Marker Of Kidney Injury Research Articles

Reno-protective effect of fenofibrate and febuxostat against vancomycin-induced acute renal injury in rats: Targeting PPARγ/NF-κB/COX-II and AMPK/Nrf2/HO-1 signaling pathways

Background 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. Methods 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. Results 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. Conclusion 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.

Stepwise developmental mimicry generates proximal-biased kidney organoids.

The kidney maintains body fluid homeostasis by reabsorbing essential compounds and excreting waste. Proximal tubule cells, crucial for renal reabsorption of a range of sugars, ions, and amino acids, are highly susceptible to damage, leading to pathologies necessitating dialysis and kidney transplants. While human pluripotent stem cell-derived kidney organoids are used for modeling renal development, disease, and injury, the formation of proximal nephron cells in these 3D structures is incomplete. Here, we describe how to drive the development of proximal tubule precursors in kidney organoids by following a blueprint of in vivo human nephrogenesis. Transient manipulation of the PI3K signaling pathway activates Notch signaling in the early nephron and drives nephrons toward a proximal precursor state. These "proximal-biased" (PB) organoid nephrons proceed to generate proximal nephron precursor cells. Single-cell transcriptional analyses across the organoid nephron differentiation, comparing control and PB types, confirm the requirement of transient Notch signaling for proximal development. Indicative of functional maturity, PB organoids demonstrate dextran and albumin uptake, akin to in vivo proximal tubules. Moreover, PB organoids are highly sensitive to nephrotoxic agents, display an injury response, and drive expression of HAVCR1 / KIM1 , an early proximal-specific marker of kidney injury. Injured PB organoids show evidence of collapsed tubules, DNA damage, and upregulate the injury-response marker SOX9 . The PB organoid model therefore has functional relevance and potential for modeling mechanisms underpinning nephron injury. These advances improve the use of iPSC-derived kidney organoids as tools to understand developmental nephrology, model disease, test novel therapeutics, and for understanding human renal physiology.

Activation of the α7nAChR by GTS-21 mitigates septic tubular cell injury and modulates macrophage infiltration

The most common and serious complication among hospitalized and critically ill patients is sepsis-associated acute kidney damage (S-AKI), which raises the risk of comorbidities and is linked to a high mortality rate. Cholinergic anti-inflammatory pathway (CAP), an anti-inflammatory pathway mediated by the vagus nerve, acetylcholine, and α7 nicotinic acetylcholine receptors (α7nAChRs), offers new perspectives for the treatment of S-AKI. In this study, we investigated the role of CAP and α7nAChR in kidney injury by employing an LPS-induced septic kidney injury mouse model and GTS-21 intervention. C57BL/6 mice were injected with LPS, with or without GTS-21, in different subgroups. Kidney function was assessed by plasma creatinine, histology, and markers of kidney injury 24 h after intervention. The results demonstrated that GTS-21 could inhibit the systemic inflammatory response and directly protect the tubular cell injury from LPS. To explore the novel gene involved in this response, RNA sequencing of the renal proximal tubular epithelial cell (HK-2), pretreated with LPS and GTS-21, was conducted. The results indicate that GTS-21 administration reduces LPS-induced cytokines and chemokines secretion by HK-2, including CCL20, a potent chemokine attracting monocytes/macrophages. Furthermore, a macrophage transmigration assay revealed that GTS-21 inhibits macrophage transmigration by downregulating the expression of CCL20 in HK-2 cells. In conclusion, GTS-21, as an α7nAChR agonist, emerges as a noteworthy and versatile treatment for S-AKI. Its dual function of directly protecting renal tubular cells and regulating inflammatory responses represents a major advancement in the treatment of sepsis-induced AKI. This finding might pave the way for novel approaches to improving patient outcomes and reducing death rates in sepsis-related complications.

Urinary α 1-microglobulin and β 2-microglobulin as markers of early kidney injury in HIV-positive male patients on tenofovir-based antiretroviral therapy.

A retrospective study was conducted to explore the urinary expression of α 1-microglobulin (α1MG) and β2-microglobulin (β2MG) in patients with human immunodeficiency virus (HIV) infection, aiming to evaluate their predictive capability for renal injury. One hundred and five male HIV-infected patients treated with Tenofovir (TDF) regimen (TDF+3TC or the third drug TDF/FTC+) were selected between March 1, 2021, and March 1, 2022, in Wuhan Jinyintan Hospital. Three months after TDF treatment, the renal function injury was evaluated with the standard creatinine clearance rate. The urinary levels of α1MG and β2MG were compared between the initiation of TDF treatment and three months thereafter. Spearman correlation was utilized to analyze the correlation between the urinary expression of α1MG and β2MG and renal injury in HIV patients. The logistic regression was used to analyze the predictive value of urinary α1MG and β 2-microglobulin expression in renal injury. Up to the first follow-up, 29 (27.6%) cases of the 105 male HIV patients had varying degrees of renal function injury, including 14 (13.3%) mild injury, 9 (8.6%) moderate injury, and 6 (5.7%) severe injury cases. Patients with severe renal injury had the highest levels of urinary α1MG and β2MG expression while those with mild injury demonstrated higher levels compared to the non-injury group (P < 0.05). Spearman correlation analysis indicated that urinary α1MG and β2MG were positively correlated with renal impairment in HIV patients (Rho = -0.568, and -0.732; P < 0.001). The ROC curve analysis demonstrated that the area under the curve (AUC) for urine α1MG and β2MG in predicting kidney damage among HIV patients were 0.928, 0.916, and 0.889, respectively. The sensitivity values were 96.55%, 82.76%, and 89.66% while the specificity values were 84.07%, 94.51%, and 89.29% for urine α1MG and β2MG, respectively. The expression level of urinary α1MG and β2MG in HIV patients was significantly higher compared to normal people. Detection of these two indexes can enable early determination of renal injury and its severity in HIV patients.

Hepatic-derived BMP9 is involved in hepatic fibrosis-induced kidney injury through inhibition of renal VEGFA

Clinical observations suggest that acute kidney injury (AKI) occurs in approximately 20–50% of hospitalized cirrhotic patients, suggesting a link between the liver and kidney. Bone morphogenetic protein 9 (BMP9) is a protein produced primarily by the liver and can act on other tissues at circulating systemic levels. Previous studies have demonstrated that controlling abnormally elevated BMP9 in acute liver injury attenuates liver injury; however, reports on whether BMP9 plays a role in liver injury-induced AKI are lacking. By testing we found that liver injury in mice after bile duct ligation (BDL) was accompanied by a significant upregulation of the kidney injury marker kidney injury molecule (KIM-1). Interestingly, all these impairments were alleviated in the kidneys of hepatic BMP9 knockout (BMP9-KO) mice. Peritubular capillary injury is a key process leading to the progression of AKI, and previous studies have demonstrated that vascular endothelial growth factor A (VEGFA) plays a key role in maintaining the renal microvascular system. In animal experiments, we found that high levels of circulating BMP9 had an inhibitory effect on VEGFA expression, while renal tubular epithelial cell injury was effectively attenuated by VEGFA supplementation in the hypoxia-enriched-oxygen (H/R) constructs of the AKI cell model in both humans and mice. Overall, we found that elevated BMP9 in hepatic fibrosis can affect renal homeostasis by regulating VEGFA expression. Therefore, we believe that targeting BMP9 therapy may be a potential means to address the problem of clinical liver fibrosis combined with AKI.

Association of urinary excretion rates of uric acid with biomarkers of kidney injury in patients with advanced chronic kidney disease.

The potential influence of hyperuricemia on the genesis and progression of chronic kidney disease (CKD) remains controversial. In general, the correlation between blood levels of uric acid (UA) and the rate of progression of CKD is considered to be modest, if any, and the results of relevant trials oriented to disclose the effect of urate-lowering therapies on this outcome have been disappointing. Urinary excretion rates of UA could reflect more accurately the potential consequences of urate-related kidney injury. Using a cross-sectional design, we investigated the correlation between different estimators of the rates of urinary excretion of UA (total 24-hour excretion, mean urinary concentration, renal clearance and fractional excretion)(main study variables), on one side, and urinary levels of selected biomarkers of kidney injury and CKD progression (DKK3, KIM1, NGAL, interleukin 1b and MCP)(main outcome variables), in 120 patients with advanced CKD (mean glomerular filtration rate 21.5 mL/minute). We took into consideration essential demographic, clinical and analytic variables with a potential confounding effect on the explored correlations (control variables). Spearman's rho correlation and nonlinear generalized additive regression models (GAM) with p-splines smoothers were used for statistical analysis. Multivariate analysis disclosed independent correlations between urinary UA concentrations, clearances and fractional excretion rates (but not plasma UA or total 24-hour excretion rates of UA), on one side, and the scrutinized markers. These correlations were more consistent for DKK3 and NGAL than for the other biomarkers. Glomerular filtration rate, proteinuria and treatment with statins or RAA axis antagonists were other independent correlates of the main outcome variables. Our results support the hypothesis that urinary excretion rates of UA may represent a more accurate marker of UA-related kidney injury than plasma levels of this metabolite, in patients with advanced stages of CKD. Further, longitudinal studies will be necessary, to disclose the clinical significance of these findings.

The usefulness of urinary netrin-1 determination as an early marker of acute kidney injury in children after cardiac surgery

The usefulness of urinary netrin-1 determination as an early marker of acute kidney injury in children after cardiac surgery

Comparison of the Impact of VRP-034 and Polymyxin B upon Markers of Kidney Injury in Human Proximal Tubule Monolayers In Vitro.

In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal model, aProximateTM. Freshly isolated primary proximal tubule cells (PTCs) were cultured in Transwell plates and treated with various concentrations of the formulations for up to 48 h. The functional expression of megalin-cubilin receptors in PTC monolayers was validated using FITC-conjugated albumin uptake assays. Polymyxin B and VRP-034 were evaluated at six concentrations (0.3, 1, 3, 10, 30, and 60 µM), and nephrotoxicity was assessed through measurements of transepithelial electrical resistance (TEER), intracellular adenosine triphosphate (ATP) levels, lactate dehydrogenase (LDH) release, and novel injury biomarkers [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and clusterin]. Additionally, histological analysis using annexin V apoptosis staining was performed. Our results indicated a significant decrease in TEER with polymyxin B at concentrations ≥10 μM compared to VRP-034. Toxic effects were observed from ATP and LDH release only at concentrations ≥30 μM for both formulations. Furthermore, injury biomarker release was higher with polymyxin B compared to VRP-034, particularly at concentrations ≥10 µM. Histologically, polymyxin B-treated PTCs showed increased apoptosis compared to VRP-034-treated cells. Overall, VRP-034 demonstrated improved tolerance in the aProximateTM model compared to polymyxin B, suggesting its potential as a safer alternative for renal protection.

Effects of glyphosate herbicide ingestion on kidney function in rats on a balanced diet.

Glyphosate is the most widely used herbicide worldwide and in Brazil. There is currently increasing concern about the effects of glyphosate on human health. The Brazilian Institute for Consumer Protection showed data on the presence of glyphosate in some of Brazil's most consumed ultra-processed products. Currently, regulations on the upper limit for these residues in ultra-processed foods have yet to be established by the National Health Surveillance, and ultra-processed food consumption is independently associated with an increased risk of incident chronic kidney disease. Since an unbalanced diet can interfere with kidney function, this study aims to investigate the effect of daily intake of 5 mg/kg bw glyphosate in conjunction with a balanced diet and the possible impact on renal function in rats. Kidney function, kidney weight, markers of renal injury, and oxidative stress were evaluated. There was a decrease in kidney weight. The main histopathological alterations in renal tissues were vacuolation in the initial stage and upregulation of the kidney injury marker KIM-1. Renal injury is associated with increased production of reactive oxygen species in mitochondria. This study showed changes in the kidney of rats exposed to a balanced diet with glyphosate, suggesting a potential risk to human kidney. Presumably, ultra-processed food that contain glyphosate can potentiate this risk. The relevance of these results lies in drawing attention to the need to regulate glyphosate concentration in ultra-processed foods in the future.

#1868 Dapagliflozin reduces urinary kidney injury biomarkers in chronic kidney disease irrespective of albuminuria level

Abstract Background and Aims The beneficial effects of Sodium-Glucose Cotransporter 2(SGLT2) inhibitor in patients with chronic kidney disease (CKD) with low albuminuria levels have not been established. In this study, we aimed to compare the effects of dapagliflozin on kidney injury biomarkers in patients with CKD stratified by albuminuria level. Method We prospectively enrolled healthy volunteers (HVs) (n = 20) and patients with CKD (n = 54) with and without diabetes mellitus (DM). Patients with CKD were divided into two subgroups by age- and sex-matched according to urinary albumin-creatinine ratio (uACR) levels (&amp;lt;300 mg/g and ≥300 mg/g). The CKD group received dapagliflozin 10 mg per day. Urine samples were collected before treatment and after 3 months and 6 months of dapagliflozin. Urinary kidney injury molecule-1 (KIM-1), interleukin-1β (IL-1β), and mitochondrial DNA nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND1) copy number were measured. Results The estimated glomerular filtration rate (eGFR) of patients with CKD was lower than that of HVs (p &amp;lt; 0.001). During the study period, eGFR decreased and uACR did not change in the CKD group. Kidney injury markers were significantly elevated in patients with CKD compared with those in HVs. Dapagliflozin reduced urinary KIM-1, IL-1β and mtDNA copy number in patients with CKD after 6 months of treatment. In further, the levels of urinary KIM-1 and IL-1β, patients with CKD decreased after 6 months of dapagliflozin treatment regardless of albuminuria level. Conclusion In this study, dapagliflozin reduced urinary kidney injury biomarkers in patients with CKD, regardless of albuminuria level. These findings suggest that SGLT2i may also attenuate the progression of low albuminuric CKD.

#554 Baseline neutrophil gelatinase-associated lipocalin (NGAL) levels for early prediction and ruling out future contrast nephropathy

Abstract Background and aims Neutrophil gelatinase-associated lipocalin (NGAL), is an early marker of acute kidney injury (AKI). There is only limited data, however, on the optimal timing for assessment, the cut-off values and its utilization for ruling out AKI We aimed to investigate the diagnostic utility of sequential NGAL measurements for both prediction and ruling out of AKI among patients with ST segment elevation (STEMI) undergoing primary coronary intervention (PCI). Methods We included 133 patients with STEMI treated with PCI. Blood samples for plasma NGAL were drawn immediately before PCI (NGAL 0) and 24 hours after PCI (NGAL 24). Optimal threshold for the development of AKI were determined using receiver operating characteristic curves (ROC). Patients were also assessed for the dynamics between NGAL 0 and NGAL 24 levels. Results Mean age was 62 ± 13 years and 78% were men, and a total of 20 (15%) developed AKI. Patients with AKI demonstrated higher plasma NGAL 0 levels (164 ± 42 vs. 95 ± 30 ng/mL; p &amp;lt; 0.001) as well as NGAL 24 levels (142 ± 41 vs. 93 ± 36 ng/mL; p &amp;lt; 0.001). There were no significant changes between NGAL 0 &amp; 24 hours within the 2 groups (Fig. 1). According to the ROC curve analysis NGAL 0 performed better than NGAL 24 for AKI prediction (Fig. 2). The optimal NGAL 0 level for AKI prediction was &amp;gt;125 ng/mL (AUC 0.841, 95% CI 0.801–0.961, p &amp;lt; 0.001), with a sensitivity of and specificity of 70% and 84% respectively, while the negative predictive value of NGAL 0&amp;lt;125 ng/mL was 94%. Conclusions Among STEMI patients, NGAL levels before primary PCI may be utilized both for ruling out and for the prediction of AKI.

#1524 SKLB023 alleviates kidney inflammation and apoptosis via inhibiting TLR4-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice

Abstract Background and Aims Sepsis is a severe and complex clinical syndrome resulting from the host's inflammatory response to infection. Acute kidney injury (AKI) is one of the major complications of sepsis with high morbidity and mortality, namely sepsis-associated acute kidney injury (S-AKI). Despite current advances, effective drugs for treatment of S-AKI are scarce. SKLB023 is a small molecule compound designed based on 5-benzylidene-thiazolidine-2,4-dione, which has a potent anti-inflammatory effect with favorable efficacy in rheumatoid arthritis. This study aims to evaluate the efficacy of SKLB023 in treating S-AKI and to explore the underlying mechanisms. Method S-AKI was induced by cecal ligation puncture (CLP) and intraperitoneal injection of LPS (10 mg/kg) in male C57BL/6 mice. SKLB023 (25 mg/kg, 50 mg/kg) was administrated by gavage three days in advance and 30 minutes earlier on the day of modeling. Mice death per group was recorded for 100 hours after CLP to evaluate the effect of SKLB023 on the survival rate of S-AKI mice. Other mice were sacrificed 16 hours after model establishment, blood and kidney specimens were collected. Renal function was measured by the detection of serum creatinine (SCr) and blood urea nitrogen (BUN). Kidney pathological injury was evaluated by the expression of kidney injury markers and the assessment of PAS/HE stainings. In vitro experiments were performed with LPS stimulation of TCMK-1 cells and SKLB023 intervention, and the doses were determined by CCK-8 assay. Possible molecular mechanisms involved in SKLB023 against S-AKI were screened by bioinformatics analysis and further validated in vivo and vitro. RT-PCR, western blot, immunofluorescence, and immunohistochemistry were applied to detect renal inflammation and apoptosis. To determine the role of TLR4, TLR4 siRNA and TLR4-KO mice were applied in S-AKI model, and TLR4 expression and the activities of NF-κB p65 and MAPK signaling pathway were assessed. One-way ANOVA was performed for comparison between groups, and logrank analysis was used for comparison of survival curve. P &amp;lt; 0.05 was considered as statistically significant. Results The S-AKI model was successfully established by CLP and LPS injection with obvious renal dysfunction and kidney pathological damage. The mice administrated with SKLB023 had a higher survival rate, lower levels of Scr and BUN, and improved kidney pathological injury than the mice in the CLP group. Transcriptomic analysis identified TLR4-mediated downstream signaling pathways as the potential mechanism of SKLB023 and further experiments in vivo and in vitro proved that SKLB023 regulated the expression of TLR4 and the activities of NF-κB p65 and MAPK signaling pathway in S-AKI mice and LPS-stimulated TCMK-1 cells. Moreover, TLR4 inhibited the expression of inflammatory cytokines including TNF-α, IL-1β, IL-6, iNOS, COX-2, HMGB-1 and alleviated kidney apoptosis in S-AKI mice and LPS-treated TCMK-1 cells. Additionally, knockout of TLR4 remarkably improved inflammation, apotosis, and kidney injury in LPS-treated mice and TCMK-1 cells. Conclusion SKLB023 confers renoprotective effects in S-AKI by modulating inflammation and apoptosis. TLR4 is a key target in S-AKI, and SKLB023 inhibits inflammation and apoptosis by inhibiting the activities of TLR4 mediated NF-κB p65 and MAPK pathways. SKLB023 may be proposed as one of the potential preventive and therapeutic agents for S-AKI.

Beta 2-microglobulin is an independent risk marker of acute kidney injury in adult patients with hemophagocytic lymphohistiocytosis

Background and AimsThe role of beta2-microglobulin (β2-MG) in predicting acute kidney injury (AKI) in hemophagocytic lymphohistiocytosis patients has been poorly studied. This study aimed to analyze the clinical characteristics of hemophagocytic lymphohistiocytosis patients and identify risk factors that predict AKI development.MethodsThis retrospective observational cohort study conducted at a single-center involved 938 patients diagnosed with hemophagocytic lymphohistiocytosis, who were divided into AKI group and non-AKI group. Patient data were collected and analyzed using univariate and multivariate binary logistic regression to identify potiential risk factors associated with AKI occurrence. ResultsAmong the enrolled patients, 486 were male (51.9%), the median age was 37 years (interquartile range, 28.0, 52.0), 58.4% experienced AKI. Mechanical ventilation (8.0% vs. 0.8%) and vasopressor support (21.7% vs. 4.1%) occurred at significantly higher rates in the AKI group compared to the non-AKI group, with significantly higher in-hospital mortality (5.5% vs. 1.3%) and 28-day mortality (12.8% vs. 5.4%). When β2-MG was used as a continuous variable, multifactorial analysis showed that β2-MG, transplantation, and vasopressor support were independently associated with risk for the development of AKI.ConclusionsThe incidence of morbidity and mortality in patients with hemophagocytic lymphohistiocytosis complicated by AKI remains high. Monitoring levels of β2-MG may provide clinicians with timely indicators of changes in renal function, facilitating adjustments to treatment strategies.Graphical abstract

Hematological and renal toxicity in mice after three cycles of high activity [177Lu]Lu-PSMA-617 with or without human α1-microglobulin

Radioligand therapy with [177Lu]Lu-PSMA-617 can be used to prolong life and reduce tumor burden in terminally ill castration resistant prostate cancer patients. Still, accumulation in healthy tissue limits the activity that can be administered. Therefore, fractionated therapy is used to lower toxicity. However, there might be a need to reduce toxicity even further with e.g. radioprotectors. The aim of this study was to (i). establish a preclinical mouse model with fractionated high activity therapy of three consecutive doses of 200 MBq [177Lu]Lu-PSMA-617 in which we aimed to (ii). achieve measurable hematotoxicity and nephrotoxicity and to (iii). analyze the potential protective effect of co-injecting recombinant α1-microglobulin (rA1M), a human antioxidant previously shown to have radioprotective effects. In both groups, three cycles resulted in increased albuminuria for each cycle, with large individual variation. Another marker of kidney injury, serum blood urea nitrogen (BUN), was only significantly increased compared to control animals after the third cycle. The number of white and red blood cells decreased significantly and did not reach the levels of control animals during the experiment. rA1M did reduce absorbed dose to kidney but did not show significant protection here, but future studies are warranted due to the recent clinical studies showing a significant renoprotective effect in patients.

Proteomic Analysis of Idiopathic Nephrotic Syndrome Triggered by Primary Podocytopathies in Adults: Regulatory Mechanisms and Diagnostic Implications.

Idiopathic nephrotic syndrome (NS) is a heterogeneous group of glomerular disorders which includes two major phenotypes: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). MCD and FSGS are classic types of primary podocytopathies. We aimed to explore the molecular mechanisms in NS triggered by primary podocytopathies and evaluate diagnostic value of the selected proteomic signatures by analyzing blood proteome profiling. Totally, we recruited 90 participants in two cohorts. The first cohort was analyzed using label-free quantitative (LFQ) proteomics to discover differential expressed proteins and identify enriched biological process in NS which were further studied in relation to clinical markers of kidney injury. The second cohort was analyzed using parallel reaction monitoring-based quantitative proteomics to verify the data of LFQ proteomics and assess the diagnostic performance of the selected proteins using receiver-operating characteristic curve analysis. Several biological processes (such as immune response, cell adhesion, and response to hypoxia) were found to be associated with kidney injury during MCD and FSGS. Moreover, three proteins (CSF1, APOC3, and LDLR) had over 90% sensitivity and specificity in detecting adult NS triggered by primary podocytopathies. The identified biological processes may play a crucial role in MCD and FSGS pathogenesis. The three blood protein markers are promising for diagnosing adult NS triggered by primary podocytopathies.

Neutrophil gelatinase-associated lipocalin (NGAL) levels for early prediction and ruling out future contrast nephropathy in patients undergoing primary coronary intervention

Abstract Funding Acknowledgements None. Background Neutrophil gelatinase-associated lipocalin (NGAL), is an early marker of acute kidney injury(AKI) . We aimed to investigate the diagnostic utility of sequential NGAL measurements for both prediction and ruling out of contrast induced AKI (CI-AKI) among patients with ST segment elevation (STEMI) undergoing primary coronary intervention (PCI). Methods We included 133 patients with STEMI treated with PCI. Blood samples for plasma NGAL were drawn immediately before PCI (NGAL 0) and 24 hours after PCI (NGAL 24). Optimal threshold for the development of CI-AKI were determined using receiver operating characteristic curves (ROC). Patients were also assessed for the dynamics between NGAL 0 and NGAL 24 levels. Results Mean age was 62 ±13 years and 78% were men, and a total of 20 (15%) developed CI-AKI . Patients with CI-AKI demonstrated higher plasma NGAL 0 levels (164 ± 42 vs. 95 ± 30 ng/mL; p &amp;lt; 0.001) as well as NGAL 24 levels (142 ± 41 vs. 93 ± 36 ng/mL; p &amp;lt; 0.001). There were no significant changes between NGAL 0 &amp; 24 hours within the 2 groups( figure 1). According to the ROC curve analysis (figure 2), the optimal NGAL 0 level for CI-AKI prediction was &amp;gt;125 ng/mL (AUC 0.841, 95% CI 0.801–0.961, p &amp;lt; 0.001), with a sensitivity of and specificity of 70% and 84% respectively, while the negative predictive value of NGAL 0&amp;lt;125 ng/mL was 94%. Conclusions Among STEMI patients, NGAL levels before primary PCI may be utilized both for ruling out and for the prediction of CI-AKI.NGAL 0 vs 24 according to CI-AKINGAL AUC

A Therapeutic Dose of Lithium Triggers Anti-inflammatory Mechanisms in The Kidneys of Treated Mice

Lithium (Li+) is an effective mood stabilizer in people with schizoaffective disorders with more than 2 million prescriptions per year. Accumulation of Li+ in blood can cause neprotoxicity, manifesting in nephrogenic diabetes insipidus, renal tubular acidosis and tubulointerstitial nephropathy. Damage to renal cells often leads to a local immune response, playing a pivotal role in the ensuing renal injury and subsequent recovery. While both pro- and anti-inflammatory actions of Li+ were reported in various tissues, our understanding of the immunomodulatory effects of Li+ in the kidney is fragmentary. Here, we studied how immune mechanisms contribute to the development of Li+-induced adverse effects in the kidneys of C57BL/6 mice receiving a 0.3% lithium carbonate diet for 28 days. Given the insidious development of Li+-induced renal injury, we hypothesize that nephrotoxic effects of Li+ are alleviated by its anti-inflammatory action. We used fluorescence-activated cell sorting, qPCR, immunoblotting and proteome profiler arrays to assess the pyroptotic inflammatory cascade, characterize the infiltrating immune cells and cytokine markers in the renal tissue isolated from Li+-treated and control mice. We found that both biomarkers of tubular damage, kidney injury marker, KIM-1, and neutrophil gelatinase-associated lipocalin, NGAL, are elevated in the renal tissue of Li+-treated mice. This correlated with a moderate but significant increase in renal fibrosis in mice on Li+ diet. Expression of most genes associated with pyroptotic inflammatory cascade, including NLRP3, Casp-1, IL-1b, was not different in the renal tissue isolated from control and Li+-treated mice. Higher mRNA levels of apoptosis-associated speck-like protein (ASC), in the renal tissue of Li+-treated mice could be attributed to its a pro-apoptotic, rather than inflammasome forming, function. This is in line with elevated levels of CD93 marker in the kidneys of mice on Li+ diet, reflecting increased clearance of apoptotic cells. In general, Li+-treated mice had markedly higher levels of anti-inflammatory cytokine markers in the renal tissue, most notably, IL-10 and adiponectin, and lower abundance of pro-inflammatory markers, such as CD26, CLCX16, PCSK9 and osteopontin. Higher abundance of proinflammatory IL-6 in the kidneys of Li+-treated mice made a notable exception. However, this cytokine can also be released by tubular epithelial cells under insult and induce polarization of anti-inflammatory M2 macrophages. Mice on Li+-diet had higher levels of macrophages (F4.80+ cells) in the renal tissue. Future studies will determine their polarization phenotype. Overall, our results suggest that Li+-induced toxic insult to the tubular epithelial cells is paralleled by the anti-inflammatory immune response localized to the renal tissue. NIDDK 1R01DK125464. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acute kidney injury causes subclinical renal and endothelial injury in female rats which predisposes to adverse outcomes of pregnancy

Clinical data report a 3-5-fold increase in adverse pregnancy outcomes, including preeclampsia and small for gestational age neonates, among women with a history of acute kidney injury (AKI) despite clinical recovery of renal function. We developed a rat model of pregnancy post-AKI: Sprague-Dawley (SD) rats undergo a bilateral renal-ischemia reperfusion and fully recover renal function as measured by creatinine clearance 30 days post-AKI. Rats are then mated and during pregnancy recovered AKI rats exhibit decreased creatinine clearance, increased uterine artery resistance, reduced plasma volume expansion, and decreased fetal growth compared to pregnant rats that received sham surgery. Healthy pregnancy demands robust renal and vascular adaptations. Whether subclinical renal and vascular injury persists following AKI in females, and whether this is exacerbated in pregnancy to drive the adverse pregnancy outcomes remains unknown. We tested the hypothesis that AKI results in subclinical renal and vascular injury that lingers into pregnancy. Female SD rats were randomized to 45-minute warm bilateral renal ischemia reperfusion or sham (N=6-8/grp) and renal and vascular injury assessments were made 30 days post-AKI/Sham (pre-pregnancy) or during pregnancy on gestational day 20 (GD20). Pre-pregnancy urine volume measured via metabolic cage was greater in post-AKI rats compared to sham (10±1 vs 21±2 ml/daily urine, p&lt;0.05). Urinary kidney injury marker-1 (KIM-1) measured via ELISA 30 days post-AKI/Sham was greater in pre-pregnant AKI rats compared to sham (9685±871 vs. 6399±198 pg/24 hrs urine, p&lt;0.05). Vascular function, measured via wire myography on 3rd order mesenteric arteries 30 days post-AKI/Sham, revealed decreased endothelial-dependent relaxation to acetylcholine (ACh) (concentration-response, 1 nM-10 μM, 2-way ANOVA, RM, *p&lt;0.05). GD20 urine volume (31±5 vs 19±2 ml/daily urine, p&lt;0.05) and KIM-1 levels (9125±673 vs 6380±297 pg/daily urine, p&lt;0.05) were elevated in post-AKI pregnant rats compared to sham pregnant rats. Mason Trichrome renal staining revealed greater glomerular fibrosis (0.93±0.08 vs 0.04±0.04, *p&lt;0.05) and tubular fibrosis (1.7±0.19 vs 0.0±0.0, *p&lt;0.05) in post-AKI pregnant rats vs. sham pregnant. Ultrastructural changes to the kidneys were evaluated via electron microscopy and further revealed extensive brush border loss, loss of mitochondrial structure and mitochondrial swelling in post-AKI pregnant rats compared to sham pregnant. Endothelial-dependent relaxation to ACh was also lower (2-way ANOVA, *p&lt;0.05), suggesting enhanced endothelial dysfunction in post-AKI pregnant rats vs. sham pregnant. Taken together, these data suggest that with a history of AKI, subclinical renal and vascular injury is present despite “recovery” of renal function using clinical definitions and may predispose to adverse pregnancy outcomes in pregnant women with a history of AKI. 1R01HL169576 4R00HL146948 1RO1DK134695 AHA967662. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Galantamine Reduces Blood Pressure and Renal Injury in Female Angiotensin II-induced Hypertensive Mice

Inflammation is a known culprit in the development and progression of hypertension. The autoimmune disease, systemic lupus erythematosus (SLE), is an important model of hypertension in the setting of chronic kidney inflammation. We have shown that administration of an acetylcholinesterase inhibitor, galantamine, attenuates the hypertension, kidney inflammation, and kidney injury in female SLE mice by activating the vagally-mediated cholinergic anti-inflammatory pathway. Although SLE hypertension represents a specific population of patients, we hypothesized that galantamine would have similar anti-inflammatory effects in the angiotensin II (AngII)-induced hypertensive mouse, which more commonly models essential hypertension. Female C57BL/6 mice were implanted with minipumps at 9 weeks of age for subcutaneous delivery of either AngII (1000 ng/kg/min) or saline (controls), and galantamine hydrobromide (4 mg/kg/day) or vehicle, for 21 days. At 12 weeks, carotid catheters were implanted and mean arterial pressure (MAP) was measured in conscious mice for two consecutive days. Mice were then euthanized, and kidneys collected. Markers of kidney inflammation and injury, including interleukin (IL)-6 and kidney injury molecule (KIM)-1, were measured by ELISA and normalized to total kidney protein. MAP (mmHg) was higher in AngII-treated mice compared to controls (174±4 vs. 133±3; n=4-5, p=0.0023). Galantamine lowered MAP in AngII mice (157±8; n=7, p=0.2567) without altering MAP in controls (133±4; n=5, p=0.9999). Renal IL-6 (pg/μg) was not different between AngII and control mice (0.004±0.0001 vs. 0.005±0.0006; p=0.6685). Although galantamine lowered IL-6 in both groups, it was only significant in controls (0.003±0.0002; p=0.0134) and not AngII mice (0.003±0.0003; p=0.4677). Renal cortical KIM-1 (pg/μg) trended higher in AngII mice compared to controls (2.53±0.50 vs 0.63±0.16; p=0.0741). Galantamine lowered KIM-1 in AngII mice (1.18±0.39, p=0.2064), but not controls (1.45 ± 0.59; p=0.6285). In summary, galantamine protected female mice from hypertension and renal injury in a model of AngII hypertension. This suggests that acetylcholinesterase inhibitor therapy may be effective in patients with hypertension. Studies funded by NIH R01HL153703 and K01HL139859 for KWM. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cystatin c as an early marker of cardiac surgery associated-acute kidney injury in children in Nigeria

Cystatin c as an early marker of cardiac surgery associated-acute kidney injury in children in Nigeria