.4 ng/mL, false discovery rate [FDR] q-value <0.003), thrombin-antithrombin complex (5.5 vs. 4.7 ng/mL, FDR q-value = 0.04), and urinary angiotensinogen (AGT) (12.2 vs. 5.3 ng/mg, FDR q-value <0.003), urinary nephrin (30.6 vs. 27.2 ng/mg, FDR q-value = 0.04), and urinary kidney injury molecule-1 (KIM-1) (0.8 vs. 0.5 ng/mg, FDR q-value <0.003), normalized to urine creatinine, were significantly higher in subjects with PA. In multivariable analysis, only urinary AGT (odds ratio = 1.058, FDR q-value <0.0001) remained a significant predictor of PA. In addition, soluble VCAM-1 (FDR q-value <0.0001), D-dimer (FDR q-value <0.0001), urinary AGT (FDR q-value <0.0001), KIM-1 (FDR q-value <0.0001), and nephrin (FDR q-value <0.0001) were significantly associated with urine albumin-creatinine ratio in multivariable analyses. Longitudinal studies to evaluate the predictive capacity of biomarkers for the development and progression of CKD in SCA are warranted.

Proteomic Correlates and Prognostic Significance of Kidney Injury in Heart Failure With Preserved Ejection Fraction.

Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear. Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death or HF-related hospital admission in models adjusted for the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. We also assessed the relationship between the KI factor score and ~5000 plasma proteins, followed by pathway analysis. We validated our findings among HFpEF participants in the Penn Heart Failure Study. KI was associated with the risk of death or HF-related hospital admission independent of the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. Both the risk score and eGFR were no longer associated with death or HF-related hospital admission after adjusting for the KI factor score. KI was predominantly associated with proteins and biologic pathways related to complement activation, inflammation, fibrosis, and cholesterol homeostasis. KI was associated with 140 proteins, which reproduced across cohorts. Findings regarding biologic associations and the prognostic significance of KI were also reproduced in the validation cohort. KI is associated with adverse outcomes in HFpEF independent of baseline eGFR. Patients with HFpEF and KI exhibit a plasma proteomic signature indicative of complement activation, inflammation, fibrosis, and impaired cholesterol homeostasis.

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

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

Irisin preserves mitochondrial integrity and function in tubular epithelial cells after ischemia-reperfusion-induced acute kidney injury.

A myokine secreted by skeletal muscles during exercise called irisin mitigates ischemia-reperfusion (I/R) injury in epithelial cells of various organs by limiting damage to mitochondria. We test whether irisin may preserve the mitochondrial integrity and function in renal tubular epithelial cells and protect against ischemia-reperfusion-induced acute kidney injury (AKI). We correlated serum irisin levels with serum creatinine and BUN levels from both AKI patients and healthy individuals. In mice with irisin administration, various renal injury markers such as serum creatinine, BUN, kidney injury molecule-1 (Kim-1), and neutrophil gelatinase-associated lipocalin (NGAL), and renal histopathology were assessed after I/R. To identify the potential mechanisms of the protective of irisin's protective effect, we perfused proximal tubules under confocal microscopy and analyzed kidney tissues by qPCR, western blot, and immunohistochemistry. Serum irisin correlated inversely with serum creatinine and BUN levels were significantly lower in AKI patients than in healthy subjects. Administering irisin to mice after I/R decreased biomarker levels for AKI including serum creatinine, BUN, Kim-1, NAGL and lessened histological changes. In kidney tissues of mice, irisin upregulated the mitochondrial autophagy marker protein microtubule-associated protein 1 light chain 3 (LC3), the mitochondrial autophagy pathway-related proteins PTEN-induced putative kinase 1 (PINK1) and Parkinson's disease 2 parkin (PARK2) and downregulated the reactive substrate protein sequestosome 1 (P62) and mitochondrial membrane proteins translocase of outer mitochondrial membrane 20 (TOM20) and translocase of inner mitochondrial membrane 23 (TIM23). Irisin protects against renal I/R injury, which may involve the preservation of mitochondrial integrity and function.

A Comprehensive Review of Advanced Biomarkers for Chronic Kidney Disease in Older Adults: Current Insights and Future Directions.

Chronic kidney disease (CKD) is a growing health concern, particularly in older adults, due to its high prevalence and association with increased morbidity and mortality. Early detection and effective management are crucial to slowing disease progression and reducing complications such as cardiovascular events and end-stage renal disease (ESRD). Traditional biomarkers, including serum creatinine and estimated glomerular filtration rate (eGFR), often have limitations in older populations, where age-related physiological changes can obscure early signs of kidney dysfunction. Advanced biomarkers offer a more precise and comprehensive understanding of kidney health, providing insights into pathological processes such as inflammation, fibrosis, oxidative stress, and tubular injury. These biomarkers have the potential to enhance early diagnosis, predict disease progression, and inform personalized treatment approaches, particularly in the elderly. This review explores the current landscape of advanced biomarkers for CKD in older adults, highlighting their clinical utility and limitations. Key biomarkers, including those related to inflammation (C-reactive protein, interleukin-6), fibrosis (transforming growth factor-beta, collagen degradation products), oxidative stress (F2-isoprostanes, malondialdehyde), and tubular injury (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin), are examined in the context of CKD. Emerging technologies, such as multi-omics and machine learning, are also discussed as they offer new opportunities for biomarker discovery and integration into clinical practice. While challenges remain, including the need for longitudinal studies and better standardization, advanced biomarkers hold promise for transforming CKD management in older adults, paving the way for earlier detection, better risk stratification, and more targeted therapeutic interventions.

A Comprehensive Review of Biomarkers for Chronic Kidney Disease in Older Individuals: Current Perspectives and Future Directions.

Chronic kidney disease (CKD) is a progressive condition characterized by a gradual loss of kidney function, leading to significant health complications and an increased risk of cardiovascular events. Early detection and effective management are crucial for slowing disease progression and improving patient outcomes. Biomarkers are valuable tools in CKD diagnosis, prognosis, and treatment. Traditional biomarkers, such as serum creatinine and urine protein, are widely used, but emerging biomarkers like cystatin C, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) offer enhanced diagnostic precision and insights into disease severity. These advanced biomarkers are particularly important in older adults, who may present with age-related physiological changes and comorbid conditions that complicate CKD management. This review explores the current state of biomarker research in CKD, focusing on their application in older populations. It highlights the role of traditional and emerging biomarkers, discusses their relevance for early detection and prognosis, and examines future directions in biomarker research, including technological innovations and personalized medicine approaches. By integrating biomarkers into clinical practice, healthcare providers can achieve more accurate diagnoses, tailor treatments to individual patient needs, and potentially improve the overall management of CKD. Continued research and development in this field are essential for addressing the complexities of CKD and advancing patient care.

Sex-specific modulation of renal epigenetic and injury markers in aging kidney.

Sex differences in renal physiology and pathophysiology are now well established in rodent models and in humans. Epigenetic programming is known to be a critical component of renal injury, as studied mainly in male rodent models; however, not much is known about the impact of biological sex and age on the kidney epigenome. We sought to determine the influence of biological sex and age on renal epigenetic and injury markers, using male and female mice at 4 mo (4M; young), 12 mo (12M), and 24 mo (24M; aged) of age. Females had a significant increase in kidney and body weights and serum creatinine levels and a decrease in serum albumin levels from 4M to 24M of age, whereas minor changes were observed in male mice. Kidney injury molecule-1 levels in serum and renal tissue greatly enhanced from 12M to 24M in both males and females. Circulating histone 3 (H3; damage-associated molecular pattern molecules) levels extensively increased with age; however, males had higher levels than females. Overall, females had markedly high histone acetyltransferase (HAT) activity than age-matched males. Aged mice had decreased HAT activity and increased histone deacetylase activity than sex-matched 12M mice. Aged females had substantially decreased renal H3 methylation at lysine 9 and 27 and histone methyltransferase (HMT) activity than aged male mice. Antiaging protein Klotho levels were significantly higher in young males than age-matched females and decreased substantially with age in males, whereas epigenetic repressor of Klotho, trimethylated H3K27, and its HMT enzyme, enhancer of zeste homolog 2, increased consistently with age in both sexes. Moreover, nuclear translocation and activity of proinflammatory transcription factor nuclear factor-κB (p65) were significantly higher in aged mice. Taken together, our data suggest that renal aging lies in a range between normal and diseased kidneys but may differ between female and male mice, highlighting sex-related differences in the aging process.NEW & NOTEWORTHY Although there is evidence of sex-specific differences in kidney diseases, most preclinical studies have used male rodent models. The clinical data on renal injury have typically not been stratified by sex. Our findings provide convincing evidence of sex-specific differences in age-regulated epigenetic alterations and renal injury markers. This study highlights the importance of including both sexes for better realization of underlying sex differences in signaling mechanisms of aging-related renal pathophysiology.

The Impact of Empagliflozin on Renal Function and Kidney Injury Markers in Patients with Diabetic Nephropathy

Background: Diabetic nephropathy affects approximately 50% of type 2 diabetes patients. Early detection of kidney disease is crucial to reducing the deterioration of renal function. Reversing microalbuminuria towards normal showed beneficial effects in delaying the onset of renal impairment or even reversing the progression of the disease. Recently, empagliflozin, a sodium/glucose cotransporter-2 inhibitor, has received attention for its anti-inflammatory and reno-cardioprotective effects. Objective: This interventional open-label randomized clinical trial aimed to evaluate the clinical outcome of empagliflozin as an add-on therapy for renal function parameters and other injury markers in type 2 diabetic nephropathy patients. Methods: The study enrolled twenty-one type 2 diabetic patients with nephropathy and nineteen without nephropathy. Each group received empagliflozin 10 mg/day for 16 weeks as an add-on to the traditional treatment. Blood and urine samples were collected at baseline and at week 16 to evaluate the glycemic status, renal function, tubular injury markers, and inflammatory and oxidative stress markers. Results: After 16 weeks, empagliflozin significantly reduced glycated hemoglobin A1c and urinary albumin/creatinine ratios in the nephropathy group. Compared with the non-nephropathy group, empagliflozin showed a significant increase in serum creatinine and a significant decrease in eGFRcr. Empagliflozin significantly reduced serum kidney injury molecule-1, cystatin C, interleukin-18, c-reactive protein, and malondialdehyde in both groups. Conclusions: Adding empagliflozin to the traditional oral antidiabetic drugs in diabetic nephropathy improved albuminuria with a mild increment in serum creatinine. Empagliflozin also effectively reduced renal injury markers, as well as inflammatory and oxidative stress markers.

Serum Procalcitonin ,Cystatin C, Kidney Injury Molecule -1 Levels in Patients with Diabetic Foot Ulcer and Relation with Chronic Kidney Disease

Objective: To evaluate the serum levels of Procalcitonin (PCT), C-Reactive Protein (CRP), Cystatin C, and Kidney Injury Molecule-1 (KIM-1) in patients with diabetic foot ulcers (DFU). Methods: This case-control study included 120 participants divided into four groups: 30 with diabetic foot ulcers (DFU), 30 with diabetic foot ulcers and chronic kidney disease (DFU &amp; CKD), 30 with diabetes mellitus (DM), and 30 healthy controls. The study was conducted from November 2023 to March 2024. Laboratory tests performed on all patients and controls included CBC, blood urea, serum creatinine, and serum CRP levels using a fully automated analyzer. PCT, Cystatin C, and KIM-1 levels were measured using the ELISA method. Results: The biomarkers PCT, CRP, and WBC showed a significant increase in the diabetic foot group and the diabetic foot with chronic kidney disease group. Additionally, there were positive correlations between PCT and CRP and Cystatin C, and between KIM-1 and Cystatin C. ROC analysis of PCT demonstrated high sensitivity and specificity (91.1% and 99%, respectively). Conclusion: Elevated Procalcitonin levels in diabetic foot patients can predict early infection even without clear clinical signs. Increased levels of Cystatin C and KIM-1 serve as good biomarkers for renal function and complications of diabetes, showing a close relationship with diabetic foot conditions.